Parkinson Disease Alternative Treatment

The Parkinson's-Reversing Breakthrough

The Parkinson's Breakthrough Program entails the most effective and natural strategies people can use to heal the root cause of Parkinson's Disease. It is a digital manual aimed at showing the users the most effective method for overcoming Parkinson's without high-priced prescription drugs riddled with harmful side effects.The program was not created to be a quick fix. In fact, like different programs, it is tasking. Yet, you will not have to spend a lot of time dealing with it. The system requires your full attention, perseverance, and discipline. For the period of its usage, you will have the opportunity to use to eat some food ingredients that will detoxify you.The methods employed in this book are natural ones that have been proven by many specialists. The users will be privy to what to do and what not to do to treat the underlying root cause of their Parkinson's and the way they can reverse the symptoms naturally and effectively. The system comes with bonus E-books- Lessons from The Miracle Doctors, Mind Control in the USA', and 10 Deadly Health Myths of The 21st Century. The book is in a digital format (PDF) and has been created at a very affordable price. More here...

The ParkinsonsReversing Breakthrough Summary

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Levodopainduced And Steroidinduced Psychosis

Antipsychotics are an integral part of the treatment of medication-induced psychotic syndromes. The psychosis induced by levodopa in the treatment of Parkinson's disease presents unique clinical dilemmas. Treatment of the symptoms with first-generation antipsychotic agents will by definition worsen the Parkinson's symptoms. The clinician is often caught between attempts to reduce the patient's severe paranoid state and attempts to keep the patient from becoming more immobile from worsening rigidity and akinesia. Recently, case reports utilizing clozapine and risperidone in this population have shown encouraging results.

Levodopa and dopamine receptor agonists

Apomorphine, one of the oldest and most potent of dopamine receptor agonists, is being increasingly used in patients with severe motor fluctuations in Parkinson's disease. It is usually given by subcutaneous infusion, but this is associated with the development of persistent nodules, causing major problems in about 10 of patients after 3 or more years. One solution is to give the drug intravenously using an indwelling cannula. Six patients, who had responded well to subcutaneous apomor-phine before nodules developed, had such can-nulae inserted (30c). The apomorphine was given at a mean rate of 9.0 mg hour to a total mean dose of 257 mg day, very similar to the subcutaneous dosage. The intravenous therapy virtually abolished off periods, reduced oral antiparkinsonian drug dosages by 59 , and produced a marked (but unquantified) reduction in dyskinesias and an improved quality of life. However, there were major problems. Two patients receiving high doses of apomorphine (450 and 290 mg...

LSD and Parkinsons Disease

Recently, however, scientists at the School of Medicine of the University of California at Los Angeles have made some significant discoveries about the interaction of LSD with dopamine, one of the neurotransmitter agents in the brain, that may lead not only to a better understanding and eventual treatment of schizophrenia, the mental disorder to which the LSD high is a kind of temporary analogue, but even of such physically, rather than mentally, crippling disorders as Parkinson's disease (UCLA Weekly, 1975 4). The investigators, Drs. Sidney Roberts and Kern von Hungen and Diane F. Hill, determined that adenyl cyclase, an enzyme in nervous tissue that is stimulated by naturally occurring neurotransmitter agents, is also stimulated by the action of LSD on receptors for one of these neurotransmitters, dopamine. In addition, LSD blocked the stimulatory actions of dopamine and other neurotransmitters (agents that aid in conducting impulses along nerve cells, specifically bridging the gap,...

Case 8 What Do the Brain Scans Show Should Parkinsons Disease Obesity and Methamphetamine Use Be Considered Alike

Andrew has Parkinson's Disease, Bob is obese, and Charlie uses methamphetamines. Neuroimaging studies of all three show changes in brain morphology that substantially influence their behavior. Yet the three are regarded differently Andrew as the victim of a disease, Bob as irresponsible for failing to exercise and control his diet, and Charlie as an addict. As far as current neuroscience can tell, changes in brain biology largely account for their patterns of behavior. Case 8 New research in neurotoxicity suggests that methamphetamine damages the same brain systems as those associated with Parkinson's Disease, the neurodegenerative disease with symptoms such as flat affect and, in later stages, a distinctive tremor and cognitive loss. Parkinson's selectively compromises a specific neurochemical transmitter system, the nigrostriatal dopamine pathway, and methamphetamine use can also damage this pathway. Although more controversial, it is also believed that the damage in Parkinson's...

Acute Extrapyramidal Side Effects Dystonia Parkinsonism Akathisia

Commonly occurring acute EPS include akathisia, dystonia, and parkinsonism, with each having a characteristic time of onset. This group of acute EPS develops relatively soon after the initiation of antipsychotic medications and remits soon after the drugs are discontinued. These movement disorders are dose-dependent and reversible. Medication-induced parkinsonism is characterized by the symptoms of idiopathic parkinsonism, including rigidity, tremor, akinesia, and bradykinesia. Risk factors include older age, higher dose, a history of parkinsonism, and underlying damage in the basal ganglia. The treatment of acute EPS depends on the specific side effect. Dystonia can be quickly and successfully treated with an intramuscular injection of an anticholinergic (i.e., benztropine, diphenhydramine). The initial treatment of parkinsonian side effects is lowering the dose of antipsy-chotic. If an adequate response is not achieved, adding an anticholinergic, or amantadine (a weak dopamine...

Results in the VTA and Substantia Nigra

Using Western blotting, Nestler and colleagues found increased GluRl levels in the VTA of rats killed 16-18 h after discontinuation of repeated cocaine, morphine, ethanol, or stress paradigms (12,13). Increased GluR1 was not observed in the substantia nigra after repeated cocaine or morphine treatment (12). The substantia nigra was not examined in stress studies (12), but after repeated ethanol administration, there was a greater increase in GluR1 in the substantia nigra than in the VTA (13). Repeated cocaine also increased NR1 in VTA but had no effect on GluR2, NR2A B, or GluR6 7 (12). Churchill et al. (14) treated rats with saline or cocaine for 7 d (15 mg kg on d 1 and 7, 30 mg kg on d 2-6), measuring locomotor activity after the first and last injections those rats that showed > 20 increase in locomotor activity were defined as sensitized. Then, protein levels of glutamate receptor subunits were determined by Western blotting 24 h or 3 wk after daily injections were...

Antiparkinsonian Drugs

Parkinson's disease is a degenerative, slowly progressing illness of the CNS characterized by bradykinesia, shuffling gait, postural instability, tremor, and loss of automatic movement, which is associated with damaged basal ganglions. The etiology of this illness is not known. The most likely cause of the aforementioned motor problems could be a lack of dopamine, which has an inhibitory effect on the regulatory function of the spinal cord. On the other hand, cholinergic neurons act in regulating the extrapyramidal system. For more than a century, treatment of Parkinsonism was based on use of central anticholinergic substances. Up until recent times, various alkaloid drugs of belladonna, which have a characteristic cholinergic action (i.e. the ability to reduce sensitivity to acetylcholine, a neurotransmitter of cholinergic synapses) have been used for Parkinsonism. Currently, a sufficient quantity of facts have been established that support the idea that Parkinsonism is a consequence...

Levodopa

The question of whether starting a benzodiazepine in patients taking levodopa is followed by a faster increase in antiparkinsonian drug requirements has been studied using drug dispensing data for all the residents in six Dutch cities (152). All were 55 years old or older and had used levodopa for at least 360 days. There were 45 benzodiazepine starters and 169 controls. Antiparkinsonian drug doses increased faster in the benzodiazepine group, but the difference was not significant (RR 1.44 95 CI 0.89, 2.59).

Substantia Nigra

A striking feature of CB1 receptor expression is the high number of CB1 receptors found in the substantia nigra (Fig. 9A and 9B). As mentioned above, these receptors Fig.9A-C. CBi receptor expression in midbrain structures detected by an antibodyagainsttheamino terminus of rat CBi. A CBi immunostaining is very strong in substantia nigra pars reticulata (SNR) but virtually absent in substantia nigra parscompacta (SNC). B Higher magnification view of SNR. When the plane of the section is perpendicular to the striatonigral pathway, immunoreactivity is apparent as puncta, from the high levels ofaxonal CBi expression. C In caudal periaqueductal gray, CBi-positive fibers (arrows) and intensely labeled neuropil (arrowheads) are apparent. Aq, lumen of the aqueduct. Scale bars 500 pm (A), 50 pm (B), and 20 pm (C). (Modified from a photomicrograph provided by Kang Tsou) Fig.9A-C. CBi receptor expression in midbrain structures detected by an antibodyagainsttheamino terminus of rat CBi. A CBi...

Parkinsons Disease

Parkinson's disease is a progressive disorder involving the degeneration of dopamine-producing neurons in the substantia nigra, resulting in symptoms such as resting tremor, bradykinesia, rigidity, gait disturbance, and postural instability 13 . Tyrosine hydrolase (TH) is critical to the formation of L-dopa, and thus dopamine, and decreases in its activity occur in animal models of Parkinson's disease. In a murine model of Parkinson's disease, oral administration of EGCG inhibited damage to dopaminergic neurons, preserving numbers of TH-positive cells and TH activity in the striatum and preventing loss of dopamine and its metabolites 13 . Dopamine is a substrate of catechol-O-methyltransferase. Since EGCG inhibits this enzyme, it may additionally increase dopamine levels in synapses by this mechanism 14 . Reactive nitrogen species (RNSs) generated by neuronal nitric oxide synthase (nNOS) are involved in Parkinson's disease pathogenesis since enzyme inhibition A number of polyphenols,...

Parkinson drugs

Apart from the more widely used ergotamine derivatives, bromocriptine and cabergoline, there is little experience regarding the use of Parkinson drugs in breastfeeding. There is insufficient experience on the use of amantadine, benserazide, benzatropine, biperiden, bor-naprine, budipin, carbidopa, n-dihydroergocryptine, entacapon, lev-odopa, lisurid, metixen, pergolide, pridinol, pramipexol, procyclidine, ropinirol, tiaprid, trihexyphenidyl, and the monoaminooxydase-B (MAO-B) inhibitors Selegilin and rasagilin during breastfeeding. There has not been, as yet, any noteworthy toxic risk indicated for the infant as a result of the occasional combination of neuroleptics or haloperidol with biperiden.

Diagnoses in Psychiatric Disorders

Psychiatrists have been debating the etiology of PD throughout this century. The psychoanalytic viewpoint became popular with Freud's investigations and theories at the turn of the century. The analysts believed that panic attacks were a manifestation of unconscious conflicted feelings such as the drive for sex and the internal prohibitions against it. They believed that people with PD could be helped In the last twenty years it has been demonstrated that PD is more frequent in people who have had stressful experiences. For example, people who have been the victims of sexual abuse have a higher rate of PD, as well as other forms of anxiety and depression. People who undergo life-threatening experiences as adults, such as extreme weather events, disasters, or combat in war also experience a higher rate of PD. Children whose parents die, divorce, or abuse alcohol have a higher rate of PD and anxiety as adults. Psychiatrists and therapists who focus on stressful life experiences often...

Role of the VTA in Behavioral Sensitization

Recently, we have shown that AMPA receptor supersensitivity can also be demonstrated in microdialysis experiments, by monitoring the ability of intra-VTA AMPA to activate VTA DA neurons and thus increase DA levels in the ipsilateral NAc. Using dual-probe microdialysis, we found that intra-VTA administration of a low dose of AMPA produced significantly greater DA efflux in the NAc of amphetamine-treated rats (11). This augmented response was transient (present 3 but not 10-14 d after the last injection) and specific for AMPA, as intra-VTA NMDA administration produced a trend toward increased NAc DA levels that did not differ between groups. Thus, both microdialysis and in vivo electrophysiological data suggest an enhancement of AMPA receptor transmission onto VTA DA neurons during the early phase of drug withdrawal. An increase in glutamate receptor expression would provide a simple explanation for such findings. For this and other reasons, a number of studies have...

The Chemical Imbalance Theory

For example, other findings supported the dopamine hypothesis of schizophrenia. Amphetamines produced an excess of dopamine and also led to psychotic symptoms. Dopa, a drug used in Parkinson's disease, is converted to dopamine in the body and can also produce hallucinations and delusions. Other drugs with widely different chemical structures that also blocked dopamine were as effective as chlorpromazine.

Regulation of Adult Neurogenesis and Gliogenesis by Abused Substances

In contrast to decreased cell division after dopamine stimulation, dopamine depletion increases progenitor proliferation. Reduction of Dj 2 receptor tone with the antagonist haloperidol increases dentate granule cell proliferation in the gerbil hippocampus (38). Similarly, a single or repeated injection of the neurotoxin (MPTP), known to selectively damage dopaminergic terminals in the dorsal striatum and cell bodies in the substantia nigra, causes a robust proliferative response in striatal and nigral regions of adult mice (14,39). Nearly all newly generated cells in the striatum, but not in the nigra, rapidly differentiate into astrocytes, whereas no neurogenesis is seen in the two affected areas even 60 d after cell birth (14). Strong striatal astrogenesis after dopaminergic insult implies the participation of astroglia in dopamine repair. The unexpected lack of striatal and nigral neurogenesis after a long period of survival may be related to the extent of MPTP damage to midbrain...

Functional Roles of Adult Neural Progenitor Cells

Under pathophysiological conditions, inducible cytogenesis can play dual roles in a given pathophysiological process. First, cytogenesis can be provoked to process aberrant functions. For example, the neurons that are formed through normal ongoing neurogenesis do not send processes to the CA3 region of the hippocampus (44,45). However, epilepsy-induced neurogenesis sends axon collaterals back onto the dentate gyrus that forms recurrent collaterals contributing to enhanced local activity for epilepsy (44). Second and more significantly, cytogenesis can be stimulated to repair (rescue or compensate) for cell loss in chronic neurodegenerative diseases, such as Parkinson's disease. In this case, repopulation of missing cells by increased endogenous neurogenesis in the diseased site could be an ideal self-repair. The newborn cells after

General adverse effects

Drugs with primarily anticholinergic effects used mainly in Parkinson's disease Of the drugs in this class used largely in parkinsonism, the tertiary amines related to diphenhydramine have some antihistaminic activity, as one would expect some of these drugs are also related to atropine. The derivatives of trihexyphenidyl (benzhexol) are also pharmacologically closely similar for example, they have some excitatory effects if given in sufficient doses.

Psychological psychiatric

Anticholinergic drugs can cause vivid and sometimes exotic hallucinations and this has led to their misuse. Plants containing atropine and related substances were used in witches' brews in the Middle Ages to conjure up the devil, but even synthetic tertiary amines given in eye-drops and depot plasters containing atropine (SEDA-13, 114) have caused hallucinations. Postoperative confusion in elderly patients has been clearly correlated with drugs that have anticholinergic properties (SEDA-13, 114), and the use of anticholiner-gic drugs for the treatment of Parkinson's disease has long been associated with neuropsychiatric adverse effects. Cyclopentolate is a short-acting cycloplegic with a rapid onset (and considerable intensity) of action, which particularly in children has been reported to cause hallucinations and psychotic episodes (2). It has been suggested that a partial structural affinity of the side-chain to some hallucinogens aggravates the problems associated with...

Contraindications

The aminoglycosides are contraindicated in patients with hypersensitivity to aminoglycosides. The amino-glycosides should not be given to patients requiring long-term therapy because of the potential for ototoxic-ity and nephrotoxicity. One exception is the use of streptomycin for long-term management of tuberculosis. These drugs are contraindicated in patients with preexisting hearing loss, myasthenia gravis, parkinson-ism, and during lactation or pregnancy. Neomycin, amikacin, gentamicin, kanamycin, netilmicin, and tobramycin are Pregnancy Category D drugs the remainder are Category C.

General Information

Apomorphine, a very potent non-selective dopamine agonist, which acts on both Di and D2 receptors, has been used with some success in Parkinson's disease, particularly in patients with severe long-term adverse effects of levodopa. Because of first-pass metabolism it has to be used subcutaneously, sublingually, or intranasally. Its adverse effects resemble those of levodopa. Persistent nodules cause major problems in about 10 of patients after 3 or more years. One solution is to give the drug intravenously using an indwelling cannula. Six patients, who had responded well to subcutaneous apo-morphine before nodules developed, had such cannulae inserted (1). The apomorphine was given at a mean rate of 9.0 mg hour to a total mean dose of 257 mg day, very similar to the subcutaneous dosage. The intravenous therapy virtually abolished off'' periods, reduced oral antiparkinsonian drug dosages by 59 , and produced a marked (but unquantified) reduction in dyskinesias and an improved quality of...

Role of Inflammation in Neurodegenerative Disorders

Previously, the brain has been considered an immune privileged environment partly owing to the existence of the brain-blood barrier. However, inflammatory responses in the brain have been increasingly associated with pathogenesis of several degenerative neurological disorders including Parkinson's disease (PD), Alzheimer's disease, AIDS dementia, and amyotrophic lateral sclerosis (ALS, 32-34).

Physiological Receptor Regulation and Disease

CB1 receptors are drastically reduced in substantia nigra and lateral globus pal-lidus in Huntington's disease (Glass et al. 1993 Richfield and Herkenham 1994). The CB1 receptor agonist nabilone significantly reduced L-dopa-induced dyskine-sia in an animal model of Parkinson's disease as well as in Parkinson's patients (Sieradzan et al. 2001 Fox et al. 2002). CB1 receptor knockout mice displayed increased neuropeptide expression in striatal output pathways and were severely hypoactive in an exploratory test, although their motor coordination was unaltered, suggesting these receptors may be important for initiation of movement (Steiner et al. 1998).

Microglial Activation Part of the Etiology of PD

The hallmark of PD is the progressive degeneration of the nigrostriatal dopaminergic system involving the loss of dopaminergic neurons in the substantia nigra and their fibers in the striatum. Sufficient damage to the dopaminergic pathways, over time, eventually leads to disorders in movement regulation. It has now been recognized that microglial activation is involved in the neurodegenerative process of PD (55-58). Furthermore, epidemiological studies appear to suggest that microglial activation, as a consequence of exposure to infectious agents and environmental toxins and occurrence of early-life traumatic brain injuries, may play a role in the early stage of the pathogenetic process of PD (59-64). Some of the important clues in favor of the hypothesis that microglial activation will result in dopaminergic neurodegeneration have come from experiments with neuron-glia cultures stimulated with the bacterial endotoxin LPS. Indeed, LPS neurotoxicity requires the presence of glia, and...

Bi Cannabinoid Receptors Participate in the Control of Locomotion

The locomotor effects of THC are thought to be mediated in part by CBi receptors in the basal ganglia (Rodriguez de Fonseca et al. 1998). In the striatum, CB1 receptors display a distinct medial-to-lateral and dorsal-to-rostral distribution, with the highest receptor densities in the lateral part of the middle striatum (Steiner et al. 1999). The striatum has two distinct output pathways, one to the substantia nigra and one to the globus pallidus (Gerfen 1992, 1993). The primary neurotransmitter of both pathways is y-aminobutyric acid (GABA), but they have different neuropeptide co-transmitters. Striato-pallidal neurons contain enkephalins, whilst striato-nigral neurons express substance P and dynorphin (Steiner and Gerfen 1998). Steiner and colleagues have shown that dynorphin and substance P mRNA levels were significantly elevated in the medio-lateral striatum of CB1 knockout mice, which also contained the highest CB1 receptor densities (Steiner et al. 1999). Enkephalin expression...

Promoting an Optimal Response to Therapy

The nurse administers this drug for the prevention or treatment of respiratory tract illness caused by influenza A virus. Some patients are prescribed this drug to manage extrapyramidal effects caused by drugs used to treat Parkinsonism (See Chaps. 29 and 32). The nurse should protect the capsules from moisture to prevent deterioration. When the drug is administered for symptoms of influenza, it is important to start therapy within 24 to 48 hours after symptoms begin.

Organs and Systems Nervous system

During a controlled clinical trial of intraventricular bethanecol in patients with Alzheimer's disease, reversible drug-induced parkinsonism was observed in one patient (SEDA-15, 5). The frequent co-existence of Alzheimer's disease and Parkinson's disease presents potential problems for therapy and adverse effects when the cholinergic system is manipulated.

Herbal Alert Passion Flower

The term passion flower is used to denote many of the approximately 400 species of the herb. Passion flower has been used in medicine to treat pain, anxiety, and insomnia. Some herbalists use the herb to treat symptoms of parkinson-ism. Passion flower is often used in combination with other herbs, such a valerian, chamomile, and hops, for promoting relaxation, rest, and sleep. Although no adverse reactions have been reported, large doses may cause CNS depression. The use of passion flower is contraindicated in pregnancy and in patients taking the monoamine oxidase inhibitors (MAOIs). Passion flower contains coumarin, and the risk of bleeding may be increased when used in patients taking warfarin and passion flower.

IDB for analytical methods

The papers describing analytical methods for drugs and poisons in human specimens were searched by the Medline. The papers were selected by the eleven scientists, who were the members of a joint study project supported by a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Science and Culture of Japan. Chemical compounds listed were natural toxins, organic solvent toxic gases, anaesthetics (local anaesthetics, inhalation anaesthetics, intravenous-injection anaesthetics and muscle relaxants), neuroleptics anti-depressants (psychopharmaceuticals, antiepileptics and antiparkinsonian drugs), amphetamines narcotics, hypnotics tranquilizers, pesticide and others. On the basis of extensive informations collected from 900 papers, the most suitable analytical method can be rapidly found by searching with a combination of a specimen name, an analytical method and a chemical name (target) to be analyzed. Each specimen (urine, blood, authentics, serum plasma, tissues or...

Research Models of PD

Disturbance Gradual loss of TH-immunoreactive, dopaminergic neurons in the substantia nigra pars compacta Reduced level of striatal terminal DA, its metabolites and uptake transporter clinically responsive to DA prodrug, l-DOPA model should exhibit as many of the phenotypic features of the disease as possible. These features should include (1) persistent depletion of close to 80 of the striatal DA and its metabolites, (2) pronounced reduction of striatal sites for DA uptake, (3) significant (near 50 ) loss of substantia nigral cells, (4) marked deficit in the animal's motor performance, and (5) formation and accumulation of inclusion bodies in nigral neurons. There are several existing experimental models of PD, which have been developed and characterized for specific purposes and used in studies that examine certain symptomatology of PD or for determining the underlying mechanisms. These models include the unilateral 6-hydroxydopamine lesion rat produced by the chemical-induced...

Contraindications Precautions And Interactions

The centrally acting antiadrenergic drugs are contraindi-cated in active hepatic disease such as acute hepatitis or active cirrhosis and in patients with a history of hyper-sensitivity to these drugs. The centrally acting antia-drenergic drugs are used cautiously in patients with a history of liver disease, renal function impairment, and during pregnancy and lactation. If methyldopa is administered with anesthetics, there is an increased effect of the anesthetic. The centrally acting antiadrenergic drugs increase the activity of sympathomimetics, possibly causing hypertension. Clonidine decreases the effectiveness of levodopa. When clonidine is administered with P-adrenergic blocking drugs, a potentially life-threatening hypertensive episode may occur.

Contraindications adverse effects precautions

- Do not administer to children under 3 years to patients suffering from Parkinson's disease. extrapyramidal syndrome (requiring administration of anticholinergic antiparkinsonian drugs), early or tardive dyskinesia in case of prolonged treatment (may be exacerbated by antiparkinsonian drugs) - Do not combine with levodopa.

Bipolar Disorder Syndromes and Their Treatment

Thyroid disorders, anemia, cancer, Alzheimer's disease, and Epstein-Barr virus infections can lead to depression. Many rare medical conditions can also cause depression, so you should consider a physical examination and appropriate laboratory work if your symptoms do not quickly improve with whatever treatment you choose. Obviously you need treatment for any medical disorder you may have. Ideally, your depression will resolve when you obtain treatment for your medical problem, although you may require treatment with antidepressants indefinitely if you have Alzheimer's or Parkinson's disease. Many prescription and recreational drugs can also contribute to depression. Coordinate the treatment for your medical problems with your primary care doctor and psychiatrist if you take medication that can cause depression. Try to stop recreational drugs that can worsen your mood once the euphoria has worn off.

The Dual Action of CRH Activator of the HPA System and Neurotransmitter

Parvocellular neurons of the hypothalamic PVN are the major source of CRH within the central nervous system. These parvocellular neurons project via the external zone of the median eminence to the anterior pituitary where CRH is released into hypophyseal portal blood vessels to activate the HPA system by triggering ACTH release from pituitary corticotropes through activation of CRH 1 receptors (CRHR1). Furthermore, CRH acts as a neurotransmitter in several brain areas. High densities of CRH-like immunoreactivity have been observed throughout the neocortex (particularly in the prefrontal and cingulate cortices), the central nucleus of the amygdala (Van Bockstaele et al. 1998), the BNST, the hippocampus, the nucleus accumbens, some thalamic nuclei, substantia nigra, raphe nuclei, locus coeruleus, periaqueductal gray, and cerebellum (Swanson et al. 1983).

Syndromes of Depression and Their Treatment

Thyroid disorders, anemia, cancer, Alzheimer's disease, and Epstein-Barr virus infections can lead to depression, so you should consider a physical examination and appropriate laboratory work before starting treatment. Ideally, your depression will resolve when you obtain treatment for your medical problem, although you may require treatment with antidepressants indefinitely if you have Alzheimer's or Parkinson's disease.

AEA and Vanilloid VR1 Receptors

VR1 is also expressed in several brain areas of primates and rodents, including the hippocampus, striatum, hypothalamus, substantia nigra compacta, and locus coeruleus (Cortright et al., 2001 Hayes et al., 2000 Mezey et al., 2000). This finding suggested the existence of endogenous ligands for vanilloid receptors (Kwak et al., 1998), as the function of VR1 as a nociceptor in the brain is rather unlikely, and instead a possible role in ligand-activated neurotransmitter modulation could be proposed (Szallasi and Di Marzo, 2000). Indeed, recent investigations have shown that VR1 activation in the brain leads to glutamate release in the locus coeruleus and substantia nigra (Marinelli et al., 2002, 2003), as well as in the periaqueductal gray (Palazzo et al., 2002 McGaraughty et al., 2003).

Preadministration Assessment

Because of memory impairment and alterations in thinking in some patients with parkinsonism, a history obtained from the patient may be unreliable. When necessary, the nurse obtains the health history from a family member. Important data to include is information regarding the symptoms of the disorder, the length of

Receptormediated Modulation Of Ca2Dependent Transmitter Release

Electrophysiological studies in the CNS have exposed the presence of an a2-autoreceptor with a different function. These are found on the cell bodies of noradrenergic neurons in the nucleus locus coeruleus of the brainstem. When activated, they depress the firing rate of noradrenergic neurons in the nucleus. This means that changes in the concentration of noradrenaline in the medium bathing these somatodendritic a2-autoreceptors will modify the firing rate of central noradrenergic neurons. Other types of neurons have equivalent autoreceptors. Examples are 5-HT1A receptors on serotonergic neurons in the Raphe nuclei and D2 3-autoreceptors on central dopaminergic neurons in the ventral tegmental area and substantia nigra.

Drugs Affecting The Dopaminergic Systems Of The Brain

In medical practice, four types of dopaminergic drugs are used, and they can be characterized as dopamine precursors (levodopa), dopamine-releasing drugs (amantadine), dopamine receptor agonists (bromocriptine), and dopamine inactivation inhibitors (selegiline). doses than levodopa. Finally, the fourth group of drugs, which is represented by selegiline, are inhibitors of a variety of monoaminooxidases (MAO-B), enzymes that ensure the intercellular inactivation of dopamine in presynaptic nerve endings. Levodopa Levodopa, (-)-3-(3,4-dihydroxyphenyl)-l-alanine (10.1.1), is a levorotatory isomer of dioxyphenylalanine used as a precursor of dopamine. There are a few ways of obtaining levodopa using a semisynthetic approach, which consists of the microbiological hydroxylation of l-tyrosine (10.1.1) 1,2 , as well as implementing a purely synthetic approach.

Drugs Are Not Always What They Appear To Be

In 1982, a group of people in San Francisco began taking a designer drug that was marketed as a better than heroin substitute. Physicians began to see a number of young patients with Parkinson's disease symptoms. By the time they figured out that the common thread was use of this drug, many young people were left either severely paralyzed or even dead. The results were irreversible. The drug, called China White, had a substance in it called MPTP, which is highly neurotoxic to dopamine neurons and brings on the Parkinson's disease symptoms. This chemical also has properties that make it very similar to MDMA. Very quickly sometimes within days young, active people looked like 70- or 80-year-olds with Parkinson's, and, sadly, the effects and paralysis were permanent.

Extrapyramidal Effects

Among the most significant adverse reactions associated with the antipsychotic drugs are the extrapyramidal effects. The term extrapyramidal effects refers to a group of adverse reactions occurring on the extrapyramidal portion of the nervous system as a result of antipsy-chotic drugs. This part of the nervous system affects body posture and promotes smooth and uninterrupted movement of various muscle groups. Antipsychotics disturb the function of the extrapyramidal portion of the nervous system, causing abnormal muscle movement. Extrapyramidal effects include Parkinson-like symptoms (see Chap. 29), akathisia, and dystonia (see Display 32-1). Extrapyramidal effects usually diminish with a reduction in the dosage of the antipsychotic drug. The primary health care provider may also prescribe an antiparkinsonism drug, such as benztropine (see Chap. 29) to reduce the incidence of Parkinson-like symptoms.

Sleep disorders with dopamine receptor agonists

The pooled relative risk of somnolence was 4.98 compared with placebo there was a nonsignificant trend for greater somnolence with ropinirole, but the confidence intervals were much wider than with pramipexole. In the other studies levodopa alone was compared with lev-odopa plus the newer drugs the relative risk was 2.06 compared with levodopa alone. It must be borne in mind that somnolence and sleep attacks may be separate phenomena, although this is controversial. The whole field of sleep disorders in Parkinson's disease has been reviewed in a consecutive series of 320 patients from Houston, with analysable data from 303 (sex distribution unknown) (37C). The mean age was 67 years and the mean duration of the disease was 9.1 years. All the patients completed the Epworth Sleepiness Scale and answered specific questions about falling asleep while driving and about the restless legs syndrome. The mean sleepiness score was 11.1, values greater than 10 being regarded as abnormal. As one...

Monoamine Oxidase Inhibitors

As with the dietary proscriptions, any medication that increases tyramine can precipitate a hypertensive crisis such medications include numerous over-the-counter preparations for coughs, colds, and allergies. The same rule applies to sympathomimetic drugs (such as epinephrine and amphetamines or cocaine) and dopaminergic drugs such as anti-parkinsonian medications.

Long Term Serotonergic Changes with MDMA

Another method of assessing loss of nerve terminals involves measuring the vesicular monoamine transporter type II (VMAT2). This is a protein on the storage compartments, or vesicles, inside the nerve's axon terminals. Because the amount of VMAT2 does not appear to be adjusted in response to drug exposure (Vander Borght et al. 1995), it is sometimes used as an indirect measure of nerve terminals in research on such neurodegenerative disorders as Parkinson's disease. In other words, diminished levels ofVMAT2 would suggest that nerve terminals and axons have been lost. Neurotoxic regimens ofMDMA (Ricaurte et al. 2000) or methamphetamine (Frey et al. 1997) have been shown to decrease VMAT2. Therefore, at least some neurotoxic regimens ofMDMA are associated with structural changes to cells.

Behavioral measures of movement turning

When a treatment that affects movement is applied bilaterally in the brain, the result obtained is increase or decrease in locomotor activity depending on the effect of the treatment. However, when the treatment is applied unilaterally (only in one side of the brain) the resulting increase in movement will be expressed as contralateral turning. The imbalance created between the two sides of the brain, higher motor output in the treated versus the untreated side, makes the animal turn towards the opposite side (contralateral) to the manipulation. Conversely, when the treatment administered unilaterally decreases movement, this will be expressed as ipsilateral turning. That is, the animal will turn towards the same (ipsi) side on which the manipulation has taken place. Turning correlates well with the cellular activation or inhibition of basal ganglia nuclei and for that reason has been extensively used in the study of basal ganglia physiology. As mentioned before, the cells in the...

Distribution of Cannabinoid Receptors within the CNS

Results obtained in autoradiographic studies with rat brain and spinal cord indicate that the distribution pattern of specific binding sites for cannabinoids within the CNS is heterogeneous, unlike that for any other known receptor type and consistent with the known ability of cannabinoid receptor agonists to impair cognition and memory, to alter motor function and movement and to relieve pain (Herkenham et al., 1990, 1991b). The highest concentrations of cannabinoid binding sites in rat brain (4-6.4pmol mg protein) are in the substantia nigra pars reticulata, the entopeduncular nucleus, the globus pallidus, the lateral caudate-putamen, the ependymal and subependymal zones at the centre of the olfactory bulb and the molecular layer of the cerebellum. Other areas of rat brain quite rich in cannabinoid binding sites (2-4pmol mg protein) include the hippocampus, cerebral cortex, intrabulbar anterior commissure, nucleus accumbens and septum. Among the areas of rat brain less densely...

Superior colliculus

The output of the substantia nigra reticulata to the superior colliculus is directed towards the site of origin of the crossed descending output system (Williams and Faull, 1988). This output system has its origin in the lateral aspect of the intermediate layers (Redgrave et al., 1986), a site where most, if not all, motor systems in the brain converge. Movement induced from this site acquires biologically relevant significance since this pathway mediates approach pursuit responses that have been interpreted as predatory behavior (Dean et al., 1989). Unilateral electrical or chemical stimulation of the lateral intermediate layers of the superior colliculus induces contralateral turning (Dean et al., 1986 Speller and Wetsby, 1996). The substantia nigra reticulata is tonically inhibiting this area and removal of this inhibition produces movement (Dean et al., 1989 Williams and Faull, 1988).

In Situ Hybridization

Cloning the CB1 receptor (Matsuda et al. 1990) made it possible to identify CBi synthesizing cells by in situ hybridization (Mailleux and Vanderhaeghen 1992 Matsuda et al. 1993). Correlating the results of the autoradiographic and in situ hybridization studies reveals several common themes of the CB1 system. The first was that in some brain regions, particularly forebrain (for example, cortex, amygdala, and hippocampus), CB1 receptors are expressed at very high levels in a very restricted set of neurons. These neurons then project widely, resulting in a dense network of CB1-positive axons. The second was that CB1 receptors were primarily found on axons and terminals. For example, high levels of CB1 are present in the striatonigral pathway and substantia nigra, yet nigral neurons express no CB1 mRNA. These findings strongly suggest CB1 receptorsare synthesizedinthe striatal projectionneurons(medium spinyneurons which containmoderatelevelsofCB1 mRNA) and are trafficked to their axons....

Treatment Options for Psychotic Disorders

Diphenhydramine (Benadryl) Antiparkinsonian agents Amantadine (Symmetrel) Benztropine (Cogentin) Biperiden (Akineton) Procyclidine (Kemadrin) Trihexyphenidyl (Artane) Side-Effect Medications Antipsychotics cause six separate muscular side effects (see chapter 19 for a more detailed discussion of each one). Atypical antipsychotics tend to cause them less frequently. Akathisia is an inner restlessness that is intensely uncomfortable. It is relieved somewhat by walking, but the incessant pacing can be distressing as well. Dystonia is a muscle spasm, often of the neck, jaw, mouth, and eyes, which usually occurs when antipsychotics are first begun. Sometimes dystonia occurs in the limbs instead. Pseudoparkinsonism is a constellation of several symptoms that mimic Parkinson's disease akinesia, a lack of muscle movements, rigidity, and tremor. Tardive dyskinesia is a form of regular, rhythmical, involuntary muscle movements, usually of the mouth, tongue, hands and toes. It is unsightly, but...

Subcortical CB1 Receptors 251

The subcortical structures with the highest level of CB1 receptor expression are the basal ganglia. In fact, the highest levels of CB1 receptors in the brain detected in autoradiography studies were found in the substantia nigra (Herkenham et al. 1991). In situ hybridization studies demonstrated that many striatal medium spiny neurons express CB1 receptors (Matsuda et al. 1993 Julian et al. 2003). In contrast, adult pallidal and nigral neurons contain little or no CB1 mRNA (Matsuda et al. 1993 Julian et al. 2003). Rather, CB1 receptors in the globus pallidus and substantia nigra are localized to the axons traversing or terminating in these structures (Tsou et al. 1998a Egertova and Elphick 2000). Thus, the high levels of pallidal and nigral CB1 receptor binding and protein observed in autoradiographic and immunocytochemical studies mostly arise from GABAergic neurons projecting from the caudate putamen. Figure 8 illustrates the intense immunostaining of CB1 receptors that begins at...

Release And Turnover Shortterm control autoreceptors

Autoreceptors are also found on the cell bodies of DA neurons, in the substantia nigra (A9) and ventral tegmentum (A10) where their activation leads to a reduction in cell firing. To what extent they are stimulated by endogenous DA is uncertain but systemic DA agonists certainly activate them to inhibit the neuron, and since DA antagonists alone can increase the firing of DA neurons that implies that the autoreceptors could be tonically active. This can have important implications, as we shall see later when considering the mode of action of DA antagonists in the treatment of schizophrenia (Chapter 17).

Dopaminergic Systems in the Central Nervous System

The dopaminergic innervation of the brain deviates from that of the other catecholaminergic systems. It is less uniform and more patchy, suggesting localization-related functions. In one of the first reviews on this topic, Moore and Bloom41 list seven dopaminergic systems in the brain nigrostriatal, mesocortical, tubero-hypophysial, retinal, incerto-hypothalamic, periventricular and olfactory bulb. The mesocortical system of this list also comprises the previously mentioned mesolimbic one. In view of the scope of this chapter, DA receptors and learning and memory, these two systems will be the focus of interest. Together with the nigrostriatal system they have been described as the meso-telencephalic system41 with the cells of origin located in the mesencephalon. For the nigrostriatal system the dopaminergic cells are found mainly in the substantia nigra (pars compacta), for the mesocortical and mesolimbic systems mainly in the ventral tegmental area. The latter two systems are...

Possible Significance of Cognitive Differences and MDMA Neurotoxicity

Studies of individual variation in symptoms associated with neurodegenerative disorders have led to two relevant concepts. First, there is a threshold of damage that must be exceeded in some brain systems before symptoms develop. This has been investigated primarily with reference to dopaminergic cell loss and Parkinson's disease (Calne et al. 1985 Brownell et al. 1999 Di Monte et al. 2000). There are fewer data on the serotonergic These are serious and legitimate concerns, and there is insufficient research to address them adequately. On the other hand, there is no direct evidence to support these concerns. Neurotoxic phenethylamines have been self-administered by humans for more than sixty years. In this time, no evidence has been published suggesting that methamphetamine or amphetamine increases the risk of Parkinson's disease, despite the fact that they damage dopaminergic axons. In contrast, the link between Parkinson's disease and MPTP, a dopaminergic neurotoxin, was discovered...

Synaptic Effects Of Exogenous Cannabinoid Ligands

Cannabinoid agonists also inhibit glutamate release throughout the CNS. To date, this effect has been demonstrated in the hippocampus (Shen et al., 1996 Sullivan, 1999), the dorsolateral and ventral striatum (Gerdeman and Lovinger, 2001 Robbe et al., 2001), the cerebellum (Levenes et al., 1998 Takahashi and Linden, 2000), the substantia nigra (Szabo et al., 2000), the prefrontal cortex (Auclair et al., 2000), and the spinal cord (Morisset and Urban, 2001). However, these effects have been more variable than those reported for GABA release in several respects. Whereas in some studies the cannabinoid-mediated inhibition of glutamate release is linked to the inhibition of VDCCs (Shen and Thayer, 1998 Sullivan, 1999), others have found that the inhibitory effects of WIN55212-2 on glutamate release are mediated by activation of a 4-aminopyridine-sensitive K+ channel (Robbe et al., 2001). Curiously, our own studies in the shell of the nucleus accumbens found no evidence for presynaptic...

Effects on later development

NIDA also reports several severe long-term effects on brain development in adulthood. For example, methamphetamine appears to damage brain cells in a way that can result in symptoms similar to those of Parkinson's disease, a disorder marked by extreme, uncontrollable trembling of the limbs. According to NIDA, high doses of methamphetamine can also damage nerve cell endings, and the ability of these cells to recover appears to be limited.

Anatomical Evidence for the Presence of CBi Cannabinoid Receptors in Axon Terminals

In the cerebellum, CB1 receptors in terminals of basket cells can be seen at the light microscopic level (Tsou et al. 1998 Diana et al. 2002). Electron microscopical studies have indicated that a great portion of CB1 receptors in the caudate-putamen (Rodriguez et al. 2001), hippocampus (Katona et al. 1999, 2000 Hajos et al. 2000) and amygdala (Katona et al. 2001) is in axon terminals. Comparison of the site of CB1 receptor synthesis (which was determined by in situ hybridisation) with the distribution of receptor protein (which was determined with receptor autoradiography and immunohistochemistry) indicates localisation of CB1 receptors in terminals of parallel fibres in the cerebellum and in terminals of striatonigral neurons in the substantia nigra pars reticulata (compare, for example, Mailleux and Vanderhaeghen 1992 Matsuda et al. 1993 Tsou et al. 1998). The changes in the CB1 receptor distribution pattern during neurodegeneration accompanying Hunting-ton's disease and...

Activitystateinfluence

Figure 7.8 Dopamine and motor function. When nigrostriatal dopamine activity is normal so is motor function. Any reduction in this DA activity, as in Parkinson's disease, results in reduced motor activity, i.e. akinesia. By contrast, too much DA activity, as in Huntington's Chorea, produces abnormal motor function, i.e. dyskinesia. The latter may be controlled by neuroleptic drugs (DA antagonists) but they can swing the balance in DA activity sufficiently to produce akinesia (Parkinsonism). DA agonists (and levodopa) may overcome akinesia but can induce DA overactivity and dyskinesia (peak dose effect) (see Chapter 15) Figure 7.8 Dopamine and motor function. When nigrostriatal dopamine activity is normal so is motor function. Any reduction in this DA activity, as in Parkinson's disease, results in reduced motor activity, i.e. akinesia. By contrast, too much DA activity, as in Huntington's Chorea, produces abnormal motor function, i.e. dyskinesia. The latter may be controlled by...

Dopamine Receptors Function And Synergism

With the discovery of five distinct DA receptors within two major families, one might hope that the effects of the different DA pathways would be mediated through different receptors. Unfortunately this is not the case. As indicated above, it is generally the D2 receptor that is important. Thus only D2 antagonists have anti-emetic activity and only D2 agonists, like bromocriptine, reduce plasma prolactin levels. In schizophrenia it is again the D2 antagonists that are effective, although D1 and D4 receptors have been implicated (see Chapter 16) while in Parkinson's disease the symptoms can be alleviated by D2 but not D1 agonists if they are given alone. In this condition, however, some D1 stimulation may augment the effect of the D2 agonists (Chapter 14), suggesting a synergism between the two receptors. This synergism has been observed in both electophysiological studies on striatal neuron activity and some animal behaviours. Figure 7.9 Synergism between dopamine Dj and D2 receptor...

Fast Excitatory Neurotransmission

Inhibition was seen in nuclei belonging to the extrapyramidal motor control system caudate-putamen, globus pallidus and substantia nigra pars reticulata (Fig. 1 shows an example of presynaptic inhibition of glutamatergic neurotransmission in the substantia nigra pars reticulata see Fig. 6 for an overview of cannabinoid effects on neurotransmission in the extrapyramidal motor control system). Inhibition of neurotransmission was also observed in the ventral tegmental area, hippocampus and the nucleus accumbens these regions are parts of the limbic system. Inhibition of the excitatory synaptic transmission in the hippocampus could contribute to the anticonvulsive effect of cannabinoids. Purkinje cells in the cerebellar cortex receive excitatory inputs from parallel fibres and climbing fibres both kinds of excitatory inputs are inhibited by activated CB1 receptors (see Fig. 7 for an overview of cannabinoid effects on neurotransmission in the cerebel-lar cortex). Moreover, cannabinoids...

Metabolites of amphetamine

The effects of cerebral injections of methamphetamine on striatal TPH activity were also investigated (figure 1). In an anesthetized rat, systemically administered methamphetamine (10 mg kg) decreased striatal TPH activity. However, bilateral injections of methamphetamine into the neostriatum (100 g) failed to decrease striatal TPH activity 3 hours after treatment. To determine whether multiple areas of the brain are involved in methamphetamine-induced changes in striatal TPH, microinjections of methamphetamine were administered into the substantia nigra or lateral midbrain and into the striatum. Three hours after treatment, injections of methamphetamine into the striatum (100 g) and the substantia nigra (25 g) or the lateral midbrain (area of B9 serotonergic cell bodies) (50 g) did not reduce TPH activity in the neostriatum.

Short Term Retrograde Endocannabinoid Signalling

Wilson and Nicoll (2001) and Ohno-Shosahu et al. (2001) independently established that physiologically relevant stimulation of single hippocampal pyramidal neurons produces an endocannabinoid or endocannabinoids that diffuse onto the terminals of presynaptic GABAergic interneurons, where they act upon cannabi-noid CBi receptors to produce transient, short-term inhibition of neurotransmitter release. Endocannabinoids also mediate depolarisation-induced retrograde signalling of interneuronal inhibitory GABAergic synapses onto cerebellar Purkinje cells (Kreitzer and Regehr 2001a Diana et al. 2002 Yoshida et al. 2002), onto neocor-tical pyramidal cells (Trettel and Levine 2003) and onto substantia nigra neurons (Yoshida et al. 2002). In addition, retrograde endocannabinoid signalling-mediated depolarisation-induced suppression of excitation (DSE) has been demonstrated for excitatory glutamatergic synaptic inputs onto cerebellar Purkinje cells from climbing fibre and parallel fibre inputs...

Endocannabinoid System

Although early structure-activity relationship (14) and initial receptor-binding studies (15) suggested the existence of cannabinoid receptors, it was not until the late 1980s that compelling evidence for a cannabinoid receptor emerged. Devane et al. (16) characterized a binding site that had all of the properties of a cannabinoid receptor. Shortly thereafter, the cannabinoid receptor was cloned, thereby verifying the existence of a specific target for cannabinoids (17). Compton et al. (18) extended these characterizations by showing a strong correlation between binding affinity for this site and cannabinoid potency for a large number of cannabinoid analogs. This receptor is referred to as the CB1 cannabinoid receptor. The cannabinoid receptor, while uniquely recognized by cannabinoids, is a member of a large family of receptors that are coupled to G proteins. CB1 receptors are also found in brain and peripheral tissues that include sensory nerve fibers, the autonomic nervous system,...

Other Endocannabinoid Targets TRP Channels

In all of the above studies, endocannabinoid signalling is mediated largely via presynaptic activation of cannabinoid CB1 receptors. However, endocannabinoids such as anandamide have some affinity for other receptors, such as the TRPV1 'noxious heat capsaicin' receptor (Di Marzo et al. 2001). Besides their predicted primary afferent localisation, TRPV1 receptors are present within discrete brain regions (Sasamuraet al. 1998 Mezey et al. 2000). Thus, in addition to CB1 -mediated presynaptic effects, exogenously applied anandamide acts via TRPV1 receptors to increase spontaneous glutamatergic synaptic transmission not only within the spinal and medullary dorsal horn (Morisset et al. 2001 Jennings et al. 2003) but also within brain regions such as the hippocampus and substantia nigra (Al-Hayani et al. 2001 Marinelli et al. 2003) (Fig. 3A). Recently, it has been demonstrated that the TRPV1 antagonists capsazepine and iodoresiniferatoxin increase glutamatergic synaptic transmission within...

Interactions Between Cannabinoids And Dopamine At The Basal Ganglia

Dopamine is a key neurotransmitter in the basal ganglia circuitry. This can be asserted from both physiological (Pollack, 2001) and therapeutic (Hornykiewicz, 1998) points of view. So, the activation of dopamine transmission in this circuitry is generally associated with an increase of movement, whereas the inhibition is followed by hypokinesia (Brooks, 2001). In fact, the basal ganglia disorder with the highest prevalence in the human population, Parkinson's disease, is a consequence of the progressive degeneration of nigrostriatal dopaminergic neurons, resulting in slowing of movement (bradykinesia), rigidity, and tremor (Dawson and Dawson, 2003). Cannabinoids are hypokinetic substances, thus producing motor depression and even catalepsy (see Romero et al., 2002 Fernandez-Ruiz et al., 2002), and it has been largely speculated that this hypokinetic effect of cannabinoids might be produced by reducing dopaminergic activity. This assumption is correct, but the role of CB1 receptors,...

Cocaine Induced D1 Receptor Adaptations

Or to block the reinforcing effects of cocaine. Dj receptor mRNA levels, receptor number, and receptor sensitivity are altered as a consequence of protracted cocaine exposure and may, in part, account for some of the Dj receptor-mediated behavioral responses to cocaine. Dj receptor mRNA is not altered in the striatum, nucleus accumbens, or substantia nigra of human cocaine abusers 83 however, elevations in Dj receptor mRNA were observed in the striatum of rats chronically treated with cocaine.84 The Dj receptor is also critical for mediating cocaine-induced expression of certain genes (the fos and Jun family immediate early genes which encode transcription factors) and molecules such as brain-derived neurotrophic factor, P-catenin, and Gaolf, which are implicated in mediating cocaine's actions in the nucleus accumbens and caudate putamen.85 Increased Dj receptor density was reported in the nucleus accumbens and olfactory tubercle in rat brain following twice-daily injections of...

Concluding Remarks

In this chapter, we have reviewed the recent advances on cannabinoid-dopamine interactions, emphasizing those processes in which dopamine has been proposed as a key neurotransmitter, such as basal ganglia functionality, corticolimbic processes, and neuroendocrine regulation. We have explored the mechanisms underlying these interactions, which represent ways for plant-derived cannabinoids to interfere with these processes. In most of the cases, we have concluded that dopaminergic neurons do not contain CB1 receptors, with some exceptions, but these receptors are located on neurons present in regions innervated by dopaminergic neurons, which allows relevant bidirectional interactions. Lastly, we have reviewed those diseases characterized by either deficiency or overactivity of dopamine transmission and where cannabinoids might be of therapeutic potential possibly through actions that facilitate, among others, a normalization of dopamine transmission. These diseases included basal...

Cocaine Induced Adaptations in D2 Receptors

The actions of cocaine on D2 receptors have been shown to be essential to the development of cocaine dependence. The D2 receptor antagonist haloperidol inhibits the development of behavioral sensitization to cocaine.74 Sensitization is believed to play an important role in drug craving and the reinstatement of compulsive drug-taking behavior 93,94 thus, altered regulation of D2 receptors may contribute to the reinforcing potential of cocaine. D2 mRNA levels were not altered in the striatum of human cocaine abusers83 or rats treated with cocaine.95,96 D2 receptor mRNA levels were decreased in the olfactory tubercle of rats treated with a single injection of cocaine,95 whereas D2 receptor mRNA levels were transiently elevated in rats treated chronically with cocaine.84 A transient increase in the binding of 3H raclopride in the olfactory tubercle and rostral nucleus accumbens and caudate-putamen was observed after binge administration of cocaine97 and elevations in 3H spiperone and 125I...

Metabotropic Glutamate Receptors

Polarization was shown to induce a transient pause in the spontaneous firing of dopamine neurons. The mGluR-mediated Ca2+ mobilization in dopamine neurons is caused by multiple intracellular pathways to exert an inhibitory control on the excitability of dopamine neurons (Morikawa et al. 2003). Dopamine neurons of the substantia nigra pars compacta receive a prominent serotonin (5-HT) projection from the dorsal raphe nucleus. MgluR-evoked postsynaptic currents are inhibitedby an activation of 5-HT2A and 5-HT4 receptors (Paolucci et al. 2003).

Regulation of Kappa Opioid Receptors by Cocaine

It is interesting that in the same animal model, K-opioid receptor mRNA was decreased in the substantia nigra, but not in the ventral tegmental area of cocaine-treated rats.156 A recent study also reported K-opioid receptor mRNA levels are decreased after cocaine self-administration in rats in the nucleus accumbens and ventral tegmental area.157 The reasons for this disconnect between k-opioid receptor binding and the K-opioid receptor mRNA are not known. However, the discrepancy may be due to the detection of multiple K-opioid receptor mRNAs or binding sites or to the binding of the 3H bremazocine to a K-opioid receptor subtype distinct from the K-opioid receptor message that was measured. While the interpretation of these studies with regards to which K-opioid receptor subtype was measured and the regulation of each subtype by cocaine is difficult at this time, recent advances in the cloning of these receptor subtypes and the development of subtype-specific radi-oligands will...

Possible role of other neurotransmitter systems in the antiemetic properties of cannabinoids

Although the cholinergic neurotransmitter system per se is not directly involved in chemotherapy-induced vomiting (see section 2.1), dopaminergic and serotonergic mechanisms do appear to be important downstream in cannabinoids' antiemetic actions. Indeed, in the feline, nabilone dose-dependently prevents emesis produced by the dopamine D2 receptor agonist apomorphine (London et al., 1979). In a similar manner, A9-THC prevents vomiting produced by dopamine D2 D3 receptor agonists such as apomorphine, quinpirole, quinelorane and 7-OH DPAT in the least shrew (Darmani, unpublished observations). In this context, the least shrew seems to be an excellent dopamine animal model of emesis since the cited selective and nonselective dopamine D2 receptor agonists can potently induce emesis in this species, whereas D2 antagonists prevent the induced behavior (Darmani et al., 1999). As discussed earlier, clinical findings further underscore the role of blockade of the dopaminergic system in the...

Abnormal Changes In The Brain

Not all changes in the brain are normal or healthy. In some brain disorders, such as Parkinson's disease and Alzheimer's disease, neurons actually die. External injuries to the brain, such as blows to the head, can also kill neurons. So can internal injuries. Strokes, which occur when a blood vessel in the brain gets blocked, prevent blood from reaching part of the brain. Without blood, neurons become starved for oxygen and, like any other cell starved for oxygen, they die. Unfortunately, the brain has at best a limited ability to make new neurons, and right now it appears that once most neurons die, they are gone for good. Depending on where and how large the damaged areas are, the functions they participate in are either lost or diminished.

Organs and Systems Cardiovascular

Postural hypotension has been estimated to occur in some 15 of patients who take plain levodopa during the first year of treatment, and in 10 of patients who take co-careldopa it is doubtful whether the difference is significant. On the other hand, some patients become hypertensive they may be individuals who absorb or metabolize the drug at an abnormal rate. Levodopa can cause ventricular dysrhythmias in patients with pre-existing cardiac disorders. Transient flushing of the skin is common palpitation is unusual.

Other features of the patient

Because of the cardiovascular effects of levodopa, patients with cardiac disorders are at risk. Levodopa should not be used in patients with a history of mental illness, hemolytic anemia, or any serious organic disease. Neurologists from Madrid have studied 168 consecutive patients treated for at least 6 months with levodopa (57). About 10 of the patients per year developed dyskinesias over 7 years. Younger age (under 50 years) at the onset of the disease and high initial levodopa dosages (more than 600 mg day) were the most important susceptibility factors identified.

Diagnosis of Adverse Drug Reactions

A group from the National Hospital for Neurology in London has described the use of continuous subcutaneous apomorphine infusions in 19 patients with Parkinson's disease with severe unpredictable motor fluctuations while taking levodopa (68). The objective was to replace levodopa during waking hours with apo-morphine monotherapy. During apomorphine treatment ranging from 9 months to nearly 8 years, there was a 65 reduction in dyskinesia severity and an 85 reduction in frequency and duration, with a 70 reduction in the off'' time. Nearly half the patients stopped taking levodopa altogether. A less radical and much less expensive approach to the management of motor fluctuations has been described in 14 patients with advanced Parkinson's disease and levo-dopa-induced motor disorders (69). Amantadine (mean dose 350 mg day) reduced the severity and duration of dyskinesias by 33-75 , depending on the parameter measured. The rationale was that amantadine blocked N-methyl-d-aspartate...

Behavior Changes That Reflect Brain Changes

People with depression, epilepsy, and Parkinson's disease all show changes in behavior. These changes are so obvious that the behavior itself is diagnostic of the disease. In fact, doctors used behavior to diagnose these diseases long before they knew what brain changes cause these

Beth Levant 1 Introduction

The central nervous system (CNS) dopamine system plays an important role in mediating the reinforcing effects of drugs of abuse (1). In addition, dopamine receptors have been the principal target of drugs employed in the treatment of neuropsychiatry disorders such as schizophrenia and Parkinson's disease. Until 1990, the dopamine receptor population in the brain and periphery was believed to consist of two subtypes, Dj and D2, which were distinguished by their pharmacology and coupling to signal transduction systems (for review see ref. 2). Dj and D2 receptors exhibit similar distributions in brain with the highest densities in the striatum (for review see ref. 3). A number of selective radioli-gands have been synthesized and extensively used to characterize the classical dopamine receptor subtypes. These radioligands include the D1-selective ligands 3H SCH 23390 and 125I SCH 23982. D2 receptor-selective ligands include the antagonists 3H spiperone, 3H YM 09151-2, and 125I...

Effects ofCannabinoid Receptor Antagonists

The motor effects of cannabinoid agonists are usually prevented by SR141716, a selective CBi receptor antagonist (Souilhac et al. 1995 Di Marzo et al. 2001 for a review see Consroe 1998), thus suggesting that they are CBi receptor-mediated (see Table 1). However, the administration of SR141716 by itself can cause hyper-locomotion (Compton et al. 1996). All these data are compatible with the idea that the pharmacological blockade of CB1 receptors might be of value for the treatment of hypokinetic signs of the sort that occur in Parkinson's disease (PD) and related disorders (see Fern ndez-Ruiz et al. 2002 for a review), an issue that will be discussed in detail below. Fig. 1. Distribution of CBi and VR1 receptors in the basal ganglia circuitry in rats. CPW,caudate-putamen GP, globus pallidus STN, subthalamic nucleus SNpr, substantia nigra pars reticulata SNpc,substantia nigra pars compacta Fig. 1. Distribution of CBi and VR1 receptors in the basal ganglia circuitry in rats....

Cannabinoid and Vanilloid Receptors

And mRNA expression for the CB1 receptor (for a review see Romero et al. 2002). In particular, the three nuclei that receive striatal efferent outputs (globus pal-lidus, entopeduncular nucleus, and substantia nigra pars reticulata), contain high levels of cannabinoid receptor binding sites (Herkenham et al. 1991a), whereas CB1 receptor-mRNA transcripts are present in the caudate-putamen, which lacks striatal outflow nuclei (Mailleux and Vanderhaeghen 1992a). This observation is compatible with the idea that CB1 receptors are presynaptically located in striatal projection neurons (see Fig. 1), a notion that has been supported by a series of anatomical studies in which specific neuronal subpopulations in the basal ganglia were lesioned (Herkenham et al. 1991b), and, more recently, by analysis of the cellular distribution of this receptor subtype in the basal ganglia using immuno-histochemical techniques (Tsou et al. 1998a). CB1 receptors are located in both striatonigral (the so-called...

Endocannabinoid Ligands

Two key regions involved in the control of movement, the globus pallidus and the substantia nigra, contain not only the highest densities of CB1 receptors in the brain (Herkenham et al. 1991a) but also the highest levels of endocannabinoids, particularly of anandamide (Di Marzo et al. 2000a). The phenotype of the nerve cells that produce endocannabinoids in the basal ganglia is presently unknown, although the precursor of anandamide, N-arachidonoylphosphatidylethanolamine, has been found in the basal ganglia (Di Marzo et al. 2000b), which supports the existence of in situ synthesis for this endocannabinoid. The synthesis of anan-damide seems sensitive to dopamine. Thus, Giuffrida et al. (1999) reported that, in the striatum, it is regulated by dopaminergic D2 receptors, which was interpreted by these authors as an indication that the endocannabinoid system serves as an inhibitory feedback mechanism that counteracts dopamine-induced facilitation of psychomotor activity (Giuffrida et...

Therapeutic Usefulness of Cannabinoids

Parkinson's disease Parkinson's disease Parkinson's disease Huntington's disease Parkinson's disease Dystonia Parkinson's disease Dystonia Failure to alleviate symptoms in PD patients (reviewed byConsroe 1998) Reduction of L-dopa-induced dyskinesia in PD patients (Sieradzan et al. 2001) Parkinson's disease Huntington's disease Huntington's disease Huntington's disease Parkinson's disease 3NP, 3-nitropropionic acid HD, Huntington's disease MPTP, PD, Parkinson's disease.

Changes in the Endocannabinoid Transmission

Compared with HD, much less data exist on the status of CBi receptors in the postmortem basal ganglia of humans affected by PD. Only recently we have found that CB1 receptor binding and the activation of G proteins by cannabinoid agonists were significantly increased in the basal ganglia as a consequence of the selective degeneration of nigrostriatal dopaminergic neurons (Lastres-Becker et al. 2001a). These increases were not related to the chronic dopaminergic replacement therapy with L-dopa that these patients were undergoing, since they were also seen in (MPTP)-treated marmosets, a primate PD model, and disappeared after chronic L-dopa administration in these animals (Lastres-Becker et al. 2001a). It has also been found that endocannabinoid levels increase in a rat model of PD and that this increase can be reversed by L-dopa (Gubellini et al. 2002 Macarrone et al. 2003). This suggests the existence of an imbalance between dopamine and endocannabinoids in the basal ganglia in PD...

Animal Models Of Human Disorders

All such animal procedures suffer from the obvious and basic problem that laboratory animals do not behave like humans and that humans cannot reliably interpret their reactions and behaviour. Thus we know that Parkinson's disease is caused by a degeneration of the dopaminergic nigrostriatal tract but its lesion in animals does not produce any condition which resembles human Parkinsonism, except in primates, even though there are functional tests (e.g. rotational movements) which readily establish that loss of dopamine function and also respond to its augmentation (Chapter 15). By contrast, there are many ways, e.g. electrical stimulation and the administration of certain chemicals, to induce convulsions in animals and a number of effective anti-epileptic drugs have been introduced as a result of their ability to control such activity. Indeed there are some tests, as well as animals with varied spontaneous seizures, that are even predictive of particular forms of epilepsy. But then...

Interaction Of Thc With Specific Receptors

The first THC receptor (CBX) was identified in rat brain (Devane et al, 1988) and is a guanine nucleotide regulatory (G) protein linked (7 Trans membrane, 7TM) receptor. CB1 Receptors in the brain are unevenly distributed, with highest concentrations in the globus pallidus, substantia nigra, cerebral cortex, striatum and the molecular layers of the cerebellum and hippocampus (Herkenham et al., 1990). A second receptor (CB2), has 44 sequence homology with the CB1 receptor and is also a G protein-linked 7TM receptor (Munro et al, 1993). Although the CB2 receptors appear to be in the periphery, CB1 receptors are found both centrally and peripherally (Pertwee, 1995).

Treatment Of Neurodegenerative Diseases

The local controlled delivery of neurotrophic factors (e.g. NGF, and glial cell-derived neurotrophic factor, GDNF) can be very advantages for the treatment of neurodegenerative diseases, such as Parkinson's, Huntington's and Alzheimer's Disease. For this purpose, biodegradable controlled release microparticles have been proposed (71,63,79-85). For instance, Pean et al. (82) prepared PLGA-based microparticles loaded with NGF and evaluated their in vivo performance in rat brain. Drug-loaded as well as placebo microparticles were injected near the septal cholinergic neurons, axotomized by an unilateral transection of the fornix-fimbria (Fig. 17A and 17B). The histological analysis 2 and 4 weeks after administration revealed a non-

Pregnancy Category None

Fected facial cysts that can leave scars. Heart impairment has been discovered among current users. Examination of former users reveals brain damage that may lead to Parkinson's disease. Autopsies find widespread blood vessel damage throughout the body, from skin to vital organs.

Conclusions And Future Perspectives

Recent clinical trials aiming to improve the treatment of brain tumors have shown promising results. Novel approaches to improve the treatment of neurodegenerative diseases (e.g. Parkinson's or Huntington's Disease) are currently in the pre-clinical state. For the future it can be expected that based on a more and more comprehensive understanding of the involved phenomena and on the progress in technology (e.g. microchip-based delivery systems, computer-assisted neurosurgery) this type of advanced drug delivery system will gain in practical importance.

Control SymptomaticPresymptomatic

Figure 15.1 PET scans in normal and Parkinsonian patients. A PET scan with 18F fluorodopa in a control subject shows that the striatum is heavily labelled whilst in a Parkinson patient with established symptoms there is little labelling. This patient's twin, whilst free of symptoms, also showed some loss of labelling and subsequently developed the disorder. Reproduced by kind permission of D Brooks, MRC Cyclotron Unit, Hammersmith Hospital, UK.

Other Prescription Hypnotics

Certain sedating anticonvulsants are reasonable third and fourth line sleep aids or add-on hypnotics for patients who do not respond or become tolerant to standard hypnotics. Bipolar patients suffering from significant insomnia may benefit from valproate, when BZD-type hypnotics are contraindi-cated, gabapentine or tiagabine might be good alternatives. Secondary insomnia due to restless legs syndrome may preferentially respond to dopaminergic drugs, such as pramipexole or levodopa. As a last resort, agitated elderly patients with dementia may preferentially respond to low dose sedating antipsychotics such as haloperidol or quetiapine. Although the new generation atypical antipsychotics are less likely to induce tardive dyskinesia, other complications like diabetes, obesity, and dyslipidemia suggest that the risks of using antipsychotics as hypnotics remain substantial.

Neuronal NonCB1 NonCB2 NonTRPV1 Receptors

Evidence for the presence of vanilloid-like receptors in the hippocampus has also been obtained by Al-Hayani et al. (2001). They found paired-pulse depression in the CA1 region of rat hippocampal slices to be increased both by anandamide and by two other TRPV1 receptor agonists, capsaicin and resiniferatoxin, in a manner that was sensitive to antagonism by capsazepine but not by the CB1 receptor antagonist AM281. Given the results obtained by Hajos et al. (see above), it is possible that these agonists were acting through central vanilloid-like receptors to cause a decrease in excitatory glutamatergic transmission. Alternatively, they may have been acting through these putative receptors to cause an increase in inhibitory y-aminobutyric acid (GABA)ergic transmission. If anandamide was acting through vanilloid-like receptors, then it apparently activates them more readily than CB1 receptors, which contrasts with reports that this endocannabinoid interacts less potently with established...

Central nervous system CNS

To evaluate the role of AEA in the CNS revealed that AEA affects body temperature and locomotor activity in rats, although with a shorter duration of action relative to A9-THC (McGregor et al., 1998). AEA has also been reported to be released extracellularly in the brain of rats via activation of membrane receptors such as the dopamine D2 receptors (Giuffrida et al., 1999). Giuffrida et al. measured the release of AEA in the dorsal striatum of mobile rats by microdialysis and gas chromato-graphy mass spectrometry. Neural activity stimulated the release of AEA, but not that of 2-AG (Giuffrida et al., 1999). Additionally, AEA release was increased eight fold when the rats were treated with a D2-like (D2, D3, D4) dopamine receptor agonist. Subsequently, the increase in AEA release in the dorsal striatum was suppressed using a D2-like receptor antagonist while administration of a D1-like (D1, D5) receptor agonist ultimately had no such effect on the levels of AEA released in the brain....

Blockade Of Da Pathways In Schizophrenia

(1) The nigrostriatal from substantia nigra (SN), the A9 nucleus There is no doubt that the nigrostriatal pathway is concerned with motor function and blocking DA transmission in it with most neuroleptics would certainly produce signs of Parkinsonism (see Chapter 15). The nucleus accumbens (and some other subcortical regions) are generally assumed to be concerned with psychotic effects although its core is also regarded as part of the basal ganglia. In rats it is involved in motor

Acetyl coenzyme A choline CH3 acetylcholine acetylcholine CH3

Dopamine, norepinephrine and epinephrine are products of the metabolism of dietary phenylalanine. This is an interesting sequence of reactions in that we will be discussing not only the three neurotransmitters formed but also considering the DOPA precursor and its use in the treatment of Parkinson's Disease. These molecules are also called catecholamines. Catechol is an ortho dihydroxyphenyl derivative. Degradation of the final product in the pathway, epinephrine, can be accomplished by oxidation (monoamine oxidase - MAO)or methylation (catecholamine O-methyl transferase - COMT). The diagram on the next page illustrates the scheme of successive oxidations which produce the various catecholamines.

Second Generation Effects Teratogenicity

Parkinson's disease is very rare in pregnancy, but has been described (14). A 36-year-old woman with a 4-year history of Parkinson's disease, who had been taking pergolide 3 mg day and levodopa 200 mg day continued to take it during pregnancy. The end-of-dose wearing-off effect completely disappeared, and reappeared at their previous intensity after delivery. There were no adverse effects in the mother. The baby was healthy at birth and remained so at the time of the report, at the age of 13 months.

Atypical Neuroleptics

So far we have generally just alluded to the neuroleptics as DA receptor antagonists. The reader will know that there are five such receptors (Chapter 7). Clearly, if the DA released at the terminals of one dopaminergic tract acted on a subset of DA receptors that were different from those found postsynaptically at other tracts then some specificity of antagonist action might be achieved. Unfortunately there is no evidence that different pathways innervate different DA receptor populations and as with the use of agonists in PD, the D2 receptor is dominant. Specific D1 antagonists have no anti-schizophrenic effect and antischizophrenic efficacy increases with neuroleptic affinity (potency) at D2 receptors as unfortunately does the tendency to produce EPSs. Thus there is no great advantage in producing more potent D2 antagonists, other than that less drug needs to be incorporated into long-term release depot preparations. Neuroleptic-induced Parkinsonism (but not tardive dyskinesias)...

Genes Encoding Therapeutic Targets

Catechol-O-methyltransferase (COMT) catalyses the O-methylation of neu-rotransmitters, catechol hormones, and drugs such as levodopa and methyl-dopa. COMT activity is caused by a single mutation. This means that it is possible to have homozygous low-activity allele subjects, i.e., those having the lowest enzyme activity, homozygous high-activity subjects, and also those who are heterozygous and have intermediate activity. Ethnic differences in COMT activity have been observed in several populations with major differences occurring between Asian and Caucasian populations in terms of the percentage incidence of low-activity COMT (18 and 50 , respectively) (Palmatier et al. 1999 McLeod et al. 1998). This is a functional polymorphism that maybe clinically important in terms of the risk of psychopathology (either schizophrenia or mood disorders) and the treatment of many neuropsychiatric disorders (Davidson et al. 1979 Henderson et al. 2000 Murphy et al. 1999 Horowitz et al. 2000 Kotler et...

Antioxidant Scavanger Action

An extract can significantly eliminate free oxygen radicals (superoxide, hydrogen peroxide and hydroxyl radicals) and has also been found to be an inhibitor of NADPH-oxidase. Scavenging activity against peroxide radicals of EGb has been proved also on liposomes and human lipoprotein, which are believed to be involved in lipid peroxidation and human atherogenesis 19 . In addition, several studies showed that EGb is able to reduce endogenous lipoperoxidation 20, 21 and can alter the activity of endogenous antioxidant enzymes such as catalase (CAT) and superoxide dismutase (SOD) in the hippocampus, striatum and substantia nigra (SN) and decrease lipoperoxidation in rat hippocampus 22 . On synaptosomal preparations from the striatum of mice, EGb761 has been shown to prevent the alteration of the neuronal dopamine uptake system and the modifications of the membrane fluidity induced by a pro-oxidant system ascorbic acid Fe2+ 23, 24 . The flavonoid fraction of EGb761 was implicated in these...

Other Anti Ischemic Effects

Although the mechanism of EGb761 is unclear, it is possible that its actions are related to mitochondria and apoptosis because earlier studies found that caspase expression was altered 46, 60 . This is potentially important since mitochondria play a pivotal role in apoptosis for both intrinsic and extrinsic pathways 61 . The intrinsic and extrinsic pathways do not occur independently in vivo but are linked at different points, one of which is the bax bcl-2 complex - an apoptotic to anti-apoptotic index 62 . Oligomerization of bax facilitates its insertion into the outer mitochondrial membrane, triggering cytochrome c release, which promotes apop-tosis. Conversely, bcl-2 forms complexes with bax in such a way that the release of cytochrome c is inhibited to prevent apoptosis. Therefore, the ratio of bax bcl-2 is crucial in determining the progress of cell apoptosis for both the intrinsic and extrinsic pathways 62 . At least two studies, by Lu et al. 63 and Loh et al. 64 , corroborate...

Inhibitory synaptic transmission

WIN-2 also decreases GABAa synaptic currents in striatal neurons, substantia nigra pars reticulata, and rostral medulla (Szabo et al., 1998 Chan et al., 1998 Vaughan et al., 1999). The mechanism implicated in the decrease of inhibitory transmission by WIN-2 appears to involve the inhibition of presynaptic Ca++ channels to diminish GABA release, in a manner similar to the cannabinoid-elicited decrease of glutamate release. So far, available data tend to indicate that full CBX agonists may decrease, whereas THC may increase, inhibitory GABA responses in brain neurons.

Observational studies

Long-term data on the efficacy and tolerability of risperidone are scant, as most of the clinical trials have been of short duration (no longer than 12 weeks). However, some additional data from open studies have emerged. In one study, 386 patients with chronic schizophrenia took risperidone 2-16 mg day for up to 57 weeks 247 patients were treated for at least 1 year (11). All but 48 patients (88 ) had been treated with antipsychotic drugs before entering the study. At the end of the study, 64 of the patients were rated as having improved on the Clinical Global Impression change scale, and extrapyramidal symptoms (scored on the Extrapyramidal Symptom Rating Scale, ESRS) tended to be lower in severity or remained unchanged over the course of risperidone treatment 27 of the patients required antiparkinsonian medication during the study, and 6.5 discontinued treatment prematurely because of adverse events. One or more adverse events were reported by 221 patients (57 ) during risperidone...

Antipsychotic Drugs The Neuroleptics

Brought it briefly into use against Parkinsonism. It was soon superseded by better agents (Chapter 8). In a search for antimalarials there was synthesized the dimethylamino homolog, promethazine, a superior antihistamine with sedative and antiemetic properties as well. Additional systematic modifications by researchers at Rhone-Poulenc in France led to the synthesis of a 2-chloro-substituted phenothiazine, where the 10-N was separated from the side-chain N atom by three, rather than the two, carbon atoms of the previous compounds. It was named chlorpromazine (CPZ). The drug was found to have some sedative properties, the ability to potentiate other CNS depressants, and, historically more important, a type of artificial hibernation a conscious state exhibiting an indifference to one's surroundings. Some described it as a pharmacological lobotomy. Its psychotropic properties were first tested in manic, then schizophrenic, patients. CPZ was introduced clinically in 1952.14 The era of...

Bi Receptor Downregulation

Several groups have demonstrated that repeated cannabinoid administration consistently leads to a reduction in CBi receptor levels in brain. Specifically, repetitive treatment with THC, CP 55,940, or WIN 55,212-2 results in a decrease in CBi receptor binding in brain sections or membrane homogenates from whole brain (Oviedo et al. 1993 Romero et al. 1997 Breivogel et al. 1999 Rubino et al. 2000b Sim-Selley and Martin 2002). Autoradiographic studies have allowed analysis of a large number of brain regions and have revealed that downregulation occurs in all CB1 receptor-containing brain regions following subchronic administration of WIN 55,212-2 or THC, including cerebellum, hippocampus, caudate-putamen, globus pallidus, substantia nigra, prefrontal, cingulate and entorhinal cortices, nucleus accumbens, amygdala, hypothalamus, thalamus, and periaqueductal gray (Sim-Selley and Martin 2002). However, the magnitude of downregulation varies in different brain regions. For example,...

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