Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PET can map neurotransmitter synthesis, storage, release, binding to receptors, and re-uptake in the brain with tracer concentrations in the picomolar or nanomolar range. Tracers are analogues of naturally occurring precursors or ligands, or are drugs, which bind with varying degrees of specificity to receptor subtypes in the brain. Tracers have been synthesised for many transmitter systems, but dopaminergic and serotonergic neurotransmissions are the main foci of current efforts to selectively trace synthesis, storage, re-uptake, or post-synaptic binding of neurotransmitters. Common measures of the tracer uptake and binding include precursor clearance (k3), a measure of transmitter synthesis and trapping, and binding potential (pB), a measure of the receptor binding per unit of unbound tracer, and hence a measure of the release of the endogenous transmitter, or the occupancy of a drug. Dopamine tracers are used in diseases of the basal ganglia, whereas serotonin, benzodiazepine, and opiate tracers are used in lesions of the cerebral cortex. PET has revealed loss of dopaminergic terminals and dopamine synthetic capacity in Parkinson's disease, MPTP intoxication, and Lesch-Nyhan's syndrome; release of dopamine after administration of cocaine and amphetamine, and in motor activity and cognition; increased synaptic dopamine and release of dopamine, and the 70-90% neuroleptic occupancy of dopamine receptors in the striatum, in patients with schizophrenia; loss of muscarinic and nicotinergic receptors in Alzheimer's disease, and benzodiazepine and opiate receptors in stroke, epilepsy, and Huntington's chorea; altered opiate receptors in chronic pain and drug abuse; and release of opiates in analgesia; but changes in serotonin synthesis, transport, and binding in affective or psychotic disorders remain elusive.
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PMID:[Receptor mapping in living human beings by means of positron emission tomography]. 1157 27

The authors propose that the placebo effect is mediated by reward-related mechanisms. Recent evidence suggests that it is the expectation of reward (in this case, the expectation of clinical benefit) that triggers the placebo response. In Parkinson's disease, the placebo effect is mediated by the release of dopamine in the striatum. The authors argue that placebo-induced dopamine release in limbic structures, particularly in the nucleus accumbens, could also be a major biochemical substrate for the placebo effect encountered in other medical disorders. Other neuroactive substances involved in the reward circuitry (e.g., opioids) are also likely to contribute to the placebo response, and such contribution may be disorder specific (e.g., opioid release in placebo analgesia; serotonin regulation in response to placebo antidepressants). In addition, placebos may have a role in substitution programs for the treatment of drug addiction.
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PMID:The biochemical bases for reward. Implications for the placebo effect. 1244 82

Nicotinic acetylcholine receptors (nAChRs) have been implicated in Alzheimer's disease, Parkinson's disease, epilepsy, nicotine addiction, schizophrenia, and autonomic dysfunctions. Although nicotine may be used therapeutically either alone or in association with other drugs, its beneficial effects are limited by its addictive properties and a number of other side effects. A deeper understanding of nicotinic cholinergic mechanisms is necessary to develop nAChR ligands that are more selective, less toxic, and more therapeutically effective than nicotine. Although there has been significant progress identifying the nAChR subunits that form functional nAChRs, there is limited information associating the location and function of nAChR subtypes in the nervous system. Several groups have genetically engineered mice in which one or more genes encoding nAChR subunits has been deleted or altered. Mice with nAChR mutations targeted to subunits that are highly expressed in the CNS have brought insight into the nAChR mechanisms involved in nicotine addiction, analgesia, aging, and nicotine-induced behaviors. Mutations targeted to nAChR subunits that are highly expressed in the peripheral nervous system have opened a window on the complex mechanisms governing autonomic control of peripheral organs. This review examines nAChRs in the autonomic control of peripheral organ systems as gleaned from studies of nAChR mutant mice.
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PMID:Nicotinic receptor mutant mice in the study of autonomic function. 1276 7

The search for the underlying pathophysiology of schizophrenia has been an active avenue of investigation since the disease was first recognized more than 100 years ago. Although a great deal of the research has been driven by the known pharmacology of effective antipsychotic drugs, i.e., overactivity of the dopamine system, recent advances in neurobiology provide evidence that reduced synaptic connectivity/neurotransmission may play a substantial role in this disorder. One neuropeptide long posited to play a role in the biology of schizophrenia is neurotensin (NT). Central nervous system administration of NT has been shown to produce a wide variety of effects. Because of its close association with the dopamine (DA) system, the role of the NT system in clinical disorders hypothesized to involve DA circuits such as schizophrenia, Parkinson's disease, and drug abuse has been closely scrutinized. In addition, NT neurotransmission has been implicated in regulation of the stress response, stress-induced gastric ulcers, temperature regulation, food consumption, and analgesia. NT also acts as a growth factor in a variety of human cancer cell lines derived from lung, colon, prostate, and pancreas. This review first provides a background of the NT system. Second, data indicating that NT may mediate the effects of antipsychotic drugs are summarized. Third, data implicating NT in the pathophysiology of schizophrenia are described. Finally, evidence suggesting the use of NTergic compounds as novel antipsychotic drugs are presented.
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PMID:Neurotensin, schizophrenia, and antipsychotic drug action. 1500 94

G protein-coupled receptors (GPCRs) have proven to be the most highly favorable class of drug targets in modern pharmacology. Over 90% of nonsensory GPCRs are expressed in the brain, where they play important roles in numerous neuronal functions. GPCRs can be desensitized following activation by agonists by becoming phosphorylated by members of the family of G protein-coupled receptor kinases (GRKs). Phosphorylated receptors are then bound by arrestins, which prevent further stimulation of G proteins and downstream signaling pathways. Discussed in this review are recent progress in understanding basics of GPCR desensitization, novel functional roles, patterns of brain expression, and receptor specificity of GRKs and beta arrestins in major brain functions. In particular, screening of genetically modified mice lacking individual GRKs or beta arrestins for alterations in behavioral and biochemical responses to cocaine and morphine has revealed a functional specificity in dopamine and mu-opioid receptor regulation of locomotion and analgesia. An important and specific role of GRKs and beta arrestins in regulating physiological responsiveness to psychostimulants and morphine suggests potential involvement of these molecules in certain brain disorders, such as addiction, Parkinson's disease, mood disorders, and schizophrenia. Furthermore, the utility of a pharmacological strategy aimed at targeting this GPCR desensitization machinery to regulate brain functions can be envisaged.
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PMID:Desensitization of G protein-coupled receptors and neuronal functions. 1521 28

As befits the coming together of two major national societies, the Bristol meeting attracted a significant array of eminent pharmacologists and physiologists. This was reflected in the presentation of over 350 poster and oral communications stretching over the 3 days, with the host institution contributing substantially to the proceedings. A significant number of communications relating to glutamatergic transmission were presented, which will be the focus of this review. New information was disclosed relating to a novel class of metabotropic glutamate receptor modulators, recent advances in Glu(K5) compounds, AMPA/kainate and AMPA/NMDA receptor discriminators, and NMDA receptor subtype-selective compounds. Disclosures pertain to therapeutic areas including epilepsy, Parkinson's disease, cognitive enhancement, analgesia and psychosis.
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PMID:British Pharmacological Society/The Physiological Society--joint meeting. Advances in glutamatergic pharmacology. 1595 78

Since the discovery of an endogenous cannabinoid system, research into the pharmacology and therapeutic potential of cannabinoids has steadily increased. Two subtypes of G-protein coupled cannabinoid receptors, CB(1) and CB(1), have been cloned and several putative endogenous ligands (endocannabinoids) have been detected during the past 15 years. The main endocannabinoids are arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG), derivatives of arachidonic acid, that are produced "on demand" by cleavage of membrane lipid precursors. Besides phytocannabinoids of the cannabis plant, modulators of the cannabinoid system comprise synthetic agonists and antagonists at the CB receptors and inhibitors of endocannabinoid degradation. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues, including immune system, reproductive and gastrointestinal tracts, sympathetic ganglia, endocrine glands, arteries, lung and heart. There is evidence for some non-receptor dependent mechanisms of cannabinoids and for endocannabinoid effects mediated by vanilloid receptors. Properties of CB receptor agonists that are of therapeutic interest include analgesia, muscle relaxation, immunosuppression, anti-inflammation, antiallergic effects, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects. The current main focus of clinical research is their efficacy in chronic pain and neurological disorders. CB receptor antagonists are under investigation for medical use in obesity and nicotine addiction. Additional potential was proposed for the treatment of alcohol and heroine dependency, schizophrenia, conditions with lowered blood pressure, Parkinson's disease and memory impairment in Alzheimer's disease.
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PMID:Cannabinoids. 1626 85

As people grow old, their need for medications increases dramatically because of the higher incidence of chronic pain, diabetes mellitus, cardiovascular and neurological diseases in the elderly population. Furthermore, the elderly require special consideration with respect to drug delivery, drug interactions and adherence. In particular, patients with chronic neurological diseases often require multiple administration of drugs during the day to maintain constant plasma medication levels, which in turn increases the likelihood of poor adherence. Consequently, several attempts have been made to develop pharmacological preparations that can achieve a constant rate of drug delivery. For example, transdermal lisuride and apomorphine have been shown to reduce motor fluctuations and duration of 'off' periods in advanced Parkinson's disease, while rotigotine allows significant down-titration of levodopa without severe adverse effects. Thus, parkinsonian patients with long-term levodopa syndrome or motor disorders during sleep could benefit from use of transdermal lisuride and apomorphine. Moreover, transdermal dopaminergic drugs, particularly rotigotine, seem the ideal treatment for patients experiencing restless legs syndrome or periodic limb movement disorder during sleep, disorders that are quite common in elderly people or in association with neurodegenerative diseases. Unlike dopaminergic drugs, transdermal treatments for the management of cognitive and behavioural dysfunction in patients with Parkinson's disease and Alzheimer's disease have inconsistent effects and no clearly established role. Nevertheless, because of their favourable pharmacological profile and bioavailability, the cholinesterase inhibitors tacrine and rivastigmine are expected to show at least the same benefits as oral formulations of these drugs, but with fewer severe adverse effects. Transdermal delivery systems play an important role in the management of neuropathic pain. The transdermal lidocaine (lignocaine) patch is recommended as first-line therapy for the treatment of postherpetic neuralgia. Furthermore, in patients with severe persistent pain, transdermal delivery systems using the opioids fentanyl and buprenorphine are able to achieve satisfactory analgesia with good tolerability, comparable to the benefits seen with oral formulations. Transdermal administration is the ideal therapeutic approach for chronic neurological disorders in elderly people because it provides sustained therapeutic plasma levels of drugs, is simple to use, and may reduce systemic adverse effects. Several transdermal delivery systems are currently under investigation for the treatment of Parkinson's disease, Alzheimer's disease and neuropathic pain. Although most transdermal delivery systems treatments cannot be considered as first-line therapy at present, some of them provide clear advantages compared with other routes of administration and may become the preferred treatment in selected patients. In general, however, most transdermal treatments still require long-term evaluation in large patient groups in order to optimise dosages and evaluate the actual incidence of local and systemic adverse effects.
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PMID:Transdermal treatment options for neurological disorders: impact on the elderly. 1682 90

Neuronal nicotinic acetylcholine receptors comprise a heterogeneous class of cationic channels that is present throughout the nervous system. These channels are involved both in physiological functions (including cognition, reward, motor activity and analgesia) and in pathological conditions such as Alzheimer's disease, Parkinson's disease, some forms of epilepsy, depression, autism and schizophrenia. They are also the targets of tobacco-smoking effects and addiction. Neuronal nicotinic acetylcholine receptors are pentamers of homomeric or heteromeric combinations of alpha (alpha2-alpha10) and beta (beta2-beta4) subunits, which have different pharmacological and biophysical properties and locations in the brain. The lack of subtype-specific ligands and the fact that many neuronal cells express multiple subtypes initially hampered the identification of the different native nicotinic acetylcholine receptor subtypes, but the increasing knowledge of subtype composition and roles will be of considerable interest for the development of new and clinically useful nicotinic acetylcholine receptor ligands.
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PMID:Brain nicotinic acetylcholine receptors: native subtypes and their relevance. 1687 83

Recent studies have begun to unveil some of the biochemical bases of the placebo effect. Thus, while placebo analgesia is related to the release of endogenous opioids, placebo-induced dopamine release leads to motor improvement in Parkinson's disease. A theory proposes that the placebo effect is mediated by the activation of the reward circuitry. These biochemical findings indicate that the placebo effect is real, and suggest that many ethical arguments and controversies regarding the use of placebos should perhaps be reconsidered. While it may be advisable to minimize the placebo effect in clinical trials in order to estimate the pure effect of the active treatment, acting in the patient's best interest may require maximizing the placebo effect in the usual clinical setting.
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PMID:[Placebo, placebo effect and clinical trials]. 1732 30


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