Specific Phobia

In specific phobia disorder the patient has an inappropriate or excessive fear of a particular stimulus or situation, such as animals, heights or thunder. An anxiety reaction is consistently and rapidly evoked on exposure to the stimulus, and there is anticipatory anxiety. Population studies have found a surprisingly high prevalence and associated disability, for example a lifetime prevalence of 12 in the National Comorbidity Survey (Magee et al. 1996). The standard treatment for specific...

Developmental Specification Serotonergic Neurons Setting the Stage

The comparatively small number of serotonergic neurons ( 20,000 and 300,000 in rodents and humans, respectively) are primarily located in the raphe nuclei, on the midline of the rhombencephalon, and in the reticular formation. Although these neurons are clustered in caudal and rostral divisions of the B1-B9 cell groups, the extensive collateralization of their terminals densely innervate all regions of the CNS. While serotonergic neurons are generated during early embryonic development...

Conclusion

As may be taken from the studies summarised in this chapter, aberrant interactions between the CRH system and serotoninergic neurotransmission may play an important role in the aetiology of (stress-related) anxiety disorders. However, the picture is far from complete at the moment. Further studies on the consequences of aberrations in the CRH system and on the balance between CRH1 and CRH2 effects will increase our understanding of the neurobiology of anxiety and may boost the development of...

Summary and Conclusions

Significant progress has been made in understanding the neurobiology of fear memory, including the signal transduction cascades that are activated and required for the formation of long-term fear memory. This has resulted in hypothesis-based novel targets and strategies for fear-related disorders, including PTSD. This progress has resulted in part from the well-defined models and neural circuitry for fear conditioning, which provides a system for testing the role of specific signaling...

Brain Derived Neurotrophic Factor

An extended assembly of other neurotrophins and growth factors also modulates the phenotype of 5-HT neurons. These include family members of the neurotrophins, such as transforming growth factor- (TGF-0), bone morpho-genetic protein (BMP), and neurokines (ciliary neurotrophic factor, CNTF) (Galter and Unsicker 2000a,b). 5-HT itself regulates the serotonergic pheno-type of neurons by sequential activation of the 5-HT1A receptor, brain-derived neurotrophic factor (BDNF), and its receptor TrkB, as...

The Cytochrome P450 Gene Family

Approximately 50 CYP enzymes, which are haem proteins, have been identified thus far. In humans there are about 10 important drug-metabolizing CYP genes. These are mainly expressed in the smooth endoplasmatic reticulum of the hepatocytes, but can also be found in gut mucosa, kidney, lung tissue, skin, and in the brain. Of these, CYP2D6, CYP2C19, CYP3A4, and CYP1A2 are important in the metabolism of antidepressant drugs and benzodiazepines (Staddon et al. 2002 Steimer et al. 2001) (see Table 1...

Retrograde Regulation of GABAergic Interneurons

Retrograde signalling adds another level of complexity to the regulation of interneuron activity. The terminals of CCK-positive GABAergic basket cells in hippocampus and amygdala contain CB1-cannabinoid receptors (Katona et al. 1999, 2001). These receptors mediate depolarization-induced suppression of inhibition (DSI) (Pitler and Alger 1994 Alger and Pitler 1995). This phenomenon is due to endocannabinoids that emanate from the postsynaptic cell and act as a retrograde signal (Wilson and...

Monoamine Oxidase A

Monoamine oxidase A (MAOA) oxidizes 5-HT, norepinephrine as well as dopamine, and is expressed in a cell type-specific manner. Abnormalities in MAOA activity have been implicated in a wide range of psychiatric disorders. Deficiency in MAOA enzyme activity due to a hemizygous chain termination mutation of the MAOA gene has recently been shown to be associated with impulsive aggression and hypersexual behavior in affected males from a single extended pedigree (Brunner syndrome) (Brunner et al....

Oxytocin

In addition to its well-known reproductive functions, oxytocin released within the mammalian brain is known to be involved in a variety of regulatory pathways including those underlying social, sexual, maternal (Argiolas and Gessa 1991 Richard et al. 1991 Landgraf 1995 Bielsky and Young 2004) and depression-like behaviour (Arletti and Bertolini 1987). Following peripheral (Uvnas-Moberg et al. 1994) or central (Windle et al. 1997) administration, an anxiolytic-like effect has been described in...

Mutagenesis and Knockout Models Hypothalamic PituitaryAdrenocortical System

Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany keck mpipsykl.mpg. de 1 Introduction Understanding Endocrine-Behavior Interactions Lessons from Mutant 2 The Stress Hormone (Hypothalamic-Pituitary-Adrenocortical) System 115 2.1 Corticosteroid Effects Are Mediated via Two Receptor Subtypes 116 2.2 The Dual Action of CRH Activator of the HPA System and 2.2.1 New Members of the Growing CRH Family 2.2.2 CRH Receptors and CRH Binding 2.3 Anxiogenesis Activation of...

Conditional GR Knockouts Reduced Versus Unchanged Anxiety Related Behavior

Since conventional disruption of GR signaling is lethal shortly after birth due to lung failure (Cole et al. 1995), a conditional G -knockout where GR function is selectively disrupted in the nervous system has been generated (Tronche et al. 1999). Using the Cre loxP system to achieve tissue-specific gene inac-tivation, expression of Cre under the control of the rat nestin promoter and enhancer results in a selective disruption of GR in neuronal and glial cell precursors (Tronche et al. 1999)....

Mechanism of Change in Phenotype in Tac1 and NK1RNull Mutant Mice

One of the most important questions that remains to be answered concerns the mechanism leading to the manifestation of the knockout phenotype. The tac1 and NK1R gene deletions could directly modulate stress-related behaviors through an altered SP NK1 signaling of limbic neuronal circuits that mediate stress-related behaviors, or act indirectly by affecting other systems. A direct involvement of NK1R signaling is suggested by the widespread expression of SP in neurons of many limbic structures,...

Antidepressant Treatment Upregulatesthe cAmpcreb Cascade

Antidepressant drugs block the reuptake or metabolism of NE and 5-HT and thereby increase the function of receptors coupled to these monoamines. One of the signal transduction cascades regulated by NE and 5-HT and linked to the actions of antidepressant drugs is the cAMP-CREB cascade (Fig. 4). There are several classes of NE and 5-HT receptors that directly couple to and activate the cAMP second messenger cascade, including p1- and p2-adrenergic receptors and 5-HT4, 5-HT6, and 5-HT7 receptor...

Extinction of Fear Memory

The extinction of fear memory occurs when a CS is presented without pairing with a US and results in a gradual decrement in conditioned responding. Extinction is thought to be an active process utilizing mechanisms similar to those involved in the acquisition ofconditioned fear. Extinction is facilitated by enhanced signaling via NMDA receptors, PKA, MAPK, and CaMKII (Falls et al. 1992 Lu et al. 2001 Miserendino et al. 1990 Szapiro et al. 2003 Vianna et al. 2001), suggesting mechanistic...

Neuroendocrine Aspects of PTSD

Psychiatry Department and Division of Traumatic Stress Studies, Mount Sinai School of Medicine and Bronx Veterans Affairs, 130 West Kingsbridge Road, Bronx NY, 10468, USA Rachel.yehuda med.va.gov 2 Basal HPA Hormone Levels in 2.1 Urinary Cortisol Levels in 2.2 Cortisol Levels Over the Diurnal Cycle in 2.3 Cortisol Levels in Response to 2.4 Observations About Baseline Cortisol Based on Single Estimates of Plasma or 2.5 Correlates of Cortisol in 2.6 CRF Levels in 2.7 ACTH Levels in 2.8...

Obsessive Compulsive Disorder

OCD is a disabling disorder that tends to run a chronic or recurrent course (Sasson et al. 1997). It is diagnosed by the presence of obsessions (recurrent, intrusive thoughts, images or impulses that are experienced as irrational and unpleasant) or compulsions (repetitive behaviours that are performed to reduce a feeling of unease). The symptoms are present for at least 1 h every day and cause impairment of important functions. Prevalence has been measured in various populations and is...

Mirtazapine

Mirtazapine has a novel mechanism of action that in theory should promote anxiolytic effects, although evidence from studies of anxiety disorders is awaited. It increases synaptic release of serotonin and noradrenaline via blockade of presynaptic inhibitory a2-adrenoceptors, as well as blocking post-synaptic 5-HT2 and 5-HT3 serotonin receptors and H1 histamine receptors. Mirtazapine has good efficacy for anxiety symptoms associated with depression (Fawcett and Barkin 1998), and in controlled...

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...

Conclusion Of Angiolytic Drug

This chapter provides a brief discussion on pharmacogenetics as it relates to the ethnic variations in drug responses in the treatment of anxiety disorders. Anxiety disorders are common and can be debilitating. Fortunately, many medications are available to help manage the symptoms of anxiety. The field of pharmacogenetics and the study of ethnic variations in drug response are important. Research in these areas is helping to build a foundation of knowledge. However, it still behooves the...

Anxiogenesis Activation of CRHR1 and Dual Mode of Action of CRHR2

Numerous investigations in animals have described anxiogenic-like effects after CRH administration (Dunn and Berridge 1990). These effects are likely to be mediated through the CRH1 receptor, as CRHR1 antagonistic approaches have anxiolytic-like properties in most, but not all anxiety paradigms (e.g., Liebsch et al. 1995 Griebel et al. 1998 Keck et al. 2001a). The effectiveness of CRHR1 blockade to reduce anxiety is likely to depend on the animal's stress level, as it has been shown that CRHR1...

Antidepressants

Time Anxiolytic And Antidepressant

The growth during the 1990s in the use of antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), for the treatment of anxiety disorders represented a major advance in the pharmacotherapy of anxiety. The efficacy of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) had been established alongside their antidepressantw actions several decades 6 12 Time (weeks) Fig. 2. Treatment response to anxiolytic drugs previously, but the launch of new,...

Introduction

Anxiety disorders can develop as a result of exposure to stress and can be chronic in nature, suggesting the relevance ofexperience-dependent processes and persistent functional alterations in the etiology of anxiety. Time-dependent adaptive processes might also be important in the treatment of anxiety. The regulation of intracellular signaling mechanisms and associated regulation of gene expression has been suggested to underlie the time-dependent effects of several classes of drugs including...

Regulation of Transcription Factors and Gene Expression

Regulation of gene transcription factors by signal transduction pathways represents one of the primary mechanisms for effecting long-term changes in neuronal function. Transcription factors bind to specific sequences of DNA in the promoter regions of genes and can either increase or inhibit gene expression. The unique pattern of promoter elements governs the expression pattern of a particular gene in the adult and during development. There are two major mechanisms for regulation of...

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...

Summary

The cumulative evidence makes a strong case that the neuroendocrine and behavioral phenotypes of anxiety disorders are at least in part mediated via modulation of CRH and AVP neurocircuitry and that normalization of an altered neurotransmission after treatment may lead to restoration of disease-related alterations. Although this concept was originally derived from peripheral HPA assessments in depressed patients, it is now clear that central CRH and AVP neuropeptidergic circuits other than...

YAminobutyrk Acid

GABA is the predominant inhibitory neurotransmitter in the CNS. It is formed by decarboxylation of glutamate, the major central excitatory amino acid, utilizing the enzyme 1-glutamic acid decarboxylase (GAD). GABA receptors consists of two different superfamilies GABAa and GABAb. Traditional anxi-olytics and sedative drugs such as barbiturates and benzodiazepines modulate the GABAA receptors. The pharmacological relevance of the multitude of structurally diverse GABAA receptor subtypes has only...

Anxiety Disorders Noradrenergic Neurotransmission

Charney2 1Mood and Anxiety Disorders Research Program, National Institute of Mental Health NIH, 15K North Drive, MSC 2670, Bethesda MD, 20892-2670, USA 2Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1102, New York NY , 10029, USA 3 Yale University School of Medicine, Molecular Imaging Program of the Clinical Neuroscience Division, 950 Campbell Avenue, West Haven NY , 10029, USA Alexander.Neumeister yale.edu 1 Neural Mechanisms of Anxiety and...

Interactions Between CRH and Serotonin Under Anxiogenic and Psychologically Stressful Conditions What Can We Learn from

Ample studies applying various 5-HT receptor agonists and antagonists have shown that 5-HT exerts anxiogenic and anxiolytic effects depending on the brain structure(s) and specific 5-HT receptor(s) involved as well as on the route of administration (for an excellent, comprehensive review see Millan 2003). Whereas from a clinical point of view, it may be sufficient to know whether a (new) compound shows anxiolytic properties after oral administration, it is known that the anxiolytic properties...

Memory Decay and Extinction

Everyone experiences how memories may dissipate with time. Responsible for this phenomenon might be spontaneous forgetting, the suppression of memory retrieval and memory extinction. Spontaneous forgetting describes the loss of learned performances that is often observed when time elapses between memory acquisition and memory retrieval. It results from different processes (Bouton et al. 1999). First, memory traces might dissipate over time. Second, information might increasingly interfere with...

Introduction Of Anxiolytics Drugs

Pharmacology has provided powerful tools to characterize the neurochemical pathways of stress and anxiety in the brain, and how these pathways are involved in the pathophysiology and treatment of anxiety disorders. In the past, this work has largely focused on classical neurotransmitter systems, including the synthesis, release, and metabolism of monoamines and receptor subtypes that control presynaptic release of neurotransmitters and their postsynaptic effects. Increasing the specificity of...

Neuroanatomical Basis for the Interactions Between CRH and Serotonin

The raphe nuclei in the brainstem, containing the majority of serotoninergic neurones (Dahlstr m and Fuxe 1964 Steinbusch 1981), can be neuroanatom-ically divided in a rostral and a caudal group (Jacobs and Azmitia 1992 T rk 1990). The caudal raphe nuclei (raphe pallidus nucleus, raphe obscu-rus nucleus, raphe magnus nucleus and serotoninergic neurones in the ventral lateral medulla) largely project to the spinal cord. In contrast, the rostral raphe nuclei, i.e. the dorsal raphe nucleus (DRN),...

Obsessive Compulsive Disorders

Obsessive-compulsive disorder (OCD) is characterized by recurring and extremely time-consuming obsessions or compulsions that cause marked distress or significant impairment in daily functioning. Obsessions can be described as recurrent, intrusive or inappropriate thoughts, images or impulses that cause feelings of anxiety. Obsessions often involve preoccupations with contamination, symmetry, pathological doubting or uncertainty or harm to self or others, as well as preoccupations with sexual...

Tricyclic Antidepressants

This group includes compounds with actions on a range of neurotransmitter systems. Their antidepressant efficacy is mediated by reuptake inhibition of serotonin and noradrenaline, although side-effects such as sedation may also be useful. Their use in anxiety disorders is supported by a long history of clinical experience and a reasonable evidence base from controlled trials. Studies support the use of clomipramine (a potent serotonin reuptake inhibitor) in panic disorder and OCD (Lecrubier et...

Involvement of SP in Stress Responses

Several lines of evidence point to an important role of SP in the regulation of stress responses. Mild stressors such as isolation (Brodin et al. 1994), sequential removal from the home cage, or short-lasting (1 min) restraint (Rosen et al. 1992) significantly increased the concentration of SP in the PAG region. Moreover, treatment with the anxiolytic drug diazepam produced a reduction of SP concentration in the PAG area and in the rostral hippocampus (Brodin et al. 1994). In contrast, more...

Corticotropin Releasing Hormone

Among the various neuropeptide systems that have been implicated in the regulation of anxiety-related behaviour, the corticotropin-releasing hormone (CRH) system plays a major role. CRH-containing circuits mainly originate in the parvocellular subdivision of the hypothalamic paraventricular nucleus (PVN) CRH neurons with a neuroendocrine role in the regulation of the hypothalamo-pituitary-adrenocortical axis (HPA) co-produce vasopressin (AVP) and terminate at the median eminence to secrete the...

Neuroactive Steroids

In the last decade, considerable evidence has emerged that certain steroids may alter neuronal excitability via their action at the cell surface through interaction with certain neurotransmitter receptors. For steroids with these particular properties, the term neuroactive steroids has been used (Majewska et al. 1986 Paul and Purdy 1992 Rupprecht and Holsboer 1999). The first behavioral observations related to these steroids date back to Se-lye, who over 50 years ago reported that progesterone...

Pathophysiology of the GABA System

If the balance between excitatory and inhibitory activity is shifted pharmacologically in favour of GABAergic transmission, then anxiolysis, sedation, amnesia and ataxia arise. On the other hand, an attenuation of the GABAergic system results in arousal, anxiety, restlessness, insomnia, exaggerated reactivity and even seizures. These pharmacological manifestations point to the contribution of inhibitory neurotransmission to the pathophysi-ology of brain disorders. A GABAergic deficit is...

Panic Disorder and Agoraphobia

In the DSM-IV description of panic disorder, recurrent and at least initially unexpected panic attacks are the key clinical feature, along with persistent concerns about having another attack, worry about the implications or the consequences of the attack, or a remarkable behavioural change related to the attacks. Here again, the panic attacks do not reflect exposure to a situation that always causes anxiety (as in specific phobia) and are not triggered, for example, by social attention. Panic...

Clinical Implications

Most basic researchers and clinicians believe that detailed knowledge about cellular mechanisms underlying the formation and extinction of aversive memories will lead to the development of novel therapeutic strategies for the treatment of human anxiety disorders. Our current knowledge about these mechanisms largely arises from results obtained in animal experiments. However, the transferability of such experimental data to the human situation depends on the validity of the experimental models...

The Metyrapone Stimulation Test

Whereas both the results of the DST and CCK challenge tests are consistent with the idea of an enhanced negative feedback inhibition in PTSD, these alter ations do not directly imply that an enhanced negative feedback inhibition is a primary disturbance in PTSD. Yehuda et al. used the metyrapone stimulation test as a way of providing further support for the enhanced negative feedback hypothesis (Yehuda et al. 1996a). Metyrapone prevents adrenal steroidogenesis by blocking the conversion of...

Inbred Mouse Strains

During the past 90 years, starting from when the first inbred mouse strains were being described, this species has become an organism of choice for modeling human diseases. More than 450 inbred strains of mice are available now, representing a variety of genotypes but also phenotypes. Thus, in the search for animals models of anxiety disorders, inbred mouse strains are an interesting resource. As an example, the two inbred mouse strains C57BL 6 and BALB c have been shown to differ in their...

GR Antisense Transgenics Born to Be Brave

To further elucidate the role of impaired GR signaling in psychiatric disorders, a transgenic mouse expressing antisense to GR mRNA was generated (Pepin et al. 1992). The transgene is driven by a neurofilament promoter and is therefore primarily active in neuronal tissue, resulting in a markedly reduced GR mRNA expression in the brain. Accordingly, HPA axis regulation in the antisense GR transgenic mice is heavily disturbed, as shown by a reduced glu-cocorticoid negative feedback efficiency,...

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...

Glaucoma

Excitotoxicity has also been implicated in glaucoma. Mild chronic intravitreal elevation in glutamate concentration by serial intravitreal glutamate injections resulted in death of retinal ganglion cells. Concurrent daily injections of me-mantine completely prevented this cell death (Vorwerk et al. 1996). As such, the memantine follow-up compound neramexane (MRZ 2 579) could also be useful for the treatment of glaucoma and this possibility is presently being tested as a proof concept for the...

Urinary Cortisol Levels in PTSD

The initial report of sustained, lower urinary cortisol levels in PTSD highlighted the disassociation between cortisol and catecholamine levels in PTSD. Norepinephrine and epinephrine levels assayed from the same urine specimens revealed elevations in both of these catecholamines, while cortisol levels in PTSD fell within the normal range of 20-90 pg day, indicating that the alteration was not in the hypoadrenal or endocrinopathologic range (Mason et al. 1986). This finding established the...

Benzodiazepines

Benzodiazepines comprise the most frequently prescribed subclass of antianxiety agents. These agents, first introduced in the early 1960s, quickly replaced the use of barbiturates as the pharmacological approach to anxiety. The popularity of these agents can be attributed to their generally quick onset of action and wider safety margin in overdose compared to the barbiturates. However, the potential of these agents to elicit physical dependence also quickly became apparent. In addition to the...

Cortisol Levels Over the Diurnal Cycle in PTSD

Among the many potential methodologic problems associated with 24-h urine collections is the possibility that persons who are asked to collect 24-h samples at home may not provide complete collections. To the extent that there may be a systematic bias in protocol nonadherence between subjects with and without PTSD, in that the former might be more likely to miss collections than the latter, this could contribute to observed low cortisol levels. One of the initial rationales for performing a...

Prolactin

Convincing evidence of an anxiolytic action of both exogenous and endogenous prolactin has recently been provided by Torner et al. (2001). While intracerebral infusion of this neuropeptide exerted anxiolytic effects on the elevated plus maze in a dose-dependent manner in both male and female rats (Fig. 3B), downregulation of the long form of the prolactin receptor by highly efficient antisense targeting resulted in increased anxiety-related behaviour. In addition to its behavioural action,...

Forced Swimming

The forced swim test, as developed by Porsolt, is often used to screen new compounds for putative antidepressant characteristics. However, forced swimming has also been found to be a very useful paradigm in assessing the effects of stress on various aspects of brain functioning (neurotransmission, c-fos and P-CREB expression, HPA axis regulation see Bilang-Bleuel et al. 2002) in rats and (mutant) mice. Forced swimming is a stressor with physical (activity, body temperature changes) and...

Cortisol Levels in Response to Stress

The potential significance of the findings of an increased range of cortisol is that the HPA axis may be maximally responsive to stress-related cues in PTSD, whereas major depressive disorder may reflect a condition of minimal responsiveness to the environment. That is, an enhanced amplitude-to-mesor ratio describes a system with particularly low background activity and, accordingly, a potentially increased capacity to respond to environmental cues. In support of this, Liberzon et al. observed...

Drugs Acting via Monoaminergic Neurotransmission

Aside from the GABAa receptor, most research into the neurochemistry of anxiety has explored the role of the monoamine transmitters serotonin (5-HT), noradrenaline and dopamine. This interest originated with the serendipitous discovery of drugs that were later found to exert their anxiolytic effects by actions on monoamine function. Advances in neuroscience research techniques have, rather than clarifying the role of these neurotransmitters, tended to present an increasingly complex picture...

The CRF Challenge Test and ACTH Stimulation Test in PTSD

Infusion of exogenous CRF increases ACTH levels and provides a test of pituitary sensitivity. In several studies of major depression, the ACTH response to CRF was shown to be blunted, reflecting a reduced sensitivity of the pituitary to CRF (e.g., Krishnan 1993). This finding has been widely interpreted as reflecting a downregulation of pituitary CRF receptors secondary to CRF hypersecretion, but may also reflect increased cortisol inhibition of ACTH secondary to hypercortisolism (Krishnan 1993...

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...

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...

CAMP Second Messenger Cascade

One of the best-characterized effectors and second messenger systems is the cAMP cascade that can be either activated or inhibited by neurotransmit-ter neuropeptide receptors, including those implicated in anxiety stress such as CRF. Receptors that activate cAMP synthesis couple with the stimulatory G protein, Gsa, and those that inhibit this second messenger couple with the inhibitory G protein, Gia, and these either stimulate or inhibit adenylyl cy-clase, the effector enzyme responsible for...

Cytochrome P450

The focus of pharmacogenetic studies has largely been on those genes that encode enzymes responsible for the metabolism of medications. However, ethnic differences may also be affected by genes controlling the function and response of therapeutic targets. A well-established example of the difference that exists between different ethnic groups is the metabolism of alcohol. One of the enzymes responsible for the metabolism of alcohol is acetaldehyde dehydrogenase (ALDH), and 40 -50 of Asian...

ACTH Levels in PTSD

Among the challenges in assessing pituitary activity under basal conditions is the fact that the normal positive and negative feedback influences on the pituitary can mask the true activity of this gland. Because the pituitary mediates between CRF stimulation from the hypothalamus and the inhibition of ACTH release resulting from the negative feedback of adrenal corticosteroids, baseline ACTH levels may appear to be normal even though the pituitary gland may be receiving excessive stimulation...

Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) have been shown to be effective in the treatment of anxiety disorders such as social anxiety and panic disorder. In a 12-week, placebo-controlled trial of patients with panic disorder, Sheehan and colleagues reported that phenelzine (45 mg day) was better than placebo however, higher doses of the MAOI (e.g., 60-90 mg day) may be more effective (Sheehan 1980 Buiges1987). Because of the potential risk of a hypertensive crisis with a tyramine-containing diet,...

Atrial Natriuretic Peptide

Whereas several peptides besides AVP are known to act synergistically with CRH, the only peptide candidate in humans that inhibits the HPA system at all regulatory levels of the system seems to be atrial natriuretic peptide (ANP). ANPhasbeen showntoinhibitthestimulatedrelease ofCRHandACTH in vitro and in vivo. This could be observed in humans as well, where ANP inhibits the CRH-induced ACTH (Keller et al. 1992), prolactin (Wiedemann et al. 1995), and cortisol secretion (Strohle et al. 1998)....

The Naloxone Stimulation Test in PTSD

Another strategy for examining CRF activity involves the assessment of ACTH and cortisol after administration of agents that normally block the inhibition of CRF. Naloxone increases CRF release by blocking the inhibition normally exerted by opioids in the hypothalamus. Naloxone was administered to 13 PTSD patients and 7 normal comparison subjects (Hockings et al. 1993). Of the PTSD subjects, 6 7 showed an increased ACTH and cortisol response to naloxone. These findings appear to contradict...

Behavioural Inhibition and Parenting Style

Behavioural inhibition describes the tendency to be shy, timid and constrained in unfamiliar situations (Kagan et al. 1984).This disposition is very stable, can be observed early in life and is assumed to be genetically determined. Offspring of parents with anxiety disorders show higher behavioural inhibition than offspring of parents without anxiety disorders (Rosenbaum et al. 1991). Behavioural inhibition has seldom been evaluated in epidemiological studies. However, those that included it...

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...

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...

Behavior of Tac1 and NK1R Knockout Mice in Models of Depression

The stress-related behavior of tac1 ' mice derived from these homozygous animals on a congenic C57BL 6J genetic background was analyzed in models of depression and anxiety (Bilkei-Gorzo et al. 2002). Based on the clinical association of depressive episodes and stressful life events, many of the animal models for the evaluation of antidepressant drug activity assess stress-precipitated be haviors. The two most widely employed animal models for antidepressant drug screening are the behavioral...

Tardive Dyskinesia

According to current concepts, tardive dyskinesia seen after long-term treatment with some neuroleptics involves progressive neuronal damage resulting from excitotoxicity and free radical production (DeKeyser 1991 Cadet and Kahler 1994). At the level of the striatum, chronic blockade of D2 inhibitory dopaminergic receptors localized on glutamatergic terminals from the cortex may lead to a persistent, enhanced release of glutamate that eventually damages output neurons (DeKeyser 1991 Gunne and...

Lactate Infusion Challenge

Sodium lactate infusion studies constitute the largest single body of pharmacological challenge research with robust and reproducible findings (Table 1). Due to a paucity of relevant preclinical data, however, the mechanisms underlying lactate-induced panic are still unclear. The limited information provided on neuronal pathways influenced by this provocation test therefore limits its value in elucidating the pathophysiology of anxiety disorders. It is important to note that, as with all...

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...

Findings of Cortisol in the Acute Aftermath of Trauma

Recent data have provided some support for the idea that low cortisol levels may be an early predictor of PTSD rather than a consequence of this condition. Low cortisol levels in the immediate aftermath of a motor vehicle accident predicted the development of PTSD in a group of 35 accident victims consecutively presenting to an emergency room Yehuda et al. 1998 . Delahanty et al. 2000 also reported that low cortisol levels in the immediate aftermath of a trauma contributed to the prediction of...

The Dexamethasone Suppression Test in PTSD

In contrast to observations regarding ambient cortisol and ACTH levels, results using the DEX suppression test DST have presented a more consistent view of reduced cortisol suppression in response to DEX administration. The DST provides a direct test of the effects of GR activation in the pituitary on ACTH secretion, and cortisol levels following DEX administration are thus interpreted an estimate of the strength of negative feedback inhibition, provided that the adrenal response to ACTH is not...

CRHR2 Knockout Increased Anxiety Related Behavior

Compared to CRHR1 mutants, behavioral and endocrine analysis of CRHR2 knockout mice has provided a less clear picture. Three different knockout lines deficient for CRHR2 have been independently created Bale et al. 2000 Coste et al. 2000 Kishimoto et al. 2000 . Interestingly, significant differences in aspects of both the endocrine and behavioral phenotype were described between the three knockout mouse lines, pointing towards the fact that most likely the genetic background of genetically...

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,...

Vasopressin

AVP and oxytocin are neuropeptides closely related to the CRH neuropeptide family. They are mainly synthesized in parvo- and magnocellular neurons of the hypothalamic PVN and supraoptic nucleus. Upon appropriate stimulation, AVP and oxytocin are secreted from axon terminals into the systemic circulation. This secretion occurs at the level of the posterior pituitary, where axons from magnocellular neurons terminate, or of the eminentia mediana, where neuropeptides of parvo- and magnocellular...

Carbon Dioxide

Voluntary hyperventilation leading to hypocapnia i.e., a low partial pressure p CO2 can precipitate panic in panic disorder patients. Training habitual hyperventilators to breathe appropriately has therapeutic benefits Salkovskis et al. 1986 but it has to be kept in mind that not all hyperventilators are anxious Bass and Gardner 1989 . Hyperventilation, therefore, may rather be the consequence, and not the cause, of panic. Although reducing pCO2 can trigger panic, the role of CO2 is further...