Parkinson Disease Alternative Treatment

The Parkinson's Disease Protocol

The creator of this program is known as Jody Knapp, She is a health and Naturopath researcher and has produced many successful programs in the medical industry for individuals with specific health problems to tackle it. Her research looks at ways to tackle theses conditions naturally and eliminate them permanently. The Parkinson's Protocol is an eBook which guides you on how to manage the symptoms of Parkinson's disease. This book is made up of information about the condition, strategies to tackle the condition, therapies and basic daily activities you can involve yourself to reduce the symptoms of the condition. While there has been no cure for this ailment or condition, there are natural ways to reduce the effects and symptoms of this condition. With these methods the symptoms of the condition will be reduced, the progression of the disease slowed and its effects on the body reversed. As stated by the author in her book, once you implement all the strategies laid down in the book, you will gradually eliminate the Parkinson's symptoms from your body. More here...

The Parkinsons Disease Protocol Summary

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The Parkinson's Protocol

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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 discontinued. In...

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...

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.

Parkinsons Disease

There is some evidence that neurodegeneration of dopaminergic pathways of the substantia nigra pars compacta (SNc) in Parkinson's disease involves excitotoxicity (Schmidt et al. 1990 Greenamyre and O'Brien 1991 Blandini and Greenamyre 1998). In rats, NMDA receptor antagonists protect against damage of dopaminergic neurons induced by the dopaminomimetic metham-phetamine (Sonsalla et al. 1991). In vitro, MPTP application inhibits the astroglial glutamate transporter (Hazell et al. 1997), probably through free radicals. MPTP induces toxicity and Parkinsonian symptoms in rats and monkeys, and this is prevented either by NMDA receptor antagonists or by lesion of the descending cortico-striatal glu-tamatergic pathway (see Blandini and Greenamyre 1998 Parsons et al. 1998). It is now widely accepted that NMDA receptor antagonists might manifest their symptomatic anti-Parkinsonian effects by attenuating an imbalance between dopaminergic and glutamatergic pathways within the basal ganglia...

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...

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

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...

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.

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...

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).

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).

Contraindications Precautions And Interactions

The dopaminergic drugs are contraindicated in patients with known hypersensitivity to the drugs. Levodopa is contraindicated in patients with narrow-angle glaucoma, those receiving a monoamine oxidase inhibitor (see Chap. 31), and during lactation. Levodopa is used cautiously in patients with cardiovascular disease, bronchial asthma, emphysema, peptic ulcer disease, renal or hepatic disease, and psychosis. Levodopa and combination antiparkinsonism drugs (eg, carbidopa levodopa) are classified as Pregnancy Category C and are used with caution during pregnancy and lactation. Levodopa interacts with many different drugs. When levodopa is used with phenytoin, reserpine, and papaverine, there is a decrease in response to levodopa. The risk of a hypertensive crisis increases when lev-odopa is used with the monoamine oxidase inhibitors (see Chap. 31). Foods high in pyridoxine (vitamin B6) or vitamin B6 preparations reverse the effect of levodopa. However, when carbidopa is used with...

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.

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....

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...

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...

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...

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...

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).

General adverse effects

When levodopa is given alone, severe gastrointestinal upsets are very common during the first year of treatment they are much less common when a decarboxylase inhibitor is also given. Postural hypertension is not uncommon. Dyskinesias occur in some patients only after starting therapy. Some mental changes are seen in a high proportion of cases. Psychological dependence occurs in a small subset of patients (1). Effects on the liver, renal function, and hema-tological parameters are usually slight. Individual prescribers and clinics tend to develop their own approaches to obtaining the best balance between effects and adverse reactions a ''drug holiday'' (for example 2 days week) has long been recommended by some workers to reduce the incidence of adverse effects (2), but others have described a neuroleptic malignant syndrome when the administration of the drug was temporarily discontinued (SEDA-17, 147) (3). Allergic type reactions do not seem to occur, but carbidopa has been reported...

Psychological psychiatric

Toxic psychoses and toxic delirium can occur, particularly in individuals with a history of postencephalitic parkin-sonism or psychiatric disease (36). Nearly half of all patients with Parkinson's disease are demented or have significant cognitive impairment (37). These patients are particularly susceptible to delirium induced by levodopa and other antiparkinsonian drugs. The author recommended dosage reduction or elimination of drugs that may be responsible, starting with anticholinergic drugs but leaving levodopa unchanged if possible. He also recommended the use of the atypical neuroleptic drugs clozapine or olanzapine in severely disturbed patients in whom drug withdrawal is not feasible. Libido has been found to increase, at least for some time, in a proportion of patients (39) whilst perhaps in part reflecting the improved mobility and sense of well-being, a causative relation with prolactin inhibition by levodopa has been suggested. There may be subtle neuropsychiatric adverse...

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...

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...

Therapeutic Usefulness of Cannabinoids

Dopaminergic replacement therapy represents a useful remedy for rigidity and bradykinesia in PD patients (Carlsson 2002), at least in the early and middle phases of this disease. Later on, the chronic use of L-dopa therapy results in aloss of efficacy and even in the appearance of an irreversible dyskinetic state. Cannabinoid-based compounds might also be useful in PD. In this disorder, CB1 receptor agonists or antagonists have both been proposed, for their use alone or as coadjuvants, against different signs of the complex motor pathology developed by PD patients (Brotchie 2000 Romero et al. 2000 Di Marzo et al. 2000a Lastres-Becker et al. 2001a Fox et al. 2002a see Table 2). For instance, it has been reported that CB1 receptor agonists However, because of the hypokinetic profile of cannabinoid agonists, it is unlikely that these compounds would be useful for alleviating bradykinesia in PD patients. This is confirmed by results obtained with humans or withMPTP-lesioned primates, as...

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.

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.

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.

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...

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...

Organs and Systems Cardiovascular

Unexpected mortality in the UK Parkinson's Disease Research Group trial (4). Head-up tilt caused selective and often severe orthostatic hypotension in nine of 16 patients taking selegiline and levodopa, but had no effect on nine patients taking levodopa alone. Two patients taking selegiline lost consciousness with unrec-ordable blood pressures and another four had severe symptomatic hypotension. The normal protective rises in heart rate and plasma noradrenaline were impaired. The abnormal response to head up tilt was reversed by withdrawal of selegiline. The authors proposed that these findings might be due to either non-selective inhibition of monoamine oxidase or effects of amfetamine and metamfetamine. A 72-year-old man who had taken levodopa for over 20 years started to take selegiline 10 mg day. He developed a strong impulse for cross-dressing, which he had never experienced before. The behavior ceased when the selegiline was withdrawn. It is not clear whether this effect was due...

Family Commelinaceae R Brown 1810 nom conserv the Spiderwort Family

Pharmaceutical interest An example of medicinal Commelinaceae is Mur-dannia edulis (musli siyah), used by Asian residing in Britain to invigorate health, regulate urination and to treat asthma and colic. A number of plants classified within the family Commelinaceae have been investigated for their therapeutic potential. Rhoeo spathacea (oyster plan) contains dopamine and could be of potential value in combating Parkinsonism. There is an expanding body of evidence to suggest that a-glucosidase inhibitors isolated from Commelinaceae prove positive in the treatment of diabetes. Approximately 20 species of Commelinaceae are medicinal in the Asia-pacific. Note that many of these plants are used to heal and soothe injured skin.

Intracranial Self Stimulation

Intracranial self-stimulation is a behavioral paradigm whereby subjects carry out an operant task to receive direct electrical stimulation of specific regions of their brains (19). Stimulation of the regions including the mesencephalic dopaminergic cell bodies or of the lateral hypothalamus that includes the ascending dopaminergic pathways are both reinforcing in this paradigm. It is believed that dopamine is involved in the reinforcing properties of this behavior, as it can be abolished by selective lesion of dopaminergic neurons (20). To investigate further the role of dopamine, fast-scan cyclic voltammetry was used to monitor dopamine in terminal regions during intracranial self-stimulation of the ventral tegmental area substantia nigra.

Miotic Direct Acting

These drugs are contraindicated in patients with hyper-sensitivity to the drug or any component of the drug and in conditions where constriction is undesirable (eg, iritis, uveitis, and acute inflammatory disease of the anterior chamber). The drugs are used cautiously in patients with corneal abrasion, pregnancy (Pregnancy Category C), lactation, cardiac failure, bronchial asthma, peptic ulcer, hyperthyroidism, gastrointestinal spasm, urinary tract infection, Parkinson's disease, recent myocardial infarction, hypotension, or hypertension. These drugs are also used cautiously in patients with angle closure glaucoma because miotics can, occasionally, precipitate angle closure glaucoma by increasing the resistance to aqueous flow from posterior to anterior chamber. See Chapter 24 for information on interactions.

General Development and Uses

Ligand-conjugated polymers were used for in vivo targeting and expression of genes. Kircheis et al. (229) reported an enhanced level of transfection in subcutaneous neuro2a tumors on intratumoral injection of transferrin-PEI pDNA compared with naked pDNA injection. On pegylating the Tf-PEI pDNA complex, the whole entity became serum resistant without losing its targetability, and the complex could be efficiently targeted to neuro2a tumors in a mouse model after IV injection (230) .Alvarez-Maya et al. (231) cross-linked neurotensin with PLL and made polyplexes with pDNA. On injecting polyplex into the substantia nigra

Pregnancy Category C

Urinalysis comparing the amounts of dextromethorphan and its breakdown product dextrorphan can identify a person's susceptibility to lung cancer. Case reports tell of dextromethorphan's success in treating infants' brain seizures. One experiment found the substance to be a useful supplement in treating older epileptics, but another study detected no improvement. Parkinson's disease patients have shown encouraging response to treatment with the drug, but using it against Huntington's disease and Lou Gehrig's disease has brought disappointment. Animal research suggests that the substance may be useful in treating stroke. A mice experiment in France tested whether dextro-methorphan can protect against the effects of the chemical warfare agent so-

Meperidine And Its Analogues

Synthesis Meperidine

Parents took him to several psychiatrists and neurologists who eventually diagnosed him with Parkinson's disease, a disease that primarily occurs in people over 65 years old and is largely incurable. The college student's life was forever changed. PARKINSON'S DISEASE NATURAL AND EXPERIMENTAL Parkinson's disease is a devastating brain disorder that occurs in approximately one out of every 100 people. The disease is marked by extreme muscle stiffness, slowness or inability to walk, difficulty initiating movements of the arms and legs, and occasionally tremors. Although the disease usually strikes elderly people over the age of 65, it can also occur in younger people. Notable celebrities that have this early onset form of Parkinson's disease include boxer Muhammad Ali (who was in his early 40s when diagnosed) and actor Michael J. Fox (who was actually 30 when he was originally diagnosed, but did not go public about the disease for another seven years). The cause of Parkinson's disease is...

Chemical Abstracts Service Registry Number 8007930 Formal Names Atropa belladonna

Belladonna substances can ease premenstrual syndrome. They can reduce spasms in smooth muscles of the digestive tract, but they cause tremors or stiffness in other muscles. Heart rate is accelerated. Migraine headaches can lessen. An experiment showed that belladonna can reduce breathing abnormalities in infants. Some medical traditions have used belladonna for reducing sweat and other secretions and against tonsilitis, meningitis, scarlet fever, whooping cough, and epilepsy. At one time medical practitioners gave belladonna to fight Parkinson's disease and drug addiction, but those treatments have been superseded by others. Belladonna preparations have modern usage against vesico-ureteral reflux, a condition in which urine flows back toward the kidney from the bladder. Caregivers have administered belladonna to treat various pains, ranging from kidney stones to sore throat. Belladonna powders and cigarettes have been used against asthma. The natural product is considered effective...

Cannabinoids And Movement Disorders

The substantia nigra, globus pallidus, and entopenduncular nucleus (Herkenham et al., 1991). In addition, CB j receptors are localized to the terminals of the subthalamo-nigral glutamatergic pathway (Mailleux and Vanderhaeghen, 1992). Therefore, the CB1 receptors are colocalized with both D1 and D2 dopamine receptors and show complex patterns of interactions with dopamine, a critical neuromodulator in the control of movement (Glass and Felder, 1997 Giuffrida et al., 1999 Beltramo et al., 2000 Meschler and Howlett, 2001). Systemic cannabinoid exposure produces an overall inhibition of movement. This may, however, be misleading in the determination of the role of endogenous cannabinoids in the control of movement, because studies have clearly shown that cannabinoids can produce markedly different effects depending on which part of the basal ganglia they are activating (Sanudo-Pena et al., 1996 Miller and Walker, 1998 Sanudo-Pena et al., 1998a Sanudo-Pena and Walker, 1998a). Cannabinoids...

Paramethoxyamfetamine PMA

Parkinsons disease Degenerative brain disorder initially characterized by trembling lips and hands and muscular rigidity, later producing body tremors, a shuffling gait, and eventually possible incapacity. Emotions may be affected and mental capacity impaired, but assessment of these is difficult because depression often accompanies the disease. The disease occurs when the brain cells that produce dopamine die. In cases where there is no known cause (the majority), it usually appears after age 40 and is referred to as Parkinson's disease. Parkinson-ism usually refers to similar symptoms resulting from certain antipsychotic drugs, re-serpine (a blood pressure drug), carbon monoxide or manganese poisoning, or MPTP (a heroin analog). Symptoms are treated with the drugs deprenyl (selegiline), L-DOPA (given with carbidopa to reduce side effects) and amantadine. Parkinsonism is named for English surgeon James Parkinson, who first described it in 1817....

Neuropsychiatry Research With Ayahuasca

Scientific and medical interest in ayahuasca long predated recent activities in the field. During the 1920s and 1930s, European and American pharmacologists and physicians began to pay attention to the exotic plant drug concoction from the tropical rain forests of South America. Working with specimens of Banisteriopsis bark, believed at that time to be the sole constituent of the legendary jungle drink, the renowned German research psychopharmacologist, Louis Lewin, in his final project before his death, succeeded in isolating one of the active alkaloids of ayahuasca, harmine, which he initially named banisterine (Lewin 1929). At Lewin's suggestion, the neurologist Kurt Beringer explored the effects of banisterine, also known as telepathine, in reference to the legendary properties of the jungle vine, in the treatment of Parkinson's Disease. Administering the drug to fifteen patients with postencephalitic Parkinsonism, Beringer reported the dramatic improvement of the classic symptoms...

What Is the Functional Role of Presynaptic Cannabinoid Receptors

Figure 6 shows the most important glutamatergic, GABAergic and dopaminergic neuronal connections within the extrapyramidal motor control system. Glutamatergic and GABAergic neurotransmission is inhibited at several sites by cannabi-noids. In contrast, dopaminergic transmission may not be influenced. A typical motor effect of high doses of cannabinoids is catalepsy (Compton et al. 1996 Sanudo-Pena et al. 1999). Catalepsy is thought to occur if the GABAergic neurons in the output nucleus of the basal ganglia, the substantia nigra pars reticulata, are firing at a high rate (Kolasiewicz et al. 1988). Among the 11 sites where cannabi-noids can act presynaptically, an action at 5 sites would indirectly enhance the firing rate of substantia nigra pars reticulata neurons, and thus would lead to Fig. 6. Effects of cannabinoids on synaptic transmission in nuclei belonging to the extrapyramidal motor control system. DA, dopamine FSN, fast spiking neuron MSN, medium spiny neuron SNC, substantia...

Fast Inhibitory Neurotransmission

Thus, cannabinoids depress cerebral cortical GABAergic neurotransmission. Neurotransmission is also depressed in nuclei belonging to the extrapyramidal motor control system caudate-putamen, globus pallidus and substantia nigra pars reticulata (Fig. 6 also shows cannabinoid effects on inhibitory neurotransmission in the extrapyramidal motor control system). GABAergic synaptic transmission in the cerebellum, a major brain region involved in motor control, is inhibited as well (Fig. 7 also shows cannabinoid effects on inhibitory neurotransmission in the cerebellar cortex). Figure 2 shows inhibition of GABAergic neurotransmission in the cerebellar cortex, and Fig. 3 shows that the inhibition is due to the inhibition of GABA release from presynaptic axon terminals. In several nuclei belonging to the limbic system (e.g. hippocampus and amygdala), activation of CB1 receptors leads to depression of inhibitory neurotransmission. Inhibition of GABA release in the ventral tegmental area where...

Substances Known to Metabolize to Methamphetamine and Amphetamine

Many medications and substances are known to metabolize to methamphetamine or amphetamine, thus giving analytical true positives (Table 2). If a patient is on one of these medications, the positive result is a clinical false positive. Enantiomeric analysis may be useful in verifying that the positive result was due to the use of a prescription drug. For example, selegiline, a drug used in the treatment of Parkinson's

Psychoanaleptic drugs

2.11.18 Parkinson drugs Parkinsonism is mainly seen in older patients, and is not normally a disease in pregnant women. Parkinson drugs which are given also for juvenile parkinsonism and restless leg syndrome are l-dopa benserazide. Some 15 exposed pregnancies have been reported, with uneventful delivery of normal children (e.g. Arai 1997, Noinoto 1997, von Graeventiz 1996). Parkinson drugs such as the dopamine agonists bromocriptine, cabergoline,

Anticholinergic Drugs Central Cholinoblockers

The first drugs used in treating parkinsonism were the alkaloids, atropine and scopo-lamine, and over the course of many years they were the only drugs used for this purpose. However, in treating Parkinsonism today, these alkaloids are used extremely rarely and have been practically replaced by synthetic drugs that exhibit central anticholinergic properties (central cholinoblockers). They suppress stimulatory cholinergic effects by suppressing cholinoreceptors. It is believed that they do not affect the synthesis, release, or hydrolysis of acetylcholine. Their action facilitates the reduction or alleviation of motor disturbances associated with damage to the extrapyramidal system. They reduce rigidity and to a lesser extent akinesia, and have a minimal effect on tremors. The therapeutic value of such drugs is relatively small and they are used either in combination with levodopa, or in cases of minor Parkinsonism, primarily for alleviating rigidity. In addition, they cause a number of...

Alexander Hamilton October 14 1791

American Hemp Medicine Bottles

Researchers began getting positive results using medical marijuana in the treatment of glaucoma, anorexia, asthma, nausea, Parkinson's Disease, and spastic muscle disorders. An article in a 1971 medical magazine reported that medical marijuana is probably the most potent anti-epileptic known to medicine today.

Polyalthia cauliflora Hook f Thoms var beccarii King J Sinclair

Lanuginosine inhibits the proliferation of several types of fungi (Ferdous AJ etal., 1992). The stem bark of Polyalthialongifolia contains liriodenine, which is cytotoxic (Wu YC etal., 1990 see Fissistigmaspecies).The leaves Polyalthia olivericontain oliveroline, which interestingly displays, in vivo, anti-Parkinson properties, whereas oliverine relaxes vascular smooth muscle in apapaverine-like way and is therefore antihypertensive (Quevauviller A etal., 1977).

Medical And Psychological Applications Of Ayahuasca

But even from the point of view of Western medicine and psychotherapy it is clear from the literature and from the stories recounted in this volume, that remarkable physical healings and resolutions of psychological difficulties can occur with this medicine. Early in the twentieth century an extract of the vine was used successfully in the treatment of Parkinson's Disease, a possible application that has not to date been followed up. There have been ancedotal accounts of the complete remission of some cancers after one or two sessions with ayahuasca. Since these occurred with ayahuasca in the context of traditional healing ceremonies, it is impossible to separate out the pharmacological effect from the psychosocial and shamanic elements. Further study of such cases and cures is surely warranted.

Meth Damages The Brain Permanently

Meth User Brain Damage

For 20 years, scientific evidence has shown that long-term use of meth depletes supplies of dopamine by damaging dopamine receptors in the brain.24 Studies indicate that this brain damage can be permanent. Long-term meth users may develop life-long problems with verbal skills, memory, and may even develop Parkinson's disease, an incurable nervous disorder with symptoms of trembling hands and extreme muscle stiffness.6, 11

Mdma Myths And Rumors Dispelled

Ecstasy Causes Parkinson's Disease Parkinson's disease is a neurological illness that affects one's ability to move fluidly and causes a tremor when a person is sitting still. Its cause is unknown, but its effects are damaged dopamine neurons in a part of the brain known as the substantia nigra. MDMA does not damage dopamine neurons in any part of the brain, and Ecstasy use does not cause Parkinson's disease. In 1983, intravenous drug users, believing they were purchasing a form of heroin called China White, inadvertently injected MPTP into their veins. Designer meperidine (Demerol) is sold as MPPP Specific conditions are required for the chemical reaction to produce MPPP. In the event of incorrect synthesis, where the pH is too low or the temperature is too high, a contaminant, MPTP, is formed. MPTP damages dopamine neurons. These intravenous drug users were left with a severe Parkinson's-like syndrome. Because MPTP and Ecstasy were

Amotivational Syndrome

Apathy refers to a set of symptoms that includes anhedonia (an inability to experience pleasure from normally pleasurable events), reduced initiative, and decreased spontaneous activity. In the neurological literature, apathy is generally considered the result of decreased function in the subcortical regions, particularly a reduction in dopa-mine, a brain chemical associated with pleasure and motivation. Apathy is also exhibited in individuals diagnosed with frontal-subcortical disorders such as Parkinson's disease and HIV dementia. In a 2006 study examining prefrontal cortex

Endocannabinoids Act via Presynaptic Cannabinoid CB1 Receptors to Inhibit Transmitter Release

THC and a number of synthetic non-selective cannabinoid receptor agonists (such as WIN 55,212-2 and HU-210) modulate neuronal excitability by presynaptic CBi-mediated short-term inhibition of glutamatergic and y-aminobutyric acid (GABA)ergic synaptic transmission (for more detailed reviews see Schlicker and Kathmann 2001 Alger 2002). Release studies have demonstrated that cannabinoids also modulate other neurotransmitter systems. In accordance with the electrophys-iological evidence, anatomical studies have demonstrated that cannabinoid CB1 receptors are located presynaptically on nerve terminals in numerous brain structures. Exogenous application of the endocannabinoids anandamide and 2-AG also modulates synaptic transmission within a number of regions throughout the central nervous system, including the hippocampus, midbrain periaqueductal grey, spinal and medullary dorsal horn, and the substantia nigra (Shen et al. 1996 Vaughan et al. 2000 Morisset et al. 2001 Jennings et al. 2003...

The Chronic Mouse MPTPProbenecid Model

Initial motor deficit (rotarod performance) is detected at 3 wk and deteriorated further 6 mo after treatment. Decrease of TH-immunoreactivity in the substantia nigra, associated with significant loss of substantia nigra neurons Persistent reduction in the levels of striatal terminal DA, its metabolites and uptake Murine inclusion bodies immunoreactive to a-synuclein and ubiquitin contain lipofuscin and lysosomal structures. Morphologically, these inclusion bodies resemble those detected in the cortex of PD. striatal levels remain low. The loss of DA neurons in the substantia nigra 6 mo after treatment is estimated to be at least 60 . The first sign of motor deficit in chronic MPTP probenecid treated mice as evidenced by the rotarod performance test is detected at 3 wk and persists for at least 6 mo after treatment (40).

Medical And Behavioral Toxicity Overview

Other drugs can also produce neurologic symptoms. High doses of some opioids, such as propoxyphene (Darvon) or meperidine (Demerol) cause seizures. Substances that can cause delirium (reversible disorientation and agitation) include cannabis (marijuana), phencyclidine (PCP), lysergic acid diethylamide (LSD), and atropine. Sudden cessation of use of CNS depressants (benzodiazepines, barbiturates, and alcohol) can result in seizures and hallucinations. Chronic use of other substances of abuse can also result in neurologic complications. Tobacco use is associated with increased rates of stroke (but it appears to be associated with lower rates of Parkinson's disease, a progressive disorder affecting control of movement). Solvent abuse (via inhalation) can cause damage to the cerebellum (the part of the brain controlling movement) and to peripheral nerves. A form of synthetic heroin (MPTP, an analog of meperidine (Demerol), has been demonstrated to cause a severe form of Parkinson's...

Cholinergic Pathways And Function

Cholinergic Pathways The Brain

The concentration of ACh in the striatum is the highest of any brain region. It is not affected by de-afferentation but is reduced by intrastriatal injections of kainic acid and so the ACh is associated with intrinsic neurons. Here ACh has an excitatory effect on other neurons mediated through muscarinic receptors and is closely involved with DA (inhibitory) function. Thus ACh inhibits DA release and atropine increases it, although the precise anatomical connection by which this is achieved is uncertain and the complexity of the interrelationship between ACh and DA is emphasised by the fact that DA also inhibits ACh release. In view of the opposing excitatory and inhibitory effects of ACh and DA in the striatum and the known loss of striatal DA in Parkinsonism (see Chapter 15) it is perhaps not surprising that antimuscarinic agents have been of some value in the treatment of that condition, especially in controlling tremor, and that certain muscarinic agonists, like oxotremorine,...

Soporific Agents Hypnotics and Sedative Drugs

Insomnia is a symptom, and its proper treatment depends on finding the cause of sleeplessness and treating the underlying etiology. The most common type of insomnia is transient insomnia due to acute situational factors. The typical factor is stress. Chronic insomnia is most commonly caused by psychiatric disorders. Numerous medical disorders can cause insomnia. Many drugs have been implicated as causing insomnia alcohol, antihypertensives, antineoplastics, -blockers, caffeine, corticosteroids, levodopa, nicotine, oral contraceptives, phenytoin, protriptyline, selective serotonin reuptake inhibitors (SSRIs), stimulants, theophylline, and thyroid hormones. The underlying cause or causes of insomnia should be treated whenever possible. The primary indication for use of hypnotic agents in patients with insomnia is transient sleep disruption caused by acute stress.

Use Of Endocannabinoidbased Substances In Animal Models Of Disorders

Although the mechanism of their action was not elucidated, it is possible that the beneficial effect of endocannabinoid inactivation inhibitors against spasticity in CREAE was because the enhancement of the endocannabinoid signal in the spinal cord might eventually lead to counteraction of exaggerated activity of neuromuscular synapses. Indeed, compensatory activities of the endocan-nabinoids against neuronal hyperactivity have been explored. In a model of Parkinson's disease, the destruction in the rat brain of the nigrostriatal fibers with 6-hydroxy-dopamine (6-OHDA) was found to result in elevated striatal endocannabinoid levels (Gubellini et al., 2002). In view of the well-established inhibitory action of presynaptic CBj receptors on glutamate release in many neurons (see Davies et al., 2002, for a review), it was suggested that this was an adaptive response of the striatum to compensate for the hyperactivity of corticostriatal glutamatergic terminals. This hypothesis was recently...

Basal Ganglia and Cerebellum

Basal Ganglia Cerebellar Pathways

The basal ganglia and the cerebellum interact with the cortex through a series of feedback circuits. The basal ganglia, a group of midbrain nuclei, are involved mainly with the initiation and execution of a movement, whereas the cerebellum tends to modulate ongoing movement (Fig. 5). Again, pathology clearly describes the role played by these structures in motor coordination. The most relevant disorders are the dyskinesias, or abnormal movements. Basal ganglia degeneration results in movement disorders such as Parkinson's disease (selective destruction of dopamine-con-taining neurons) and Huntington's disease (selective destruction of GABA interneurons). Parkinson's disease is classically associated with the triad of resting tremors, muscle rigidity (cogwheel-like), and slowness of movement (bradykinesia, with a festinating gait). Huntington's dyskinesias tend to be the opposite of Parkinson's, The association cortex and substantia nigra send excitatory impulses to the caudate...

Toxification Detoxification

Figure 15.11 Possible scheme for the formation of free radicals from the metabolism of dopamine. Normally hydrogen peroxide formed from the deamination of DA is detoxified to H20 along with the production of oxidised glutathione (GSSG) from its reduced form (GSH), by glutathione peroxidase. This reaction is restricted in the brain, however, because of low levels of the peroxidase. By contrast the formation of the reactive OH-radical (toxification) is enhanced in the substantia nigra because of its high levels of active iron and the low concentration of transferin to bind it. This potential toxic process could be enhanced by extra DA formed from levodopa in the therapy of PD (see Olanow 1993 and Olanow et al. 1998) progression of PD. Trials with selegiline (deprenyl) on hundreds of new untreated patients initially suggested that this was the case since almost twice as many patients in the control group needed to receive levodopa in the first year compared with those on the MAOb...

Bibliography On Magic Muchrooms

80-81, 84, 94, 96 Panaeolus tropicales, 96 Panaeolus variabilis, 41 Panaeolus venenosus, 37 Parkinson, J., 12 Peden, N.R., 88 Peyote, 109 Phantastica, 102ff Pholiota spectabilis, 51 Pholiotina filaris, 62 Picker & Rickards, 84 Pluteaceae, 58 Pluteus spp., 58-60 Pluteus nigroviridis, 59 Pluteus salicinus, 58-60, 59, 60 Pollock, S.H., 83 Potocki, V., 12 Prague research, 26, 34 Primordia, 67 Psathyrella, 38

Measurement of Cannabinoid Effects on Brain Metabolism

Effects of Chronic 49-THC on Brain Glucose Metabolism Marijuana users had lower baseline cerebellar metabolism than controls (Volkow et al. 1996). This finding, coupled with the finding of increased rCGM after acute exposure to cannabi-noids suggests that the decreases in basal cerebellar metabolic rates found in habitual marijuana users may reflect a compensatory response to chronic exposure to the drug. Functions known to be associated with the cerebellum, such as motor coordination, proprioception and learning, are adversely affected both during acute marijuana intoxication and in habitual users of the drug (Varma et al. 1988). The PET scanner used in these investigations lacked sufficient resolution to examine metabolic rates in other brain areas, such as hippocampus, substantia nigra, and caudate nucleus, which contain high concentrations of cannabinoid receptors. However, increased rCGM has not been seen in these areas in rodents using autoradiographic imaging with 2-DG. Studies...

Attack of the cloners

The idea is that if you are going to use embryonic stem cells for therapy, then you want to make sure that they are not going to be rejected from the body. One way around having to use anti-rejection drugs is for the cells to be genetically identical to those of the patient. So you make a cloned embryo from that patient, harvest the stem cells from it, and coax them to develop into the type of cell you need to cure the patient pancreas cells for those suffering from diabetes, or brain cells for Parkinson's or Alzheimer's patients. If the person's disease is due to a specific genetic defect, then the defect could be corrected in the cloned cells and then implanted to cure the disease.

The Acute and Subacute Mouse MPTP Model

Initial increase followed by decrease of motor activity. The activity returns to normal within a week. No long-term motor deficit Initial decrease, but later returning to normal of TH-immunoreactivity in the substantia nigra. No long-term loss of nigral cells Reduced level of striatal terminal DA, its metabolites and uptake these levels return to normal after extended survival period. No evidence of detecting the formation of a-synuclein- and ubiquitin-containing inclusion bodies survival times are extended, the neurotoxic effects of MPTP in mice are reversed gradually (40-43). A loss of tyrosine hydroxylase (TH)-immunoreactive cells in the substantia nigra has been shown in some studies (34,44,45) but not in others (41,42). Behaviorally, the motor response to subacute MPTP is quite variable. In general, MPTP causes a transient hyperactivity immediately after injection, followed by some decrease in activity, but the activity returns to normal after 5-7 d (46). Despite the evidence for...

Pharmaceutical interest

There is an expanding body of evidence to suggest that over representation of atypical Parkinsonism and progressive supranuclear palsy in the French West Indies could be due to the ingestion of Annona muricata L. A case-control work carried on 87 patients with Parkinsonism indicates that 29 patients with progressive supranuclear palsy and 30 patients with atypical Parkinsonism were regularly ingesting the fruit of Annona muricata L. (Caparros-Lefebvre D et al., 1999). Movement disorder is a symptom of extrapyramidal motor dysfunction and a prominent manifestation of diseases affecting the basal ganglia. The basal ganglia receives impulses from different parts of the cerebral cortex and plays a key role in the control of movement. The basal ganglia consists of the caudate nucleus, putamen, globus pallidus, substancia nigra and subthalamic nucleus, which are interconnected by dopaminergic and cholinergic neurons, deep within the cerebral hemispheres (Fig. 5). Under normal condition, the...

Non Invasive CNS Drug Delivery

Cns Drug Formulations

In order to dramatically improve lipophilicity, drug can also be conjugated to a lipid moiety, such as fatty acid, glyceride or phospholipid. For example, several acid-containing drugs, including levodopa, GABA, niflumic acid, valproate or vigabatrin have been coupled to diglycerides or modified diglycerides (52). A promising prodrug has been developed to treat Parkinson's disease. SPD148903 represents a new type of prodrug. The compound has an enone structure that undergoes oxidative bioactivation to the catecholamine S-5,6-diOH-DPAT, which is delivered enantioselectively into the CNS. S-5,6-diOH-DPAT displays mixed dopamine D(1) D(2) receptor agonist properties similar to apomorphine. This concept has the potential to improve therapeutic outcomes in Parkinson's disease by complimenting L-dopa therapy, the current treatment of choice (63). Rotigotine (Neupro) is formulated as a transdermal delivery system designed to provide a selective, non-ergot D3 D2 D1 agonist to the systemic...

Aetiology And Prevention

If the symptoms of PD arise when nigra cell loss results in a particular depletion of striatal DA (e.g. 50 or more) and, as is generally assumed, there is a gradual loss of nigra cells during ageing then we should all develop PD if we live long enough. Fortunately this is not the case as many people can reach 90 or 100 years without developing PD. In fact, PM studies show that in normal subjects nigra DA cell loss proceeds at 4-5 per 10 years but in PD sufferers it occurs at almost ten times this level (Fearnley and Lees 1991). Thus either the gradual loss of nigral cells and striatal DA is accelerated for some reason in certain people, so that these markers fall to below 50 of normal around 5560 years, or some people experience a specific event (or events) during life which acutely reduces DA concentration. This could be to a level which is not enough to produce PD at the time but ensures that when a natural ageing loss of DA is superimposed on it the critical low level will be...

Regulation of tyrosine hydroxylase activity

Metabolism Noradrenaline

Receptor is unknown but it has been suggested that a dysfunction of I2-receptors could contribute to neurodegenerative disorders such as dementia and Parkinson's disease. There is also some evidence for subtypes of COMT but this has not yet been exploited pharmacologically. Certainly, the majority of COMT is found as soluble enzyme in the cell cytosol but a small proportion of neuronal enzyme appears to be membrane bound. The functional distinction between these different sources of COMT is unknown. COMT inhibitors also exist (e.g. pyrogallol), mostly as catechol derivatives, but so far, most have proved to be highly toxic. Only recently have drugs been developed which are selective for COMT one of these agents, tolcapone, is used currently in treatment of Parkinson's disease (see Chapter 15).

Neuronal Actions of Amphetamine in the Rat Brain

The inhibition of firing of catecholamine neurons resulting from amphetamine administration is likely due to activation of somatodendritic autoreceptors. This causes a hyperpolarization of the somatodendritic membrane of both locus coeruleus noradrenergic and substantia nigra dopamine neurons, probably as a consequence of an increase in potassium conductance (Lacey et al. 1987 Williams et al. 1985). Amphetamine can alter neostriatal unit activity directly by enhancing the release of dopamine from terminals of the midbrain dopamine projections of the substantia nigra and, at higher doses, by increasing serotonin release in the neostriatum. It may also indirectly alter neostriatal activity by changing activity in systems that project into the neostriatum, including the neocortex. thalamus, and amygdala. The net effect of amphetamine on neostriatal activity will be determined by the relative magnitudes of these various influences. In our studies, we examined how amphetamine altered the...

Prophylactic Use of Anticholinergics in Patients on Long Term Neuroleptic Treatment a Consensus Statement u

Anticholinergics (that is, agents which antagonise the action of acetylcholine at muscarinic receptor sites) are not only commonly used for the treatment of early neuroleptic-induced extrapyramidal side-effects (Parkinsonism, dystonia), but are also sometimes administered from the onset of antipsychotic therapy, with the aim of preventing the occurrence of such effects. Nevertheless, several arguments against the prescription of anti-Parkinsonian preventive medication can be advanced (h) Many patients on antipsychotic therapy do not develop Parkinsonism, so that anti-Parkinsonian preventive treatment is sometimes unnecessary. On the basis of these considerations, the prophylactic use of anticholinergics in patients on neuroleptic treatment is not recommended, and may be justified only early in treatment (after which it should be discontinued and its need should be reevaluated. As a rule, these components should be used only when Parkinsonism has actually developed, and when other...

Cannabinoids in the Hypothalamus and Pituitary

Christmas Pics Color

Schematic drawing of different forebrain and midbrain areas to show the presence of cannabinoid receptor immunoreactivity (darkspots). Differences between fibres and cell bodies are not shown. Also not shown are quantitative differences between different areas in CBi receptor density. Only structures expressing CBi receptor immunoreactivity are labelled. The numbers indicate the distance from the interaural line (according to the Paxinos-Watson atlas, see also Fig. 1 for explanations). Abbreviations of structures labelled in this and in consecutive figures (in alphabetical order) 2n,optic nerve i , third ventricle A77,A11 dopamine cells A13, A13 dopamine cells aca, anterior commissure Acb,accumbens nucleus AHA, anterior hypothalamic area DMH, dorsomedial hypothalamic nucleus f, fornix fr, fasciculus retroflexus LH, lateral hypothalamic area LV, lateral ventricle mfb, median forebrain bundle MPO, medial preoptic nucleus MS, medial septal nucleus mt,mamillothalamictract...

Drug Drug Interactions General

Levodopa Potentiation or prolongation of other drug effects due to inhibition of hepatic drug-metabolizing enzymes Alcohol (all types) Anesthetics Antihistamines Antiparkinsonian agents Barbiturates Benzodiazepines Chloral hydrate Hypoglycemic agents Opiate analgesics Thyroid extract Tricyclic antidepressants

Measurement of Cannabinoid Receptor Density

CB1 Receptor Mapping Autoradiographic studies with high-affinity THC analogs both in rat brain tissue (Herkenham et al. 1990) and in postmortem human brain tissue (Thomas et al. 1992 Biegon and Kerman 2001) have demonstrated high concentrations of cannabinoid receptors in the basal ganglia and especially in its outflow nuclei, the globus pallidus, and substantia nigra. High concentrations are also found in hippocampus and cerebellum. The cerebral cortex, especially the cingulate gyrus, also has a fairly high CB1 receptor density. Some other regions, including most of the brainstem and the thalamus, contain few CB1 receptors.

Neurotransmitter Systems

Ips Drug Screening

Low doses of the dopamine agonist, apomorphine, induce SWS and, in humans, dopamine agonists can induce somnolence which is a problem when treating Parkinson's disease. This action is thought to be due to activation of presynaptic D2-autoreceptors and some antagonists of this receptor increase waking state and reduce both non-REM and REM sleep. That a reduction in firing of dopaminergic neurons is associated with reduced arousal is consistent with evidence that local infusion of GABA into the dopaminergic ventral tegmental area also reduces waking. However, others have suggested that activation of postsynaptic D2-receptors in the dorsal striatum is responsible.

Pharmacology Of The Dopamine Synapse

Those for the D2 receptor (e.g. bromocriptine) have a particular value in the treatment of Parkinson's disease by reproducing the effects of the dopamine lost through degeneration of the nigrostriatal tract (Chapter 15). They are also used to reduce the undesirable effects of prolactinaemia (high plasma prolactin), such as amenorrhoea and galactorrhoea.

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