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)

Nicotine addiction is the single largest preventable cause of morbidity and mortality in the Western World. Smoking is not any more just a bad habit, but a substance addiction problem. The pharmacological aspects of nicotine show that this substance has a broad distribution in the different body compartnents, due mainly to its lipophilic characteristic. There are nicotinic receptors as members of cholinergic receptors' family. They are located in neuromuscular junction and in the central nervous system (CNS). Although they are similar, pentameric structure with an ionic channel to sodium, there are some differences in the protein chains characteristics. Repeated administration of nicotine in rats, results in the sensitization phenomenon, which produces increase in the behavioral locomotor activity response. It has been found that most psychostimulants-induced behavioral sensitization through a nicotine receptor activation. Nicotine receptors in CNS are located mainly in presynaptic membrane and in that way they regulated the release of several neurotransmitters, among them acetylcholine, dopamine, serotonin, and norepinephrine. In some activities like sleep-wake cycle, nicotine receptors have a functional significance. Nicotine receptor stimulation promotes wake time, reduces both, total sleep time and rapid eye movement sleep (REMS). About nicotine dependence, this substance full fills all the criteria for dependence and withdrawal syndrome. There are some people that have more vulnerability for to become nicotine dependent, those are psychiatric patients. Among them schizophrenia, major depression, anxiety disorders and attention deficit disorder, represent the best example in this area. Nicotine may have some beneficial effects, among them are some neuroprotective effects in disorders like Parkinson's disease, and Gilles de la Tourette' syndrome. Also there are several evidences that support the role of nicotine in cognitive improvement functions like attention, concentration, and memory. Finally there are several strategies to deal with nicotine dependence, Nicotine Replacement Therapy (NRT), which are nicotine chewing-gum, transdermal nicotine patches, and nicotine inhalators device. Also some antidepressants like bupropion has shown to be effective in smoking cessation treatment. To know more about nicotine phenomenon would be important, because that will allow a more mature perspective about the damage and beneficial effects of that substance.
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PMID:Nicotine dependence and psychiatric disorders. 1501 38

The aromatic beta-carbolines norharman and harman have been implicated in a number of human diseases including Parkinson's disease, tremor, addiction and cancer. It has been shown that these compounds are normal body constituents formed endogenously but external sources have been identified. Here, we summarise literature data on levels of norharman and harman in fried meat and fish, meat extracts, alcoholic drinks, and coffee brews. Other sources include edible and medicinal plants but tobacco smoke has been identified as a major source. Exposure levels from these different dietary sources are estimated to a maximum of 4 microg norharman per kg body weight (bw) per day and 1 microg harman per kg bw per day. Exposure via tobacco smoke depends on smoking habits and type of cigarettes but can be estimated to 1.1 microg/kg bw for norharman and 0.6 microg/kg bw for harman per package of cigarettes smoked. Studies on toxicokinetics indicate that inhalative exposure leads to a rapid increase in plasma levels and high bioavailability of norharman and harman. Oral bioavailability is lower but there are indications that sublingual absorption may increase dietary uptake of beta-carbolines. Endogenous formation can be estimated to be 50-100 ng/kg bw per day for norharman and about 20 ng/kg bw per day for harman but these rates may increase with high intake of precursors. Biomarker studies on plasma levels of beta-carbolines reported on elevated levels of norharman, harman or both in diseased patients, alcoholics and following tobacco smoking or consumption of beta-carboline-containing food. Cigarette smoking has been identified as major influence but dietary exposure may contribute to exposure.
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PMID:Exposure to beta-carbolines norharman and harman. 1503 3

Since Parkinson's disease (PD) patients could suffer from a reward deficiency syndrome, they are particularly prone to develop addictive behaviours. Dopamine is involved in reward processing and in addiction. Pulsatile administration of antiparkinsonian drugs may lead to the development of dyskinesias and addictive behaviours. However, this phenomenon occurs in very few cases. Indeed, both processes share molecular mechanisms although with some differences such as the topography of the changes (it predominates in motor regions in PD with dyskinesias and in limbic regions in addictions). Nevertheless, investigations conducted to know the physiopathology of levodopa-induced dyskinesias may lead to important cues for understanding the underlying mechanisms responsible for addiction. Thus, this may have important implications for the discovery of new therapeutic strategies.
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PMID:[Hypothesis: Parkinson's disease, reward deficiency syndrome and addictive effects of levodopa]. 1508 61

The endogenous cannabinoid system is a new signaling system composed by the central (CB1) and the peripheral (CB2) receptors, and several lipid transmitters including anandamide and 2-arachidonylglycerol. This system is the target of natural cannabinoids, the psychoactive constituents of Cannabis sativa preparations (marijuana, hashish). Acute and chronic cannabis exposure has been associated with subjective feelings of pleasure and relaxation, but also to the onset of psychiatric syndromes, a decrease of the efficacy of neuroleptics and alterations in the extrapyramidal system regulation of motor activity. These actions point to a tight association of the cannabinoid system with the brain dopaminergic circuits involved in addiction, the clinical manifestation of positive symptoms of schizophrenia and Parkinson's disease. The present work discusses anatomical, biochemical and pharmacological evidences supporting a role for the endogenous cannabinoid system in the modulation of dopaminergic transmission. Cannabinoid CB1 receptors are present in dopamine projecting brain areas. In primates and certain rat strains it is also located in dopamine cells of the A8, A9 and A10 mesencephalic cell groups, as well as in hypothalamic dopaminergic neurons controlling prolactin secretion. CB1 receptors co-localize with dopamine D1/D2 receptors in dopamine projecting fields. Manipulation of dopaminergic transmission is able to alter the synthesis and release of anandamide as well as the expression of CB1 receptors. Additionally, CB1 receptors can switch its transduction mechanism to oppose to the ongoing dopamine signaling. Acute blockade of CB1 receptor potentiates the facilitatory role of dopamine D2 receptor agonists on movement. CB1 stimulation results in sensitization to the motor effects of indirect dopaminergic agonists. The dynamics of these changes indicate that the cannabinoid system is an activity-dependent modulator of dopaminergic transmission, an hypothesis relevant for the design of new therapeutic strategies for dopamine-related diseases such as the psychosis and Parkinson's disease.
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PMID:Role of the endogenous cannabinoid system as a modulator of dopamine transmission: implications for Parkinson's disease and schizophrenia. 1511 Dec 59

The D(3) dopamine receptor has been implicated in several neuropsychiatric disorders, including schizophrenia, Parkinson's disease and addiction. Sequence variation in the D(3) gene can lead to subtle alteration in receptor structure or gene expression and thus to a different phenotype. In this study we examine the sequence variation in the D(3) gene in 96 rat strains and substrains. Interestingly, the analyses revealed 10 polymorphisms in the 5'flanking region and four polymorphisms in intronic regions of the gene. Moreover, two single nucleotide polymorphisms (SNPs) that result in amino acid changes were found in the last exon of the D(3) gene in the RNU/Mol strain. Additionally, bioinformatic analysis of the 5'flanking region and first intron of the gene revealed putative transcription factor binding sites that are conserved between mouse and human and are affected by the SNPs, possibly resulting in altered regulation of the subsequent transcription factor.
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PMID:Identifying polymorphisms in the Rattus norvegicus D3 dopamine receptor gene and regulatory region. 1514 9

The brain contains 2 major groups of dopamine neurons. One is located in the arcuate nucleus of the hypothalamic median eminence and is involved in neuroendocrine regulation. The other, which is the subject of this article, is located in the ventral mesencephalon and projects to the forebrain. Although dopamine neurons are few (<1/100 000 brain neurons), they play an important role in regulating several aspects of basic brain function. They are necessary for the normal tasks of the regions they innervate, including motor behavior, motivation, and working memory. Dopamine neurons are also a central element in the brain reward system that controls the learning of many behaviors. Disappearance of nigrostriatal neurons results in Parkinson disease, whereas blockade of dopamine receptors has therapeutic effects in psychosis. Finally, artificial increase in dopamine transmission is the common mechanism of action of drugs of abuse that leads to addiction. Understanding how dopamine works is a major goal of neurobiology. Much progress has been accomplished in identifying the intracellular signaling pathways that underlie the immediate actions of dopamine and account for its long-term effects on brain properties. Recent findings allow us to identify molecules that may represent future therapeutic targets in neurology and psychiatry.
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PMID:The neurobiology of dopamine signaling. 1514 38

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

We describe two cases where increases in dopaminergic therapy were initiated by the patients due to perceived deterioration in symptoms of idiopathic Parkinson's disease. Shortly afterwards, both cases also met clinical criteria for pathological gambling. To date, only 29 cases of pathological gambling in patients with Parkinson's disease have been reported. This "pathological gambling disorder" is an addiction-like behavior triggered by excessive dopaminergic drugs and does not respond to standard therapy for pathological gambling. It only responds to an adjustment of Parkinson's disease therapy.
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PMID:Pathological gambling in two patients on dopamine replacement therapy for Parkinson's disease. 1522 29

Dopaminergic dysfunction is an important pathogenetic factor for brain pathologies such as Parkinson's disease, ADHD, schizophrenia, and addiction as well as for metabolic disorders and anorexia. Dopaminergic neurons projecting from the midbrain to forebrain regions, such as the nucleus accumbens and the prefrontal cortex, regulate motor and cognitive functions and coordinate the patterned response of the organism to sensory, affective, and rewarding stimuli. In this study, we showed that dopaminergic neurotransmission is highly dependent on M4 cholinergic muscarinic receptor function. Using in vivo microdialysis, we found elevated dopamine (DA) basal values and enhanced DA response to psychostimulants in the nucleus accumbens of M4 knockout mice. We also demonstrated impaired homeostatic control of cholinergic activity that leads to increased basal acetylcholine efflux in the midbrain of these animals. Thus, loss of M4 muscarinic receptor control of cholinergic function effectuates a state of dopaminergic hyperexcitability. This may be responsible for pathological conditions, in which appetitive motivation as well as affective and cognitive processing is impaired. We propose that M4 receptor agonists could represent an innovative strategy for the treatment of pathologies associated with hyperdopaminergia.
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PMID:M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related CNS pathologies. 1523 26

Catecholaminergic neurons control diverse cognitive, motor, and endocrine functions and are associated with multiple psychiatric and neurodegenerative disorders. We present global gene-expression profiles that define the four major classes of dopaminergic (DA) and noradrenergic neurons in the brain. Hypothalamic DA neurons and noradrenergic neurons in the locus coeruleus display distinct group-specific signatures of transporters, channels, transcription, plasticity, axon-guidance, and survival factors. In contrast, the transcriptomes of midbrain DA neurons of the substantia nigra and the ventral tegmental area are closely related with <1% of differentially expressed genes. Transcripts implicated in neural plasticity and survival are enriched in ventral tegmental area neurons, consistent with their role in schizophrenia and addiction and their decreased vulnerability in Parkinson's disease. The molecular profiles presented provide a basis for understanding the common and population-specific properties of catecholaminergic neurons and will facilitate the development of selective drugs.
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PMID:Molecular basis for catecholaminergic neuron diversity. 1535 88


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