Anxiety Attack Causes and Treatment

Panic Away End Anxiety and Panic Attacks

Psychologists agree that when a person has anxiety of a certain situation, he may suffer from a panic attack. This person then fears that specific location or event. When he find himself in a similar situation, he fears the onset of an attack and essentially cause himself to have an anxiety attack in the process. The One Move method teaches you how to conquer these fears and end this vicious cycle. The core of the program is the 21 7 Technique, which is made up of the 21 Second Countdown and the 7 Minute Exercise. This is then followed by C.A.L.M. Recovery, which helps to integrate this technique into your life. Panic Away aims to restore you back to your former care free self through eliminating panic attacks and reduce general anxiety fast. The best thing about this eBook is that its simple and detailed course. Moreover, audio series, video presentations, 60-Day money back Guarantee, members forum and the one on one coaching and counseling with Barry made this program very affordable for me. Continue reading...

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Animal Models of Anxiety

2 Tests for 2.1 Behavioral Expression of 2.1.1 Avoidance of Unprotected Areas as Index for Anxiety 39 2.1.2 Exploration The Counterpart of 2.1.3 Risk Assessment A Sensitive Indicator for Anxiolytic Activity 41 A Dissociation Between Panic and Generalized Anxiety 42 2.1.6 Cognition A Primary Feature of Pathological Anxiety 43 2.3 Tests for Conditioned Anxiety 3.1 Genetically Based Animal Models of Abstract Animal models for anxiety-related behavior are based on the assumption that anxiety in animals is comparable to anxiety in humans. Being anxious is an adaptive response to an unfamiliar environment, especially when confronted with danger or threat. However, pathological variants of anxiety can strongly impede the daily life of those affected. To unravel neurobiological mechanisms underlying normal anxiety as well as its pathologi- cal variations, animal models are indispensable tools. What are the characteristics of an ideal animal model First, it should display reduced anxiety when...

Avoidance of Unprotected Areas as Index for Anxiety

Independent of the test set-up, there are species-specific behavioral expressions that are related to anxiety in rodents. For example, it is well known from both field studies and laboratory observations that rodents tend to avoid the unprotected area of a novel environment when first entering it (Barnett 1963 Belzung and LePape 1994 Treit and Fundytus 1989). In an experimental set-up, usually represented by a defined area, rodents will typically start to explore the environment along the walls while avoiding the open, i.e., unprotected, area (Fig. 1). The aversive character of an area can be modulated by illumination levels, with a brightly lit area being more aversive for a rat or mouse, thus producing a more pronounced avoidance behavior than a dark area. Another way to increase a rodent's aversion against an unprotected area can be achieved by elevating it and by enabling the animal to see the edge. In fact, the expression of avoidance behavior depends on the visual capabilities...

Risk Assessment A Sensitive Indicator for Anxiolytic Activity

When confronted with a threatening stimulus, rodents display species-specific behavioral patterns, such as stretched-attend posture and directed sniffing, which are categorized as risk assessment behavior (Blanchard and Blanchard 1989 Cruz et al. 1994 Rodgers et al. 1997). The biological function of these behaviors is to gather information regarding the potential threat by cautiously approaching the threatening stimulus or by scanning the surroundings. Risk assessment behavior is thought to be a defense behavior (Blanchard et al. 1993), thus being indicative of anxiety. It is of note that factor analyses on complex ethological measures found risk assessment behavior to represent a behavioral dimension independent from avoidance behavior Fig. 3 Behavior of high (HAB) andlow(LAB) anxiety rats (see Sect. 2.1.2) after treatment with either vehicle or diazepam (1 mg kg). While avoidance behavior towards an unprotected area remains unaffected, the number of stretched-attend postures is...

Flight Related Behavior A Dissociation Between Panic and Generalized Anxiety

Within the group of anxiety disorders, panic disorder shows an increasing prevalence (Lecrubier and Ustun 1998), thus giving rise to an urgent need for causal treatment strategies. As panic disorder is classified by the DSM-IV system by the presence of symptoms that mostly are impossible to model in animals, such as fear of dying or paresthesias, the assessment of the reliability of tests for panic behavior predominantly is based on pharmacological validation. Specific tests based on conditioned behavior, such as the conditioned suppression of drinking, have been shown to be indicative for antipanic effects of drugs (Commissaris et al. 1990 Ellis et al. 1990 Fontana et al. 1998,1989). Although not revealing the expected effects of panicogenic compounds, the conditioned suppression of drinking is considered to represent a reliable test for panic disorder (Blanchard et al. 2001a). Behavioral assays such as the suppressed drinking test are based on the conflict between approach and...

Anxiety Animal studies

Musty et al. (1985) found CBD increased licking for water in the lick suppression test in a dose related fashion (mg kg). Equivalent effects were found with the classic anxiolytic drug diazepam. In an effort to find more potent effects, they tested two analogs, 2-pinyl-5-dimethylheptyl resorcinol (PR-DMH) and Mono-methyl canna-bidiol (ME-CBD-2). ME-CBD-2 had anxiolytic activity, but was less potent than CBD, while PR-DMH had no anxiolytic properities. Of the two active compounds, both were less potent than diazepam. a measure of anxiety or fear. Both CBD and diazepam decreased the amount of time spent in the enclosed arms. Since these studies were conducted, Petitet et al. (1998) reported CBD is an antagonist of the CBX receptor in the micromolar range suggesting that CBD may have pharmacological effects as an antagonist of the CBj receptor. Since the discovery of the synthetic, highly potent CBX receptor antagonist, SR 141716, by Rinaldi-Carmona, Barth, Heaulme et al., several other...

Tests for Conditioned Anxiety

Another behavioral approach used to assess aspects of anxiety in animals relies on conflict paradigms in combination with punishment, mostly induced by electric foot shock. Due to ethical and also ethological considerations, paradigms based on electric shock are less often used than tests for unconditioned anxiety. However, it has been hypothesized that behavioral expressions displayed in tests for unconditioned and conditioned anxiety may reflect profoundly different aspects of anxiety (File 1995 Griebel 1996 Millan and Brocco 2003). Thus, shock paradigms are quite frequently included in behav ioral phenotyping procedure used to characterize novel animal models for anxiety or anxiety-modulating compounds. The Vogel conflict test (Vogel et al. 1971) has been modified from the Geller-Seifter test (Geller and Seifter 1960) in that the initially used food reward was replaced by a water reward. The test is based on an operant conditioning procedure, where water-deprived animals are given...

Genetic Alterations of the Murine Serotonergic Gene Pathway The Neurodevelopmental Basis of Anxiety

2 Anxiety-Like Behavior in Knockout 3.3.1 Anxiety-Related of intellectual history. Although current views emphasize the joint influence of genes and environmental sources during early brain development, the physiological complexities of multiple gene-gene and gene-environment interactions in the developmental neurobiology of fear and anxiety remain elusive. Variation in genes coding for proteins that control serotonin (5-hydroxytryptamine, 5-HT) system development and plasticity, establish 5-HT neuron identity, and modulate 5-HT receptor-mediated signal transduction as well as cellular pathways have been implicated in the genetics of anxiety and related disorders. This review selects anxiety and avoidance as paradigmatic traits and behaviors, and it focuses on mouse models that have been modified by deletion of genes coding for key players of serotonergic neurotransmission. In particular, pertinent approaches regarding phenotypic changes in mice bearing inactivation mutations of 5-HT...

Anxiety Like Behavior in Knockout Mice

Recent advances in gene targeting (constitutive or conditional KO knockin techniques) are increasingly impacting our understanding of the neurobiolog-ical basis of anxiety- and depression-related behavior in mice (Lesch 2001a). However, the majority of neural substrates and circuitries that regulate emotional processes or cause anxiety disorders remain remarkably elusive. Among the reasons for the lack of progress are several conceptual deficiencies regarding the psychobiology of fear and anxiety, which make it difficult to develop and validate reliable models. The clinical presentation of anxiety disorders and the lack of consensus on clinical phenotypes or categories further complicates the development of mouse models for specific anxiety disorders. In addition, human anxiety disorders encompass not only the behavioral trait of inappropriate fear but also the cognitive response towards this disposition. This response, however, is substantially modulated by environmental factors...

Anxiety Related Behavior

Table 1 Mice with inactivation of serotonergic genes displaying an anxiety-like or related behavioral phenotype anxiety-related AC VIII, adenylyl cyclase type VIII BDNF, brain-derived neurotrophic factor CamKII, calcium-calmodulin kinase II GIRK2, G protein-activated inward rectifying potassium 2 MAOA, monoamine oxidase A n.d., not determined NCAM, neural cell adhesion molecule nNOS, neuronal nitric oxide synthase Petl, ETS domain transcription factor tPA, serine protease tissue-plasminogen activator (tPA). f 4, Increase decrease in anxiety-related behavior. -, No effect. of anxiety-related behaviors (Heisler et al. 1998 Parks et al. 1998 Ramboz et al. 1998). With the exception of an enhanced sensitivity of terminal 5-HT1B receptors, no major neuroadaptational changes were detected. Worthy of note is that this behavioral phenotype was observed in animals in which the mutation was bred into mice of Swiss-Webster (SW), C57BL 6J, and 129 SV backgrounds, substantiating the assumption that...

Syndromes of Anxiety and Their Treatment

Your body and mind contain complex structures to alert you to danger and respond to it effectively. There are many ways for these systems and structures to malfunction. As a result, there are many different syndromes of anxiety, each with its own unique etiology, pathogenesis, and constellation of symptoms. Each syndrome requires a different approach. Biological Causes of Anxiety It is important to rule out any medical causes of anxiety. Thyroid disorders, hypoglycemia, Cushing's disease, and pheochromocy-toma, a rare tumor of the adrenal gland, can cause symptoms similar to anxiety. You should consider a medical exam if your anxiety does not have an obvious cause. Many drugs cause anxiety. Work with your doctor to avoid theophylline preparations used for asthma. Avoid decongestants like pseudoephedrine (Sudafed) and phenylephrine, as they invariably make people more anxious. The recreational drug that worsens anxiety the most is caffeine. Don't forget that caffeine is in sodas and...

Gene Environment Interaction at the Neurodevelopmental Interface of Anxiety

At the core of the gene-versus-environment debate, the relative influences of adverse experiences early in life on susceptibility to behavioral and psychiatric disorder is still a matter of intense debate. Investigations in rats have shown that maternal behavior has long-lasting consequences on fear-related behavior of the offspring. Maternal separation for several hours a day during the early postnatal period results in increased anxiety-like behaviors as well as increased stress responsivity in adult animals (Kalinichev et al. 2002). Similarly, pups that are raised by mothers that display low licking-and-grooming behavior show higher levels of anxiety-like behavior than pups raised by high licking-and-grooming mothers, and cross-fostering studies show that these influences are primarily environmental (Caldji et al. 1998 Liu et al. 2000). Cross-fostering offspring of low licking-and-grooming mothers to high licking-and-grooming mothers is able to impart low anxiety-like behavior to...

Review of Linkage and Association Studies of Anxiety Disorders

There has been a plethora of linkage and association studies attempting to identify genes for anxiety disorders. The neurotransmitter systems that have been implicated in anxiety disorders include adenosine, adrenaline, noradrenaline, dopamine, serotonin, cholecystokinin, and y-aminobutyric acid (GABA). In Of all the anxiety disorders, panic disorder has been given the most attention. Despite a long list of linkage and association studies (Benjamin et al. 1997 Crawford et al. 1995 Crowe et al. 1987a,b, 1990,1997,2001 Deckert et al. 1997, 1998,1999,2000 Fehr et al. 2000a,b, 2001 Gelernter et al. 2001 Gratacos et al. 2001 Hamilton et al. 1999, 2000a,b, 2001, 2002, 2003 Han et al. 1999 Hattori et al. 2001 Inada et al. 2003 Ise et al. 2003 Ishiguro et al. 1997 Kato et al. 1996 Kennedy et al. 1999 Knowles et al. 1998 Matsushita et al. 1997 Mutchler et al. 1990 Nakamura et al. 1999 Ohara et al. 1996, 1998a,b, 1999, 2000 Philibert et al. 2003 Sand et al. 2000 Schmidt et al. 1993 Steinlein et...

High Risk Studies of Anxiety Disorders

Given the early age of onset for anxiety disorders, studies of children of parents with anxiety have become an increasingly important source of information on the premorbid risk factors and early forms of expression of anxiety. Increased rates of anxiety symptoms and disorders among offspring of parents with anxiety disorders have been demonstrated by Turner (1987), Biederman (1991), Sylvester (1988), Last (1991), Warner (1995b), Beidel et al. (1997), Beidel (1988), Capps et al. (1996), Merikangas et al. (1998a), Unnewehr et al. (1998), and Warner et al. (1995a). Table 2 shows that the risk of anxiety disorders among offspring of parents with anxiety disorders compared to those of controls averages 3.5 (range 1.3-13.3), suggesting specificity of parent-child concordance within broad subtypes of anxiety disorders. However, similar to studies of adults that show common familial and genetic risk factors for anxiety and depression (Kendler et al. 1996 Merikangas 1990 Stavrakaki and Vargo...

Future Directions for Research on Anxiety

There are several directions that willbe fruitful for future research. Better comprehension of the phenomenology of the specific anxiety disorders and their overlap among each other and with other forms of psychopathology should guide the development of the next phase of diagnostic categories of anxiety. In addition, as neuroscience and genetics inform our knowledge regarding neural processes underlying anxiety disorders and the role of genetic and environmental factors in their evolution, studies of treatment and prevention strategies will assume increasing importance in reducing the magnitude and burden of this major source of mental disorders. - Establish more accurate and developmentally sensitive methods of assessment of anxiety with a focus on developing objective measures of the components of anxiety - Investigate the specificity of putative markers with respect to other psychiatric disorders and the longitudinal stability of specific subtypes of anxiety disorders - Examine the...

Interactions Between Corticotropin Releasing Hormone and Serotonin Implications for the Aetiology and Treatment of

4.1 Anxiety Tests Involving Unconditioned 4.2 Anxiety Tests Involving Conditioned Abstract The amount of evidence for a role of aberrant serotoninergic neurotransmission in the aetiology of anxiety disorders, such as generalised anxiety and panic disorder, has been increasing steadily during the past several years. Although the picture is far from complete yet partly due to the large number of serotonin (5-HT) receptors and the often-disparate effects of receptor agonists and antagonists in animal models of anxiety SSRIs and the 5-HT1A agonist buspirone have now earned their place in the treatment of anxiety disorders. However, these drugs show as they do in depressed patients a delayed onset of improvement. Therefore, new therapeutical strategies are being explored. Corticotropin-releasing hormone (CRH), which plays a key role in the autonomic, neuroendocrine and behavioural responses to stress, is a strong anxiogenic neuropeptide and a promising candidate for therapeutical...

Anxiety Tests Involving Unconditioned Responses

Many tests employed to assess putative anxiolytic characteristics of new drug compounds or anxiety profiles of mutant animals make use of innate fear and or the perceiving of conflict in rodents. Although, on the one hand, rats and mice want to explore their environment, they are on the other hand afraid of open spaces open field paradigm, elevated plus (or X) maze , of heights (elevated plus maze) and of brightly lit areas (light-dark box). Clearly, these animals will experience fear when encountering a possible predator predator exposure, fear defence test battery (rat), anxiety defence test battery (rat) and mouse defence test battery (see for comprehensive review Blanchard et al. 2003) . Microdialysis studies on serotoninergic neurotransmission during most unconditioned anxiety tests are scarce or absent. However, a picture starts to emerge from studies performing microdialysis during the elevated plus maze test and during exposure to a predator. The group of Charles Marsden was...

Anxiety Tests Involving Conditioned Responses

Anxiety tests involving conditioned (trained) responses are used extensively not only to screen for drugs with anxiolytic properties but also to elucidate the neurobiological mechanisms underlying fear and anxiety. Although the microdialysis technique may be of relevance especially for the latter purpose, until now it has not been widely applied in this field of research. Wilkinson et al. (1996) found that conditioned fear stress causes a rise in the extracellular levels of 5-HT in the hippocampus of rats, which seems to be related to the contextual aversive cues (and not to the conditioned discrete stimulus). Increased levels of 5-HT (Yoshioka et al. 1995 Hashimoto et al. 1999) and an increased turnover of this neurotransmitter (Inoue et al. 1994) were also observed in the rat prefrontal cortex during fear conditioning. Moreover, during the Vogel conflict test (punishment of drinking behaviour by an electric shock) elevated levels of 5-HT were observed in the (dorsal) hippocampus of...

Neural Mechanisms of Anxiety and Fear

Classical fear conditioning is a form of associative learning in which subjects come to express fear responses to neutral conditioned stimuli (CS) that are paired with an aversive unconditioned stimulus (US). The CS, as a consequence of this pairing, acquire the ability to elicit a spectrum of behavioral, autonomic, and endocrine responses that normally would only occur in the context of danger (Blair et al. 2001). Fear conditioning can be adaptive and enable efficient behavior in dangerous situations. The individual who can accurately predict threat can engage in the appropriate behaviors in the face of danger. In the clinical situation, specific environmental features (CS) may be linked to a traumatic event, spontaneous panic attack, or embarrassing social situation (US), such that re-exposure to a similar environment produces a recurrence of symptoms of anxiety and fear. Patients often generalize these cues and experience a continuous perception of threat to the point that they...

Other anxiolytic drugs

Buspirone binds to serotonin and dopamine receptors, opipramol is a dibenzazepine derivative, and kavain is a cavalactone that is present in the roots of Piper methysticum (Cava-Cava). In the USA, cava was also used in health foods in some countries it was removed from the market because of hepatotoxicity. No data are available for the use of any of these drugs during pregnancy (see also Chapter 2.19). Hydroxyzine is an antihistamine with sedative and anxiolytic properties. Several studies covering about 240 pregnancies have been published (e.g. Diav-Citrin 2003, Einarson 1997, Schatz 1997). No increased incidence of malformations has been found, but more data are needed to exclude a possible teratogenic risk. Recommendation. If anxiolytic therapy is required, benzodiazepines are the drugs of choice. Buspirone, kavain, hydroxyzine, meprobamate, and opipramol should be avoided during pregnancy. Inadvertent use is not an indication for a termination of pregnancy or invasive diagnostic...

F41 Other anxiety disorders

F41. 0 Panic disorder episodic paroxysmal anxiety F41. 1 Generalized anxiety disorder F41. 2 Mixed anxiety and depressive disorder F41. 3 Other mixed anxiety disorders F41. 8 Other specified anxiety disorders F41. 9 Anxiety disorder, unspecified F42 Obsessive& shy compulsive disorder .20 Brief depressive reaction .21 Prolonged depressive reaction .22 Mixed anxiety and depressive reaction

Relieving Anxiety and Fear

The patient with newly diagnosed diabetes often has many concerns regarding the diagnosis. For some, initially coping with diabetes and the methods required for controlling the disorder creates many problems. Some of the fears and concerns of these patients may include having to give themselves an injection, having to follow a diet, weight control, the complications associated with diabetes, and changes in eating times and habits. An effective teaching program helps relieve some of this anxiety. The patient in this situation needs time to talk about the disorder, express concerns, and ask questions.

Overview of Anxiety Induced Signal Transduction and Neural Plasticity

Exposure to situations that cause anxiety and or stress results in activation of many neurotransmitter and neuropeptide systems. The actions of these extracellular signaling systems are subsequently mediated by activation of metabotropic (i.e., G protein-coupled receptors of many classes) and ionotropic receptors for amino acid neurotransmitters (i.e., y-amino butyric acid and glutamate). The metabotropic receptors in turn result in activation of intracellular signal transduction cascades, including the cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), inositol triphosphate (IP3) and diacylglycerol pathways. Ionotropic receptors gate ions (e.g., Cl-, Na+, and Ca2+) that influence the charge of neurons but that also lead to regulation of signaling cascades. In most cases the activity of these signaling systems occurs via regulation of protein phosphorylation. This occurs through the addition (via protein kinases) or the removal (via phosphatases) of...

Intracellular Signal Transduction Pathways in the Treatment of Anxiety

The most commonly prescribed treatments for anxiety are benzodiazepines and antidepressants. These therapeutic agents have very different mechanisms of action, time course of effect and side effect profiles. Benzodiazepines enhance the responsiveness of GABA, the major inhibitor neurotransmitter in the brain, by binding to the GABA benzodiazepine (GABA BZ) receptor complex. This results in rapid anxiolytic activity in rodent models and in humans, but can be accompanied by sedation. Antidepressants most often used for anxiety include the serotonin selective reuptake inhibitors (SSRIs), which block the serotonin (5-HT) transporter and increase synaptic levels of this monoamine. However, the therapeutic action of antidepressants for the treatment of anxiety, as well as depression, requires several weeks and sometimes months. This has led to the widely held hypothesis that adaptations, or neural plasticity changes, to the acute elevation of 5-HT are necessary for a therapeutic effect....

Neuropeptides in Anxiety Modulation

2 Anxiety-Related 3 Neuropeptides Involved in the Regulation of Anxiety-Related Behaviour . . . 340 Abstract This review is focused on the involvement of neuropeptides in the modulation of physiological and pathological anxiety. Neuropeptides play a major role as endogenous modulators of complex behaviours, including anxiety-related behaviour and psychopathol-ogy, particularly due to their high number and diversity, the dynamics of release patterns in distinct brain areas and the multiple and variable modes of interneuronal communication they are involved in. Manipulations of central neuropeptidergic systems to reveal their role in anxiety (and often comorbid depression-like behaviour) include a broad spectrum of loss-of-function and gain-of-function approaches. This article concentrates on those neuropeptides for which an involvement as endogenous anxiolytic or anxiogenic modulators is well established by such complementary approaches. Particular attention is paid to...

Anxiety Related Behaviour

Negative emotions such as anxiety are founded on circuits in the brain that evolved to facilitate survival and reproduction in a dangerous and challenging environment. Trait anxiety reflects a genetic predisposition, i.e. hard-wired basal anxiety including reactions to danger. While some animals rely mainly on these reactions, mammals, including rodents and humans, are able to make the transition from reaction to action, including anticipation. Based partic ularly on forebrain expansion and the development of the emotional brain, action comprises both emotional and cognitive factors that have trait (i.e. genetically predisposed) roots. The wide range of anxiety-related behaviour is orchestrated by a system of many genes, each probably with small effects (Glatt and Freimer 2002 Tabor et al. 2002). Accordingly, all signalling circuits in probably all brain areas are involved directly or indirectly in regulatory patterns underlying anxiety. There is no doubt that neuropeptides fulfil the...

Generalized Anxiety Disorder

The essential clinical feature of generalized anxiety disorder (GAD) is long-lasting, excessive and unrealistic anxiety or worry about a number of life circumstances occurring. The worry and tension is causeless and more severe than the degree of anxiety most people experience. The anxiety further is associated with increased cognitive and physiological arousal. Usually, people with GAD expect the worst they worry excessively about money, health, family or work, even when there are no signs of trouble at all. For a diagnosis to be made according to DSM-IV, the person must experience the worries over aperiodof6monthsormore, symptoms must cause marked distress or significant impairment in daily life. At least three of the following six symptoms also need to be persistent restlessness, being easily fatigued, difficulty in concentrating, irritability, muscle tension and sleep disturbance. This diagnosis needs to be distinguished from anxiety arising as part of a mood disorder, or anxiety...

Comorbidity Within the Anxiety Disorders

Although less studied, epidemiological investigation has also shown that there is a considerable degree of overlap within the anxiety disorders. In the NCS, associations (in terms of ORs) within different forms of anxiety disorders were found to range between 3.8 and 12.3 for generalized anxiety disorder, 5.8 and 11.9 for agoraphobia, 4.9 and 8.5 for specific phobia, and 3.8 and 7.8 for social phobia (Wittchen et al. 1994 Magee et al. 1996). The strongest comorbidity was found between panic disorder and agoraphobia, due to the fact that agoraphobia with panic disorder and agoraphobia without panic were not distinguished in the diagnostic criteria of agoraphobia. Interestingly, only about one third of the respondents who meet criteria for DSM-III-R agoraphobia additionally reported panic attacks. This result confirms earlier results found in the ECA and Zurich study (Angst and Dobler-Mikola 1985 Weissman et al. 1986) that panic seems to be involved only in a minority of people with...

Clinical Management of Anxiety

Comorbidity Other anxiety disorder Depression Harmful use of alcohol drugs Comorbidity Other anxiety disorder Depression Harmful use of alcohol drugs diagnosis of a specific anxiety disorder is an invaluable part of the assessment process, as a correct diagnosis has a great influence on the treatment offered. Anxiety disorders frequently present with comorbid conditions, particularly depression, alcohol or substance use problems, and other anxiety disorders. These must be detected and managed appropriately. Patients tend to present when their anxiety impairs their occupational, social or domestic functioning, and identification of the key complaints and motivations for seeking treatment is critical in drawing up an effective management plan. For example, a patient with generalized anxiety disorder (GAD) may present because her resulting insomnia is impairing her ability to work management should include strategies to improve sleep efficiency as well as treatment of the anxiety....

Inducing Anxiety In Humans

One advantage of studying humans is that it is possible to confirm that a given experimental intervention does actually induce anxiety in the subject. A disadvantage is that any research into the neurobiological changes that underlie the subjects' psychological status is limited to the analysis of accessible tissue samples, such as plasma or urine. Such measurements will, at best, be indirect indications of what is happening in the brain. As a result, research of anxiety in humans has concentrated on drugs with a known pharmacological target (usually a neurotransmitter receptor) and has compared their effects in anxious patients and normal subjects. Some treatments that induce or Table 19.3 Substances that induce panic attacks in humans exacerbate anxiety in humans are listed in Table 19.3 and their presumed neuro-biological targets have formed the bases of theories to explain the cause(s) of this disorder. A full appraisal of this topic is beyond the scope of this chapter but the...

Monoamines In Anxiety

The first suggestion that abnormal noradrenergic transmission was linked with anxiety came from Redmond's laboratory in the 1970s when he drew attention to the similarities in the symptoms and signs of anxiety with those of the acute stress response (Redmond and Huang 1979). He went on to stimulate the locus coeruleus of (chair-restrained) monkeys and showed that this caused behavioural changes, some of which resembled a cluster of behaviours displayed by the animals when under threat. This work led to the proposal that anxiety was due to (or exacerbated by) excessive Panic patients Figure 19.8 A schematic representation of the GABAa receptor shift hypothesis. This proposes that patients with panic disorder have dysfunctional GABAa receptors such that the actions of drugs that behave as antagonists in normal subjects are expressed as inverse agonism in panic patients. It is unlikely that this theory extends to generalised anxiety disorder (GAD), for which benzodiazepine agonists are...

Generalised Anxiety Disorder

GAD is a prevalent, chronic, disabling anxiety disorder. It is comorbid with other anxiety or mood disorders in the majority of cases (Ballenger et al. 2001). Whilst it is a relatively new diagnostic concept, longitudinal studies have reinforced its validity (Kessler et al. 1999). The core symptoms are chronic worry and tension, and GAD frequently presents with somatic complaints such as headache, myalgia or insomnia (Lydiard 2000). The diagnosis requires symptoms to be present for at least 6 months, although the duration of illness at presentation is usually much longer than this. The presence of comorbidity leads to a worse prognosis (Yonkers et al. 1996). Cognitive behavioural therapy (CBT) has been shown to be effective in GAD and should be considered if available (Durham et al. 1994). Table 6 DSM-IV classification of anxiety disorders Generalised anxiety disorder Obsessive-compulsive disorder Panic disorder ( agoraphobia) Social anxiety disorder Excessive worry anxiety about...

Social Anxiety Disorder

This disorder is characterised by anxiety symptoms in social or performance situations, accompanied by a fear of embarrassment or humiliation. Situations are avoided or endured with distress. There may be a specific fear of one or two situations (most commonly public speaking), or of three or more situations in the generalized subtype. Epidemiological studies find this to be the most prevalent anxiety disorder among the general population (Magee et al. 1996). Its peak onset is around the time of adolescence, and the resulting impairments can have a profound effect on social and occupational development. If untreated it tends to follow a chronic, unremitting course. Social anxiety disorder is frequently comorbid with depression, other anxiety disorders, alcohol problems and eating disorders. It is associated with an increased rate of suicide that is significantly higher in the presence of comorbidity (Schneier et al. 1992). drug treatment of choice. Treatment is started at standard...

General Issues on the Pharmacogenomics of Anxiety and Anxiolytic Drugs

As mentioned above, not all patients treated with anxiolytic or antidepressant drugs respond favorably to these treatments. There is some evidence from family studies that suggests an important contribution of genetic factors. Already in the early 1960s, studies on the effects TCAs were conducted in families (Angst 1961 Pare et al. 1962). O'Reilly et al. (1994) reported a familial aggregation of response to tranylcypromine, a MAO inhibitor in a family with eight members affected with major depression over two generations. These initial case reports were followed by only a few systematic studies. A study by Franchini et al. (1998) indicated a possible genetic basis of response to the SSRI fluvoxamine in 45 pairs of relatives. In light of these data, some groups have used response to a certain antidepressant drug or mood stabilizer as an additional phenotype in classical linkage analyses for mood disorders in the hope of identifying genetically more homogeneous families (Serretti et al....

Psychological Disorders Anxiety Depression Bipolar Disorder Schizophrenia Alcohol Dependence

Anxiety In a review, Musty (28) concluded that for CB1 antagonists, it seems that the preponderance of the data suggest that these compounds are anxiolytic. Agonists, on the other hand, seem to have biphasic effects low doses seem to be anxiolytic, high doses anxiogenic. In addition, it seems that the context is important. Further research is needed to sort out the differences among various studies, but it is clear that both antagonists and agonists on the CB1 receptor have anxiolytic properties. Standardization of testing procedures across laboratories might be helpful, the problem being that there are many variables that have not been explored with behavioral methods used to test for anxiolytic properties. Because it is widely known that activation and inactiva-tion of CB1 receptors has a multitude of modulatory effects on neurotransmitter systems, it would be advantageous for researchers to examine what changes in neurotransmitter activity occur in conjunction with the...

Conventional CRHR1 Knockout Decreased Anxiety Related Behavior and Alcohol Problems

To investigate the physiological role of CRHR1 in both anxiety-related behavior and HPA system regulation, two mouse lines deficient for CRHR1 have been independently generated (Smith et al. 1998 Timpl et al. 1998). Their phenotype confirms the obligatory role of CRHR1 in both the stress-associated response of the HPA system and anxiety in particular, homozygous CRHR1 mutants display a severe impairment of stress-induced HPA system activation and marked glucocorticoid deficiency. In addition, homozygous mutants exhibit increased exploratory activity and significantly reduced anxiety-related behavior under both basal conditions and following alcohol withdrawal (Timpl et al. 1998). There is a relation between stress, anxiety disorders, and alcohol drinking. Stressful life events and maladaptive responses to stress influence alcohol drinking and relapse behavior (e.g., Kreek and Koob 1998) and there is a substantial comorbidity between anxiety disorders and alcohol abuse (Kessler et al....

CRHR2 Knockout Increased Anxiety Related Behavior

The physiological role of CRHR2 in mediating anxiety-like behavior has been the subject of a controversial discussion. Indeed, the behavioral performance reveals significant differences between the three independently created CRHR2-deficient mouse lines. Whereas Coste et al. (2000) found no differences in anxiety-related behavior, Bale and co-workers (2000) and Kishimoto et al. (2000) detected a significant increase in anxiety-like behavior in their CRHR2 mutants. Interestingly, the latter behavioral phenotype could be observed only in male, but not in female CRHR2-deficient mice.

Behavior of Tac1 and NK1R Knockout Mice in Models of Anxiety

The behavior of tad ' mice was also analyzed in several animal models of anxiety. The open-field test is a widely used tool for behavioral research, but less specific for the evaluation of the anxiety state of the animal, because it is a summation of the spontaneous motor and the exploratory activities, and only the latter is influenced by the anxiety level (Choleris et al. 2001). Under aversive environmental conditions (high level of illumination) the animals' activity is strongly affected by the emotional state, while less aversive situations (familiar, dimly lit environment) are useful to assess the general motor activity of mice. Because rodents avoid open areas, the activity of mice in the central part of the open-field arena is inversely correlated to the anxiety level. Tad + + mice spent only 6.5 of their total activity in the central part, which represented 11 of the total field, indicating that they avoided this aversive area. In contrast, tad ' mice spent 13.6 of their...

Anxiety Related Responses

The converging evidence that 5-HTT deficiency plays a role in anxiety and related disorders lead to the generation of mice with a targeted inactivation of the 5-HTT gene (Slc6a4). Behavior of the 5-HTT KO mice was tested in a variety of conditions evaluating fear, avoidance, conflict, stress responsiveness, status of the neuroendocrine system, and effects of various pharmacological agents on the behavior. In particular, anxiety-related behaviors were characterized using a battery of tests including open field, elevated plus maze, and light-dark box. In these tests both male and female 5-HTT KO mice show consistently increased anxiety-like behavior and inhibited exploratory locomotion. The selective 5-HT1A receptor antagonist WAY 100635 produced an anxiolytic effect in the elevated plus maze in 5-HTT KO mice, suggesting that the abnormalities in anxiety-like and exploratory behavior is mediated by the 5-HT1A receptor (Holmes et al. 2003). Unlike heterozygous 5-HT1A+ - mice, 5-HTTmice,...

Depression with Concomitant Anxiety

The prevalence of depression in patients with anxiety disorders is high, as is the prevalence of anxiety in patients with depression (Tylee et al. 1999 Kessler et al. 1998). Among patients presenting for treatment of anxiety symptoms, a large proportion will have a primary diagnosis of depression. In these situations it is critical to offer a treatment plan that will prove effective against both anxiety and depression (Nutt 2000). The presence of both disorders together causes an increase in disability, increased severity of symptoms, a higher likelihood of suicidal thoughts and a poor response to treatment (Lepine et al. 1997). Antidepressants would be the obvious drug class to select in this patient group, and a number of controlled studies have demonstrated their efficacy. Both SSRIs and TCAs are effective, with the most evidence being for the SSRI paroxetine and the TCAs clomipramine and amitriptyline (Feighner et al. 1993 Ravindran et al. 1997 Stott et al. 1993). Comparative...

The Neurochemical Basis of Fear and Anxiety

Specific neurotransmitters and neuropeptides act on brain areas noted above in the mediation of fear and anxiety responses. These neurochemicals are released during stress, and chronic stress results in long-term alterations in function of these systems. Stress axis neurochemical systems prepare the organism for threat in multiple ways, through increased attention and vigilance, modulation of memory (in order to maximize the utilization of prior experience), planning, and preparation for action. In addition, these systems have peripheral effects, which include increased heart rate and blood pressure (catecholamines) and rapid modulation of the body's use of energy (cortisol). The neurobiological responses to threat and severe stress are clearly adaptive and have survival value, but they also can have maladaptive consequences when they become chronically activated. Examination of the preclinical data concerning neurochemical substrates of the stress response, the long-term impact of...

SP and NK1 Receptor Antagonists in Animal Models of Anxiety

To test the potential involvement of SP in the modulation of anxiety, some studies used a systemic administration of this peptide. The results were, however, inconclusive. Both anxiogenic (Baretta et al. 2001) and anxiolytic (Hasenohrl et al. 2000) effects were reported. In contrast, SP microinjection into separate brain areas provided more conclusive results and showed that the effect of SP is dependent on the site of injection. SP applied into the lateral septal nucleus elicited anxiogenic responses using the elevated plus-maze test (Gavioli et al. 1999), while administration into the nucleus basalis of the ventral pallidum produced anxiolytic effects (Nikolaus et al. 1999). In addition to the regional specificity, the effects of SP were also dose-dependent a low dose of SP elicited an anxiolytic while a higher dose produced an anxiogenic effect when each was injected into the nucleus basalis (Hasenohrl et al. 1998). Although the availability of receptor-selective antagonists...

BuspironeIs Anxioselectivity Possible

The question arises whether anxiolytic activity must always be accompanied by concomitant skeletal muscle relaxant and anticonvulsant activity as well as strong sedation. Can an anxioselective drug exist that will not interact significantly and additively with CNS depressant compounds, particularly alcohol More significantly, both from a medical and sociologic viewpoint, will it be possible to treat anxiety and stress without the added complication of potent sedative effects, dependency, and abuse Evaluation of a series of cyclic imides as potential psychotropic agents yielded three candidates with tranquilizing action and very low sedative effects. The compound chosen for detailed pharmacologic evaluation, MJ9022-1, buspirone (BS), was marketed in 1986 as the first member of a new class of azaspirodecanediones. Early screening led to the erroneous belief that the compound might have antipsychotic properties. However, when further testing revealed that the compound had a taming effect...

Effects on Anxiety and Insomnia

Cannabis smoking produces a relaxant effect which most users value and it has been suggested that the beneficial effects of cannabis and THC observed in neurological disorders such as motor tics, dystonias and Huntingdon's chorea are due to sedative and anxiolytic actions. In addition, sedation is by far the most common side effect of cannabis, and in particular THC, observed in clinical trials against a range of disorders. This has lead to the suggestion that cannabis and some cannabinoids may be useful in disorders accompanied by anxiety and or insomnia. Sethi et al. (1986) noted a reduction of anxiety in 50 chronic cannabis users compared to controls, in terms of scores on the Taylor Manifest Anxiety Scale. Oral preparations of cannabis have a sedative or tranquillising effect in man, accompanied by diminished anxiety at doses much lower than those producing psychoactivity (Graham and Li, 1976). However, anxiety and panic, possibly due to depersonalisation, intoxication and loss of...

Anxiolytics Tranquilizers

Many illnesses are accompanied by anxiety, a worried state during which a syndrome characterized by feelings of helplessness, despair, dark premonitions, and asthenia begins to develop. It can be accompanied by headaches, increased perspiration, nausea, tachycardia, dry mouth, etc. A state of anxiety can originate from neurological reasons, and can also be of a somatopsychic nature, which is associated with pathological development in diseases of the cardiovascular system, neoplasms, hypertonia, and diseases of the gastrointestinal tract. Drugs used for relieving anxiety, stress, worry, and fear that do not detract attention from or affect psychomotor activity of the patient are called anxiolytics or tranquilizers. Most of them have sedative and hypnotic action, and in high doses their effects are in many ways similar to barbiturate action. However, the primary advantage of this group over barbiturates lies in their significantly increased value in terms of the ratio of sedative...

Panic Disorder and Agoraphobia

Panic disorder is also a common, chronic and disabling disorder with its peak incidence in young adulthood (Ballenger et al. 1998a). A panic attack is defined as the sudden onset of anxiety symptoms, rising to a peak within 10 min. DSM-IV requires 4 of 13 defined symptoms to be present. The symptoms are physical symptoms corresponding to those caused by autonomic arousal and psychological symptoms (fear and depersonalisation derealisation, an altered perception of oneself or the world around). Panic disorder occurs when there are recurrent panic attacks, some of which are uncued or unexpected, and there is fear of having further attacks. Agoraphobia is present in around half of cases (Wittchen et al. 1998) and is a poor prognostic indicator. For some patients the anticipatory anxiety or agoraphobia may be considerably more disabling than the panic attacks themselves. Panic disorder is comorbid with episodes of depression at some stage in the majority of cases (Stein et al. 1990), with...

Cognition A Primary Feature of Pathological Anxiety

In recent years a fundamental relation between anxiety and cognitive processes has been demonstrated (Belzung and Beuzen 1995 McNaughton 1997). It has been argued that cognitive alterations may be the primary presenting feature of pathological anxiety (Hindmarch 1998). Gray (1990) already suggested that anxiety emerges when there is a mismatch between the information perceived by an individual and the information already stored. McNaughton (1997) hypothesized that generalized anxiety disorder could be the consequence of a purely cognitive dysfunction that results in inappropriate emotional responses. On the other hand, there is extensive evidence that emotional arousal modulates both affective memory and declarative memory (i.e., factual knowledge) for emotional events (Cahill and McGaugh 1998 McGaugh et al. 1996). Still, little is known about the interaction between emotionality and non-emotional cognitive processes. Using animals to characterize the interaction of emotion and...

Introduction Of Anxiolytics Drugs

These are exciting times for physicians involved in the treatment of anxiety disorders. Therapeutic options are increasing whilst the level of public interest in the field has never been greater. Patients can equip themselves to be active partners in the therapeutic process using the various available sources ofmed-ical information. Longstanding controversies, such as the relative merits of psychological therapies versus medication and the safety of long-term medical treatments of anxiety, are debated in the national media. Perversely, at a time when psychiatrists have more to offer their anxious patients than ever before, the validity of their role is challenged from some quarters. Nevertheless, medical practice is now based on a substantial volume of clinical experience and evidence from controlled trials, and we can justify with confidence many of the treatment options we put before our patients. Since the publication of the work of Donald Klein (1964) that described the...

Cannabinoids and anxiety

Cannabis for the relief of anxiety was about 1500 bce in India. In modern times the 1860 Report of the Ohio State Medical Committee on Cannabis indica 1 stated Anxiolytic effects of CB1 receptor antagonists Musty 2 found that cannabidiol (CBD) inhibited the development of stress-induced ulcers in rats as compared with diazepam, which produced an equivalent reduction in the number of stress-induced ulcers. Guimaraes et al. 3 tested rats in the elevated-plus maze. In the test, rats are placed in a plus-shaped maze which is elevated above the floor. Two of the maze arms are enclosed with walls and two are not. Time spent in the enclosed arms is taken as a measure of anxiety or fear. Both CBD and diazepam decreased the amount of time spent in the enclosed arms. Since these studies were conducted, Petitet et al. 4 and Thomas et al. 5 have reported CBD is an antagonist of the CB1 receptor in the micromolar range, suggesting that CBD may have pharmacological effects an antagonist of the CB1...

Intracellular Signaling Pathways Involved in Anxiety

The cAMP PKA pathway is the most studied signaling system with respect to long-term functional changes induced by drugs of a variety of classes and is also implicated in functional alterations induced by some anxiolytic drugs. cAMP-dependent pathways may also regulate experience-dependent plasticity mechanisms that promote anxiety. An example in support of this comes from knockout mice that are deficient in the AC8 isoform of adenylyl cyclase. AC8 is a calcium-stimulated AC that is normally present in brain areas involved in neuroendocrine andbehavioral responses to stress such as thalamus, habenula, and paraventricular nucleus (PVN). AC8 knockout mice do not show the typical stress-induced increase in anxiety and do not have the stress-induced increases in phosphorylation of CREB seen in wild-type mice after restraint stress, suggesting that AC8 is required for these stress responses (Schaefer et al. 2000). Hippocampal LTD is also reduced in these mice. AC8 activation and consequent...

Exploration The Counterpart of Anxiety

Being confronted with novelty, behavior in rodents is determined by the conflict between the drive to explore the unknown area object and the motivation to avoid potential danger. Exploration behavior summarizes a broad spectrum of behavioral patterns such as risk assessment behaviors, walking, rearing, climbing, sniffing, and manipulating objects (Barnett 1963 Kelley 1993 Sheldon 1968). It is suggested that exploration is gradually inhibited by anxiety, and, Fig. 2 Different exploration strategies in mice. While C57BL 6 mice explore a novel environment along the walls (thigmotaxis), BALB c mice build a home base by first exploring the area close to the starting point. Referring to the standard measure for anxiety, i.e., the time spent in the unprotected area, BALB c mice seem to be less anxious than C57BL 6. Moreover, treatment with diazepam decreases the time spent in the unprotected area in both mouse strains, suggesting an anxiogenic effect. However, looking at the exploration...

Conditional GR Knockouts Reduced Versus Unchanged Anxiety Related Behavior

Further, disruption of the GR in the nervous system results in reduced anxiety-like behavior. In two tests based on the natural avoidance behavior of mice (dark-light-emergency task and elevated zero-maze see also chapter Ohl, this volume), significantly reduced anxiety-like behavior was recorded while the general locomotor activity of mutant and control mice was similar (Tronche et al. 1999). Ligand-activated GRs control transcription either by binding as homod-imers or heterodimers (together with a MR molecule) to positive or negative GC response elements (pGREs or nGREs) in the promoter region of GC-regulated target genes. Alternatively, the GR can act as a monomer by interacting with a transcription factor through protein-protein interactions. By introducing a point mutation in one of the dimerization domains of the GR, formation of GR-GR dimers is no longer possible, allowing dissection of GR effects that require DNA binding from effects upon gene activity through GR interaction...

Anxiety

Anxiety is a vague uneasiness or apprehension that manifests itself in varying degrees from expressions of concern regarding drug regimen to total lack of compliance with the drug regimen. When anxiety is high, the ability to focus on details is reduced. If the patient or caregiver is given information concerning the medication regimen during a high anxiety state, the patient may not remember the information. This could lead to noncompliance. The anxiety experienced during drug administration depends on the severity of the illness, the occurrence of adverse reactions, and the knowledge level of the patient. Anxiety is decreased with understanding of the therapeutic regimen. To decrease anxiety before discussing the treatment regimen with the patient, the nurse takes time to talk with and actively listen to the patient. This helps to build a caring relationship and decrease patient anxiety. It is critical for the nurse to allow time for a thorough explanation and to answer all...

Tests for Anxiety

Various test paradigms have been developed to assess behavioral parameters indicating anxiety in rodents. In the following, some well-established and available tests for anxiety will be described. These tests and also other test paradigms of unconditioned and conditioned anxiety, not explicitly mentioned here, are valuable tools in determining the implication of genetic factors in the whole complexity of behavior, and specifically in identifying the profile of anxiety-related behavior in rodents. Moreover, they are known to be extremely useful in behaviorally phenotyping drugs that potentially affect distinct aspects of anxiety. However, it should be taken into account that behavioral expressions represent a combination of behavioral dimensions influenced by genetic as well as environmental factors. The results of behavioral tests might be strongly influenced by testing conditions and the test procedure used. Therefore, it is essential to carefully define these factors when testing...

Antianxiety Drugs

Antianxiety drugs anxiety anxiolytics benzodiazepine withdrawal Discuss the uses, general drug actions, general adverse reactions, contraindications, precautions, and interactions associated with the administration of the antianxiety drugs. Discuss important preadministration and ongoing assessment activities the nurse should perform on the patient taking antianxiety drugs. List some nursing diagnoses particular to a patient taking antianxiety drugs. Discuss ways to promote an optimal response to therapy, how to mange common adverse reactions, and important points to keep in mind when educating patients about the use of antianxiety drugs. Antianxiety drugs (tranquilizers) The antianxiety drugs are discussed in this chapter. Antidepressant drugs and antipsychotic drugs are discussed in Chapters 31 and 32, respectively. Anxiety is a feeling of apprehension, worry, or uneasiness that may or may not be based on reality. Anxiety may be seen in many types of situations, ranging from the...

Stress And Anxiety

In addition to the euphoriant effects of marijuana smoking, dysphoric effects including anxiety and panic reactions are also commonly observed phenomena induced by cannabis consumption (Ashton,1999). In animal studies, A9-THC (Oinaivi et al., 1990, 1995), HU-210 (a very potent synthetic cannabinoid, Giuliani et al., 2000a) and anandamide (Chakrabarti et al., 1998) induced anxiety in the plus maze (fewer entries onto the open, anxiety-provoking arms). Moreover, both A9-THC and anandamide had an activational effect on the neuroendocrine (hypothalamus-pituitary-adrenal, HPA) axis, which plays a central role in the stress response (Weidenfield et al., 1994). Thus in that study, depletion of corticotropin-releasing factor (CRF), together with increased serum ACTH and corticosterone were observed. Further support for a direct hypothalamic effect of cannabinoids on the activation of the pituitary-adrenal axis comes from an interesting study by Rodriguez de Fonseca and colleagues (1996)....

Panic Disorder

Of the anxiety subtypes, panic disorder has been shown to have the strongest degree of familial aggregation. A recent review of family studies of panic disorder by Gorwood et al. (1999) cited 13 studies that included 3,700 relatives of 780 probands with panic disorder compared to 3,400 relatives of 720 controls. The lifetime prevalence of panic was 10.7 among relatives of panic disorder probands compared to 1.4 among relatives of controls, yielding a sevenfold relative risk. In addition, early onset panic disorder, panic associated with childhood separation anxiety, and panic associated with respiratory symptoms have each been shown to have a higher familial loading than other varieties of panic disorder (Goldstein et al. 1997). Although there has been some inconsistency reported by twin studies of panic disorder (see McGuffin et al. 1994), two studies applying DSM-III-R diagnostic criteria demonstrated considerably higher rates in monozygotic twins compared to dizygotic twins...

Anxiety Disorders

Anxiety disorders have a high prevalence and are the most common cause of medical intervention in primary care (Weiller et al. 1998). The pharmacology of the GABA system supports the view that GABAergic dysfunctions are causally related to symptoms of anxiety. For instance, pentylenetetrazole acts by blocking GABAA receptor function and produces extreme anxiety, traumatic memories and extreme avoidance behaviour when used clinically (Kalueff and Nutt 1997). Conversely, enhancing GABAergic transmission, e.g. by benzodiazepines, is a powerful mechanism to inhibit the experience of anxiety and its aversive reinforcement. Neuroimaging has given fresh insight into the role of GABAergic inhibition in anxiety disorders. In a recent positron emission tomography (PET) study using 11C-flumazenil, a significant global reduction in flumazenil binding to GABAA receptors was apparent throughout the brain in patients with panic disorder (Malizia et al. 1998). The greatest decrease observed occurred...

Anxiolytics

L-838,417 This benzodiazepine site ligand displays a dramatic subtype selective efficacy. L-838,417 failed to modulate the GABA response at a1 receptors but enhanced the GABA response at a2, a3 and a5 receptors (McKernan et al. 2000). L-838,417 showed a high potency in anxiolytic tests (elevated plus maze and fear-potentiated startle) and in anticonvulsant tests pentylenetetrazole (PTZ), audiogenic seizures . However, L-838,417 failed to impair the motor performance (rotarod test, chain pulling test) (McKernan et al. 2000). Thus, ligands with subtype-selective efficacy as factor that distinguishes a2, a3 and a5 receptors from a1 receptors, provide a new way to develop selective anxiolytics without sedative component. A further improvement of anxiolytic efficacy may be achieved by focusing the ligand affinity or efficacy more specifically on a2 receptors. SL65.1498 The pyrido-indole-4-carboxamide derivative SL65.1498 shows higher affinity for a1, a2 and a3 GABAA receptors compared to...

Buspirone

The interaction of itraconazole with the active 1-(2-pyri-midinyl)-piperazine metabolite of buspirone has been studied after a single oral dose of buspirone 10 mg (66). Itraconazole reduced the mean AUC of the metabolite by 50 and the Cmax by 57 , whereas the mean AUC and Cmax of the parent drug were increased 14.5-fold and 10.5fold respectively. Thus, itraconazole caused relatively minor changes in the plasma concentrations of the active piperazine metabolite of buspirone, although it had major effects on the concentrations of buspirone after a single oral dose.

Panic Attack

Panic attacks are brief, recurrent, unexpected and discrete periods of feelings of intense fear or discomfort. For a diagnosis according to DSM-IV, at least four of the following typical panic symptoms must be present pounding heart or accelerated heart rate, sweating, trembling or shaking, sensations of shortness of breath or smothering, feeling of choking, chest pain or discomfort, nausea or abdominal stress, feeling dizzy, light-headed or faint, unsteady, de-realization (feelings of unreality) or depersonalization, fear of losing control or going crazy, fear of dying, paresthesias, and chills or hot flushes. Spontaneous panic attacks occur out of the blue without any obvious environmental or situational triggers. The DSM-IV also identifies (1) situationally bound (cued) panic attacks, in which the panic attack almost invariably occurs immediately on exposure to the situational trigger, and (2) situationally predisposed panic attacks, which are more likely to occur on exposure to...

Anxiolytic Drugs

The use of substances for their anxiolytic properties dates to the beginning of recorded human history. The twentieth century saw a substantial development of their use for medical purposes, and major progress was made in the 1990s, the decade of anxiety, as advances in neuroscience provided a basis for the targeted design of new treatments. There is now a greater range of drugs available that are better tolerated, although not necessarily more effective, than their predecessors. However, despite increased knowledge of the

Managing Anxiety

The patient in preterm labor may have many concerns about her pregnancy, as well as the effectiveness of drug therapy. The woman is encouraged to verbalize any fears or concerns. The nurse listens to the patient's concerns and carefully and accurately answers any questions she may have concerning drug therapy. In addition, the nurse offers emotional support and encouragement during the time the drug is being administered. If allowed by the institution, the presence of family members may decrease anxiety in the woman experiencing preterm labor.

Food Intake Inhibition

Food intake is considered a reliable indicator for the anxiolytic properties of drugs. Rodents usually are reluctant to eat unknown food (Boissier et al. 1976 Soubrie et al. 1975). When both familiar and unknown food are presented, rodents will typically show a longer latency to the first intake of unknown food compared to the intake of familiar food. Anxiolytic drugs not only reverse this food intake inhibition (Fletcher and Davies 1990 Hodges et al. 1981) but also result in an increased consumption of food (Britton and Britton 1981).

Selectively Bred Rat Lines

Animal models based on genetic selection are intended to model the genetically based susceptibility known to be one risk factor for the development of anxiety disorders. Animal models of high innate anxiety, gained by selective breeding, are valuable tools since these animals do not exhibit pathological anxiety due to stress exposure (see also Sect. 3.2) instead, the anxiety is the result of an enduring feature of a strain or an individual, probably involving multiple genetic and environmental factors. Studies on selective breeding of rats began already some 80 years ago, when Edward C. Tolman selected rats for their learning capacities (1924). Several years later, Calvin Hall initiated the first rat

Roman High and Low Avoidance Rats

To have a genetic basis (Castanon et al. 1994, 1995), determining a specific sensitivity to environmental factors (Steimer et al. 1998). Notably, differences in a variety of additional behavioral and cognitive processes are described for the two rat lines, such as reduced locomotor activity and exploration (Corda et al. 1997 Giorgo et al. 1997), as well as better spatial learning and memory performance (Escorihuela et al. 1995) in highly emotional RLA rats. Thus, although representing an interesting animal model for a complex behavioral trait, including altered emotional reactivity, the face value of RLA rats as a model for anxiety or mood disorders is difficult to assess.

The Flinders Sensitive Rats

At Flinders University in Australia, two other lines of rats were developed in the late 1970s (Overstreet et al. 1979) by selective breeding for differences in the hypothermic response to the cholinesterase inhibitor diisopropylfluo-rophosphate. This approach aimed at reversing the order of questions asked by typical selective breeding programs it chose a physiological response to specific pharmacological agents as the selection criterion. Only afterwards did behavioral alterations enter the evaluation in order to identify possible anxiety-related or depressive-like characteristics. From a number of various findings it was concluded that the Flinders sensitive line, being hypersensitive to cholinergic agonists, may rather represent an animal model of depression more than anxiety disorder, because these rats exhibit several symptom patterns of depression, such as reduced locomotor activity, reduced body weight, increased rapid eye movement (REM) sleep, and cognitive (learning) deficits...

ENUMutagenized Mice The Phenotype Driven Approach

For example, ENU-mice have been found that performed an increased or decreased anxiety-related behavior (Fig. 8), while being inconspicuous regarding other behavioral patterns. A well-known example of this technique was given by the identification of the Clock gene based on studies performed in the mid-1990s (Vitaterna et al. 1994 Antoch et al. 1997). These findings gained fundamental insights into the molecular mechanisms underlying mammalian circadian rhythms, thus emphasizing the power of the phenotype-driven approach.

Experience Related Models of Altered Emotionality

There exists a broad spectrum of anxiety disorders. These disorders are known to have a high comorbidity between each other. In addition, mood disorders (especially) are often accompanied by symptoms of altered anxiety (Holsboer 1999 Nesse 1999 Ramos and Mormede 1998 Reul and Holsboer 2002). Anxiety disorders and depression have been classified as separate types of disorders for decades. This view is under discussion now (Nemeroff 2002), because the efficacy of major psychotropic drugs is known for the treatment of both anxiety and mood disorders. Moreover, anxiety and depression share at some points a common pathophysiology (Holsboer 1995) and there is increasing evidence that both disorders share a common genetic background (Kendler 2002). Therefore, animal models conceptualized to elucidate mechanisms underlying depression often show altered anxiety-related behavior (Henn et al. 1993 M ller and Keck 2002), thus making them of high use to assist us in gaining new insights into the...

Functional Neuroanatomy of Emotionality Focus on the Serotonin System

Phenomena of fear and anxiety (Gorman et al. 2000). Fear and anxiety-related circuits involve pathways transmitting information to and from the amygdala to various neural networks that control the expression of avoidant, defensive, or aggressive reactions, including behavioral, autonomic, and stress hormone responses. While pathways from the thalamus and cortex (sensory and prefrontal) project to the amygdala, inputs are processed within intra-amygdaloid circuitries and outputs are directed to the hippocampus, brain stem, hypothalamus, and other regions. Perception of danger or threat are transmitted to the lateral nucleus of the amygdala, which projects to the basal nuclei where information regarding the social context derived from orbitofrontal projections is integrated with the perceptual information. Behavioral responses can then be initiated via activation of projections from the basal nuclei to various association cortices, while physiological responses can be produced via...

Serotonin Receptor 1A

The 5-HT1A receptor subtype has long been implicated in the pathophysiology of anxiety and depression its role as a molecular target of anxiolytic and antidepressant drugs is well established (Griebel 1995 Griebel et al. 2000 Olivier et al. 1999). Patients with panic disorder and depression display an attenuation of5-HT1A receptor-mediated hypothermic and neuroendocrine responses, reflecting a reduced responsivity ofboth pre- and postsynaptic 5-HT1A receptors (Lesch et al. 1990b Lesch et al. 1992). Likewise, a decrease in 5-HT1A ligand binding has been shown in postmortem brain of depressed suicide victims (Cheetham et al. 1990) as well as in forebrain areas such as the medial temporal lobe and in the raphe of depressed patients elicited by positron emission tomography (PET) (Drevets et al. 1999 Sargent et al. 2000). Both glucocorticoid administration and chronic stress, a pathogenetic factor in affective disorders, have also been demonstrated to result in downregulation of 5-HT1A...

Serotonin Receptor 1B

These results further support the notion that distinct receptor subtypes modulate different dimensions of behavior that may be either synergistic or antagonistic. Opposite to 5-HT1A receptor-deficient mice, 5-HT1B KOs are more reactive and more aggressive but show dramatically less anxiety-related behavior than control mice, although both 5-HT1A and 5-HT1B receptors control the tone of the serotonergic system and mediate some of the postsynaptic 5-HT effects (Zhuang et al. 1999). The regional variation of 5-HT receptor expression and the complex autoregulatory processes of 5-HT function that are operational in different brain areas may lead to a plausible hypothesis to explain an inconsistency that is more apparent than real. Assessment of 5-HT1A receptor expression in male mice selected for high and low offensive aggression showed that high-aggressive mice are characterized by a short attack latency, decreased plasma corticosterone concentration, and increased levels of 5-HT1A mRNA...

Other Serotonin Receptors

Prior to the generation of 5-HT2C receptor-deficient mice, studies with nonse-lective agonists had suggested potential roles for this receptor in the serotoner-gic regulation of feeding and anxiety. Consistent with the pharmacological evidence, 5-HT2C mutant mice display hyperphagia-evoked weight gain but also infrequent and sporadic spontaneous seizures, suggesting a globally enhanced neuronal network excitability. Behavioral analysis of 5-HT2C KO mice revealed abnormal performance in a spatial learning task and altered exploratory behavior associated with altered long-term potentiation restricted to the dentate gyrus perforant path synapse (Heisler and Tecott 1999). However, abnormalities of hippocampal function-dependent cognitive function were subtle and did not generalize to contextual fear conditioning. Studies in mice with a targeted inactivation of other 5-HT receptor subtypes, such as the 5-HT5A and 5-HT7, or a transgenic line that overexpresses 5-HT3, demonstrate that these...

Tryptophan Hydroxylases

In the face of preferential expression of TPH2 in the brain, the identification of a gene encoding a neuron-specific TPH isoform, and unaltered anxiety-like behavior in TPH1KO mice, this conclusion calls for reconsideration. Among the questions that need to be answered are whether TPH1 expression is restricted to the early stages of brain development and whether peripheral 5-HT impacts on the development of limbic circuits setting the stage of emotional behavior and thus influencing susceptibility to anxiety, depression, and suicidality in adulthood. In anticipation of a mouse model with a targeted disruption of the TPH2 gene, clarification of the effect of brain 5-HT deficiency on anxiety-related and aggressive behavior seems to be imminent.

Neuroadaptive Changes

Analogous to 5-HT1A KO mice, the neural mechanisms underlying increased anxiety-related behavior and reduced exploratory locomotion in mice with a disruption of the 5-HTT gene may relate to excess serotonergic neurotransmission which is expected to cause enhanced activation of postsynaptic 5-HT receptors. Both in vivo microdialysis in striatum and in vivo chronoamperom-etry in hippocampus revealed that 5-HTT null-mutant mice exhibit an approximately fivefold increase in extracellular concentrations of 5-HT and an absence of transporter-mediated clearance, although brain tissue 5-HT concentrations are markedly reduced by 40 -60 (Bengel et al. 1998). Therefore, a partial downregulation of postsynaptic 5-HT1A receptors in some forebrain regions but a several-fold increase in extracellular concentrations of 5-HT in 5-HTT null-mutant mice could still cause excess net activation of postsynaptic 5-HT1A receptors, resulting in increased anxiety-like behavior and its reversal by WAY 100635...

Adenylyl Cyclase Type VIII

Stress results in alterations in behavior and physiology that can be either adaptive or maladaptive. Although mice deficient in the calcium-stimulated adenylyl cyclase type VIII (AC8) exhibit indices of anxiety comparable with that of wildtype mice at baseline, AC8 KO mice do not show normal increases in behavioral features of anxiety when subjected to repeated stress such as repetitive or post-restraint stress testing in the elevated plus maze test (Schaefer et al. 2000). Although these findings suggest a role for AC8 in the modulation of anxiety, the mechanism by which AC8 deficiency results in impaired stress- induced anxiety may be complex, involving impaired long-term depression (LTD) in the CA1 region of the hippocampus and failure to activate CRE-binding protein (CREB) in the CA1 region after restraint stress. Interestingly, it was recently reported that CREB1 polymorphisms predispose to depressive disorder in a gender-specific manner, further strengthening the assumption that...

Protein Activated Inward Rectifying Potassium Channel

The G protein-activated inward rectifying potassium (GIRK) channels regulate synaptic transmission and neuronal firing rates. The GIRK1-4 subunits exhibit unique but overlapping tissue localization patterns and contain cytoplasmic amino and carboxyl termini, two transmembrane domains, and a hydrophobic pore region similar to other potassium-selective channels. Evidence for homo-and heteromultimerization of GIRK subunits has been derived from heterol-ogous expression and biochemical studies (Wischmeyer et al. 1997). They are regulated by neurotransmitters and hormones through G protein-coupled receptors, including muscarinic M2, dopamine D1-3, a2-adrenoreceptor, 5-HT1A, adenosine A1, GABAb, p- 8-, and K-opioid, and somatostatin receptors. The GIRK2 (Kir 3.2) channel is abundantly expressed in the mammalian CNS (Karschin et al. 1996) and co-localization with dopamine receptors in the mesolimbic system and 5-HT1A receptors in serotonergic raphe neurons suggests a role in modulation of...

Neuronal Nitric Oxide Synthase

The discovery of a considerable number of hyperaggressive mutant strains in the course of gene KO experiments highlights the extraordinary diversity of genes involved in the genetic influence on emotionality. Interestingly, genetic support for a role of 5-HT in anxiety and aggression also derives from mice lacking specific genes such as the neuronal nitric oxide synthase (nNOS) that either directly or indirectly affect 5-HT turnover or 5-HT receptor sensitivity. Male nNOS ' mice and wildtype mice in which nNOS is pharmacologically suppressed are highly aggressive (Chiavegatto et al. 2001). Excessive aggressiveness and impulsiveness of nNOS KO mice depend on the presence of testosterone but seem to be caused by a selective decrease in 5-HT turnover and deficient 5-HT1A and 5-HT1B receptor function in brain regions regulating emotion. These findings indicate an interaction of nNOS and the 5-HT system mediated through 5-HT1A and 5-HT1B receptors, but the specific molecular mechanisms in...

Transcription Factor Pet1

While nearly all serotonergic neurons fail to differentiate in mice lacking Pet1, the remaining exhibit deficient expression of genes required for 5-HT synthesis, uptake, and vesicular storage (Hendricks et al. 2003). In target fields including cortex and hippocampus, 5-HT-specific fibers as well as 5-HT and 5-HIAA concentrations were also dramatically reduced in Pet1 KO mice, whereas no major cytoarchitectural abnormalities in nuclear groups of several brain regions were detected. Interestingly, Pet1-deficient mice show evidence for increased anxiety-like behavior in the elevated plus maze test and enhanced aggressiveness in the resident-intruder test as a consequence of disrupted 5-HT system development. These findings further support the notion that Pet1 may represent the terminal differentiation factor that establishes the final identity of 5-HT neurons. Finally, the Pet1-dependent transcriptional program appears to couple 5-HT neuron differentiation during brain development to...

Neural Cell Adhesion Molecule

NCAM plays a critical role during brain development and in adult plasticity. In particular, NCAM is involved in neuronal migration, neurite outgrowth, synaptic plasticity, and emotional behavior (Schachner 1997). NCAM-deficient mice display both elevated anxiety and aggression levels (Stork et al. 1999). Although 5-HT1A binding as well as brain 5-HT and 5-HIAA tissue concentrations were unaltered, lower doses of 5-HT1A agonists are necessary to reduce anxiety and aggressiveness in the NCAM- - mice, suggesting a functional change in the 5-HT1A receptor (Stork et al. 1999). Interestingly, the expression of one of the effectors of the 5-HT1A receptor, the G protein-activated inward rectifying potassium channel 2 (GIRK2) is greatly upregulated in NCAM KO mice, thus identifying disrupted 5-HT1A-activated cellular pathways as an additional cause for their anxiety- and aggression-related behavior (Delling et al. 2002) (also see Sect. 3.4.3). Taken together, these findings indicate an...

Tissue Plasminogen Activator and Growth Associated Protein

Adaptive responses to stressful events comprise physiological processes and behavior aimed at sustaining homeostasis, while severe stress may modify this response and lead to exaggerated fear reaction and persisting anxiety and depression. At the center of the functional neuroanatomy of the stress circuit are the amygdala and the hippocampus, which both exhibit dendritic remodeling following repeated inescapable stress. Although several key players of the stress circuit have been characterized, the mechanism that underlies stress-induced neural plasticity leading to anxiety and associated cognitive impairment remains to be elucidated. Recently, Pawlak and coworkers (2003) identified acute restraint stress-induced upregulation of the serine protease tissue-plasminogen activator (tPA) in the amygdala as a critical mechanism in stress-related neural remodeling that is either adaptive and directed toward attenuation of the deleterious impact of stress on the brain or is reflecting the...

Neurokinin 1 Receptor

Although substance P (SP) and its receptor, neurokinin 1 receptor (NK1R), have been implicated in the control of mood, anxiety, and stress, the efficacy of NK1R antagonists as both antidepressants and anxiolytics has been matter of considerable debate (Lesch 2001a). Santarelli and associates (2001) have recently made a strong argument for a critical role of the SP NK1R system the modu lation of anxiety-related behaviors in mice. Targeted inactivation of the NK1R produced a phenotype that is associated with an increase of fear and anxiety in the elevated plus maze, novelty suppressed feeding, and maternal separation paradigms. Results derived from pharmacologic, immunohistochemical, autoradiographic, endocrine, and electrophysiological studies convincingly identify the 5-HT system as a important participant in anxiety-related responses to NK1R KO, while an association of the NK1R with noradrenergic neurons seems to mediate this behavioral phenotype. Thus, NK1R antagonists may exert...

Introduction Understanding Endocrine Behavior Interactions Lessons from Mutant Mice

Anxiety disorders are common, and lifetime prevalence for the group of disorders is estimated to be as high as 25 (Kessler et al. 1994). These disorders display a substantial lifetime and episode comorbidity between each other and between other psychiatric conditions, particularly mood disorders (Hettema et al. 2001). With respect to the neuroendocrine phenotype, increased concentrations of corticotropin-releasing hormone (CRH) in the cerebrospinal fluid have been reported in stress-related clinical conditions (Holsboer 1999, 2003). In major depression, the combined dexamethasone (DEX) CRH test, in which DEX-pretreated subjects receive a single dose of CRH, has proved to be the most sensitive tool for the detection of altered hypothalamic-pituitary-adrenocortical (HPA) regulation. Depending on age and gender, up to 90 of patients with depression show this neuroendocrine phenomenon (Heuser et al. 1994). Panic disorder patients do not show any relevant alterations in their basal...

Corticosteroid Effects Are Mediated via Two Receptor Subtypes

Activation of GRs at the level of the PVN reduces CRH and AVP activity (Erkut et al. 1998). This negative feedback is a fundamental way in which the HPA system is restrained during stress and activity, and this restraint of HPA activation by glucocorticoids is rapid and profound. In contrast, induction of CRH expression by increasing glucocorticoid levels has been described to occur at the level of the central amygdala and the bed nucleus of the stria terminalis (BNST) (for review Schulkin et al. 1998 Watts 1996). The latter is derived embryologically from the amygdala, and plays a fundamental role in the regulation of the HPA system during stress. This dual mechanism of glucocorticoid action on the central nervous system suggests that corticosterone appears capable of interacting with at least two different neuronal mechanisms to regulate CRH gene transcription. One is seen in paraventricular neurosecretory neurons, where increasing corticosteroid concentrations reduce CRH mRNA...

CRH Receptors and CRH Binding Protein

The biological actions of CRH, UCN, UCN II, and UCN III stresscopin are mediated by specific, high-affinity, G protein-coupled membrane receptors. To date, two distinct receptor subtypes have been characterized CRHR1 and CRHR2 display a markedly different tissue distribution and pharmacological specificity (Chalmers et al. 1995). CRHR1 has been proposed to mediate the effects of CRH on HPA system function and anxiety-related behavior (Liebsch et al. 1995,1999 Skutella et al. 1998), whereas CRHR2 might be predominantly involved in the regulation offeedingbehavior (Spina et al. 1996), cardiovascular function, and the recovery phase of the HPA response (Coste et al. 2000). The CRHR2 receptor family has additional diversity in that two isoforms have been described CRHR2a and CRHR2 (Chalmers et al. 1995 Lovenberg et al. 1995a). The CRHR2a receptor is expressed primarily in subcortical neuronal populations, whereas the CRHR2 isoform is expressed in non-neuronal cells in the central nervous...

Vasopressin Increasingly Recognized Importance

Beyond hyperactivity of central CRH neuropeptidergic circuits, AVP neuronal systems are thought to play a causal role in the etiology and symptomatology of anxiety disorders (H kfelt et al. 2000 Keck and Holsboer 2001 Keck et al. 2002, 2003b). In support of this, AVP has been shown to exert both behavioral effects, such as increased anxiety following intracerebroventricular administration, and to increase CRH-induced ACTH secretion from pituitary corticotrope cells (Antoni 1993 Landgraf et al. 1998 Bhattacharya et al. 1998 Insel and Young 2000). After prolonged stress, AVP is increasingly expressed and released from hypothalamic neurons in both humans and rodents (e.g., Antoni 1993 Keck et al. 2000). In a clinical study, plasma AVP concentrations were found to be significantly correlated with anxiety-related symptoms in healthy volunteers in response to an anxiogenic drug challenge (Abelson et al. 2001). Moreover, administration of the non-peptide AVP 1b (V1b) receptor antagonist...

CRH Overexpression Novel Insights into Old Problems

In 1992, a transgenic mouse line overexpressing CRH was developed (Stenzel-Poore et al. 1992). These animals exhibit prominent endocrine abnormalities involving the HPA system, such as high plasma levels of ACTH and corti-costerone. CRH transgenic mice display physical changes similar to those of patients with Cushing's syndrome, such as excess fat accumulation, muscle atrophy, thin skin, and alopecia (Stenzel-Poore et al. 1992). Behavioral analysis revealed increased anxiety-related behavior when transgenic mice were tested in a light dark box (Heinrichs et al. 1997) or on the elevated plus-maze. In the latter paradigm, increased anxiety-related behavior in transgenic animals could be reversed by administration of the non-selective CRH antagonist a-helical CRH (Stenzel-Poore et al. 1994). Interestingly, adrenalectomy did not attenuate the anxiogenic effect of CRH overproduction, although it normalized plasma corticosterone levels in these animals (Heinrichs et al. 1997), suggesting...

CRHBinding Protein Overexpressing Mice

Behavioral analyses revealed that the mice overexpressing CRH-BP exhibit increased locomotor activity in a novel environment (Burrows et al. 1998). In addition, a tendency towards decreased anxiety-related behavior was observed on the elevated plus maze, which would be in line with limited availability of free CRH due to enhanced binding by CRH-BP in these animals.

Conditional CRHR1 Knockout

Ways in behaviorally relevant limbic neuronal circuitries significantly reduced anxiety-related behavior. The anxiety-reduced phenotype of CRHR1loxP loxP CaMKIIaCre conditional mutants was confirmed in two different behavioral paradigms based on the natural avoidance behavior of mice, the light dark box paradigm, and the elevated plus-maze test. Basal activity of the HPA system was normal in the conditional mutant mice (M ller et al. 2003). Thus, CRHR1 deficiency outside the CRH system responsible for HPA system regulation is able to reduce anxiety. This finding underlines the fact that central neuropeptidergic circuits other than those driving the peripherally accessible HPA system act independently and could be therapeutic targets of antagonist actions (Holsboer 2003).

CRHR1CRHR2 Double Knockout Life Without CRH Receptors

CRHR2 CRHR2 double knockout mice were first generated in 2001. Studies on the HPA axis in these animals confirmed the data obtained with the single gene mutants, although the CRHR1 mutation had a dominating influence (Preil et al. 2001). It could be shown that mice lacking both known CRH receptors are still viable, again pointing towards the importance of compensatory pathways maintaining and activating HPA system activity under both basal and stress-associated conditions. In line with this, AVP mRNA levels were found to be increased in double-mutant mice. Later, these data were confirmed by others (Bale et al. 2002). Results from testing for anxiety-like behaviors showed that the double-mutant mice are sexually dichotomous. Although the female double-mutant mice displayed less anxiety-like behavior, the male double-mutants showed more anxiety-like behavior compared with the females (Bale et al. 2002).

V1b Receptor Knockout Reduced Aggression

In the rat, extrahypothalamic AVP-containing neurons have been characterized mainly in the medial amygdala and the BNST, which innervate limbic structures such as the lateral septum and the ventral hippocampus (e.g., Caffe et al. 1987). In these brain regions, AVP acts as a neurotransmitter, exerting its action by binding to specific G protein-coupled receptors, i.e., V1a and V1b (Barberis and Tribollet 1996 Hernando et al. 2001). To further elucidate the role of V1b receptors, null mutant mice were generated. These V1b receptor-null mutant mice show significantly reduced aggression when tested in a resident-intruder paradigm (Wersinger et al. 2002). This finding might also be indicative of a decreased anxiety-related behavior. Anxiety-related behavior on the elevated plus-maze, however, was found to be indistinguishable between knockouts and wildtype mice. This observation is in line with the finding that infusion of an V1a antisense oligodeoxynucleotide into the rat lateral septum...

Conditional GR Overexpression Preliminary Results

So far, data on conditional overexpression of GR under the brain-region specific promoter calcium-calmodulin-dependent kinase IIa (CaMKIIa) have been presented only in abstract form (Wei et al. 2001). Those conditional GRs overexpressing mice were reported to display normal locomotor activity, but increased anxiety-related behavior in the dark-light test. Basal plasma ACTH and corticosterone levels were reported to be indistinguishable from wildtype littermates. The expression of CRH mRNA was increased in the central nucleus of the amygdala, rostral part, whereas CRH levels in the PVN and BNST remained unchanged. It was suggested that conditional GR-overexpressing mice may provide a suitable model for increased anxiety-related behavior not secondary to altered levels of circulating stress hormones.

Familial and Genetic Factors

The familial aggregation of all of the major subtypes of anxiety disorders has been well-established (Merikangas and Herrell 2004). As reviewed in the following section, when taken together, the results of more than a dozen controlled family studies of probands with specific subtypes of anxiety disorders demonstrate a three- to five-fold elevated risk of anxiety disorders among first-degree relatives of affected probands compared to those of controls. The Table 1 Summary of family and twin studies of anxiety disorders Table 1 Summary of family and twin studies of anxiety disorders 3 Generalized anxiety NR, no range reported OCD, obsessive-compulsive disorder. NR, no range reported OCD, obsessive-compulsive disorder. importance of the role of genetic factors in the familial clustering of anxiety has been demonstrated by numerous twin studies of anxiety symptoms and disorders (Kendler et al. 1996 Kendler et al. 1994). However, the relatively moderate magnitude of heritability also...

Obsessive Compulsive Disorder

There are also very few controlled family studies of obsessive-compulsive disorder. Two of the three studies (Pauls et al. 1995) reported familial relative risks of 3-4, whereas a third study (Black et al. 1992) found no evidence for familial aggregation. Nestadt et al. (2000) found that both an early age of onset and obsessions, but not compulsion were associated with greater familiality. Twin studies have yielded weak evidence for heritability of obsessive-compulsive disorder (Bellodi et al. 1992 Carey and Gottesman 1981 Lenane et al. 1990).

Family Studies and Phenotypic Definitions

The lack of success in identifying specific genes for anxiety disorders is not surprising given their complexity. Similar to several other psychiatric disorders, the anxiety disorders are complicated by (1) etiologic and phenotypic heterogeneity, (2) a lack of valid diagnostic thresholds, (3) unclear boundaries between discrete anxiety subtypes, and (4) comorbidity with other forms of psychopathology. The major impediment to estimating genetic influences in youth is the lack of rediability and validity of the measures themselves. For example, heritability estimates differ dramatically by the source of the information (child vs. parent) (Eaves et al. 1997). The family study approach, particularly when employed with systematic community-based samples, is one of the most powerful strategies to minimize heterogeneity, since etiologic factors for the development of a particular disorder can be assumed to be relatively homotypic within families. There is a dearth of studies that have...

Effects of Central Administration of CRH and Related Peptides on Serotoninergic Neurotransmission

The anxiogenic properties of CRH after central administration in rodents have been extensively described (see Dunn and Berridge 1990 Arborelius et al. 1999). Moreau and colleagues have shown that central administration of uro-cortin 1 also induces anxiety-like behaviour in various classical tests for anxiety in rats and mice (Moreau et al. 1997). In contrast, two recent reports have found no effect or increased anxiety in urocortin 1-deficient mice (Wang et al. 2002 Vetter et al. 2002). The role of the CRH system in anxiety has become more complex with the recent observations that urocortin 2 and urocortin 3 may exert anxiolytic properties. Urocortin 3 displays an acute (10-min pre-treatment interval) anxiolytic effect in rats tested on the elevated plus maze (Valdez et al. 2003). Interestingly, the anxiolytic effects of urocortin 2 were delayed, i.e. this neuropeptide increases open arm exploration in the elevated plus maze not earlier than 4 h after administration (Valdez et al....

Activation of Serotonin Neurones as Indicated by Expression of cFos

Expression of the immediate early gene product c-fos is often used as an indicator of neuronal activation. Various anxiety-inducing challenges, such as the elevated plus maze (Silveira et al. 1993), social defeat (Martinez et al. 1998), forced swimming (Cullinan et al. 1995) and inescapable tail shock (Grahn et al. 1999) all induce the expression of c-fos in the DRN and or MRN. Recent evidence shows that anxiogenic drugs of different chemical classes activate a specific subset of neurones in the DRN (Abrams et al. 2002). Intracere-broventricular (i.c.v.) administration of CRH and urocortin 1 causes a profound increase in the expression of c-fos in the DRN, whereas only moderate effects in the MRN and in some caudal nuclei were observed (Bittencourt and Sawchenko 2000). Urocortin 2 did not influence c-fos expression in the raphe

Extracellular Levels of Serotonin and 5Hydroxyindoleacetic Acid

In a recent in vivo microdialysis study we have assessed the effects of CRH and urocortin 1 on the extracellular levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus of conscious, freely moving, male Wistar rats. We focused on the hippocampus based on its intricate involvement in the regulation of neuroendocrine and behavioural responses to stress. Moreover, the hippocampus is thought to play a critical role in the pathophysiology of anxiety (and affective) disorders. Intracerebroven-tricular injections of low and high doses of CRH and urocortin 1 (dose range 0.03-10 g) increase extracellular levels of both 5-HT and 5-HIAA in the hippocampus (Linthorst et al. 2002). These results have recently been confirmed in Sprague-Dawley rats (1.0 g CRH) by another research group (Kagamiishi et al. 2003). The CRH2-selective neuropeptides urocortin 2 and urocortin 3 also enhance hippocampal extracellular levels of 5-HT and its metabolite after central...

Psychologically Stressful Challenges

In the following two sections I will discuss the effects of two psychologically stressful challenges on serotoninergic neurotransmission. Although these challenges are not used as tests for anxiety per se (and are even often used in research on symptoms of depression), they certainly involve aspects of fear and anxiety and will activate brain circuits involved in these responses. Importantly, attempts have been made by various research groups to elucidate the role of the CRH system in the changes in serotoninergic neurotransmission induced by psychological stress.

Posttraumatic Stress Disorder

There is extensive clinical evidence that NE plays a role in human anxiety. Well-designed psychophysiological studies have been conducted that have documented heightened autonomic or sympathetic nervous system arousal in combat veterans with chronic PTSD. Because central noradrenergic and peripheral sympathetic systems function in concert (Aston-Jones et al. 1991), the data from these psychophysiology investigations are consistent with the hypothesis that noradrenergic hyperreactivity in patients with PTSD may be associated with the conditioned or sensitized responses to specific traumatic stimuli.

Receptor for Anxiolysis

New strategies for the development of daytime anxiolytics that are devoid of drowsiness and sedation are of high priority. Experimentally, the anxiolytic-like action of diazepam is due to the modulation of a2 GABAA receptors as shown by the lack of tranquillizing action of diazepam in a2(H102R) mice (elevated plus maze light dark choice test). The a2 GABAA receptors, which comprise only about 15 of all diazepam-sensitive GABAA receptors, are mainly expressed in the amygdala and in principal cells of the cerebral cortex and the hippocampus, with particularly high densities on their axon initial segments (Nusser et al. 1996a Fritschy et al. 1998a,b). Thus, the inhibition of the output of these principal neurons appears to be a major mechanism of anxiolysis. It had previously been postulated that the anxiolytic action of diazepam is based on the dampening of the reticular activating system, which is mainly represented by noradrenergic and serotonergic neurons of the brain stem. These...

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