Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 relatively recent development of the psychosocial rehabilitation has its origins mainly in the progress of modern psychopharmacology, the assertion of the rights of the patients and the result of the studies showing that the evolution of persons suffering from severe and persistent mental illnesses can prove to be positive in many cases. In spite of the heterogeneity of the experiences and of the theoretical references, the core principles of the psychosocial rehabilitation imposed themselves. These principles can be classified according to three levels, that of relational ethics, that of the method of intervention and that of the institutional device. A recent study showed that 2.4@1000 of the general adult population of the Canton of Vaud live in sociotherapeutic and rehabilitation accommodations. In this sample, there is a important percentage of relatively young persons (55.3% are under 40). In institutional accommodation there is a majority of patients suffering from major personality disorders and addiction (40.6%), followed by psychotic disorders (37.2%), persistent mood disorders (12.3%), neurotic disorders (6.6%) and psycho-organic disorders (3.3%). In home based rehabilitation, the ratio of patients with psychotic disorders is more important (53.1%). This difference would indicate that people with schizophrenia would have a better social outcome than personality disorders with addiction.
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PMID:[Psychosocial rehabilitation at the dawn of the 21st century. I: Principles, population targets, and pathologic causes]. 1520 48

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

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

Tobacco dependence among individuals with a mental illness or an addiction is a tremendous problem that goes largely ignored. Studies of genetics, neuroimaging, and nicotinic receptors support a neurobiological link between tobacco use and alcohol dependence, drug dependence, schizophrenia, depression, attention-deficit hyperactivity disorder (ADHD), and anxiety disorders. This paper summarizes the recent literature on this topic and discusses how treatment for tobacco can no longer be ignored in mental-health and addiction-treatment settings. More research is needed as well as a national organized effort to address tobacco in this large segment of smokers.
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PMID:Addressing tobacco among individuals with a mental illness or an addiction. 1523 8

We used exploratory and confirmatory statistical approaches to study the severity of neuropsychological (NP) impairment in 42 crack/cocaine addicted subjects and in 112 comparison subjects (40 alcoholics and 72 controls). Twenty neuropsychological test indices most reliably defining predetermined cognitive domains were submitted to exploratory factor analysis. A four-dimensional model of neurocognitive function was derived: Verbal Knowledge, Visual Memory, Verbal Memory, and Attention/Executive functioning accounted for 63% of the variance. We then examined this model's association with resting glucose metabolism in the brain reward circuit measured with 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography. Results revealed that (1) cocaine addicted individuals had a generalized mild level of neurocognitive impairment (<1 S.D. below control mean); and (2) controlling for age and education, relative metabolism in the dorsolateral prefrontal cortex significantly predicted the Visual Memory and Verbal Memory factors and relative metabolism in the anterior cingulate gyrus significantly predicted the Attention/Executive factor. Nevertheless, it remains to be determined whether metabolic changes in these regions are associated with addiction. Our results also suggest that compared to cocaine, alcohol has a more detrimental effect on Attention/Executive functioning, as assessed with traditional NP measures. We conclude that relative to other psychopathological disorders (such as schizophrenia), the severity of neuropsychological impairment in cocaine addiction is modest, albeit not indicative of the absence of neurocognitive dysfunction. The impact of such small differences in performance on quality of life, and possibly on craving and relapse, may be substantial. Tasks that simulate real-life decision-making or that target specific putative cognitive-behavioral or motivational-emotional mechanisms might offer greater sensitivity in characterizing the changes that accompany addiction to drugs. Obtaining valid estimates of alcohol use in cocaine addicted subjects is essential in characterizing neurocognitive functioning in individuals addicted to drugs.
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PMID:Severity of neuropsychological impairment in cocaine and alcohol addiction: association with metabolism in the prefrontal cortex. 1524 83

The prevalence of comorbidity of psychosis and substance abuse/addiction has been on the rise during the last 10-20 years. Meanwhile, dual diagnosis patients (DD patients) represent a large core group among patients with schizophrenia, and they are difficult to treat. Biological, psychological, and social factors may account for the comorbidity, and the single factors may interact with each other. DD patients tend to have poor compliance and unfavorable outcomes with frequent psychotic relapses and hospitalizations. Efficient treatment models integrate traditional psychiatric therapy and therapy of addiction and modify or adjust the two components to each other. The most successful programs offer integrated treatment for both disorders in one setting. These programs focus on outpatient treatment, they offer pharmacotherapy, motivation therapy, psychoeducation, cognitive-behavioral therapy, and family interventions, and they can achieve significant improvements of social adjustment and decreases of substance use.
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PMID:[Dual diagnosis of psychosis and addiction. From principles to practice]. 1529 8

Adolescence comes in association with puberty, when maturation and rearrangement of major neurotransmitter pathways and functions are still taking place. The neurobiological processes occurring in the brain during this developmental period have been so far poorly investigated. Yet, it is during adolescence that some major neuropsychiatric disorders may become evident, including ADHD, schizophrenia, and drug abuse. Moreover, the age-related neurobehavioural plasticity renders adolescents particularly vulnerable to the consequences of psychoactive drug exposure. In this view, there is an increased likelihood that addiction will develop when psychoactive drug use starts early during adolescence. From all these observations adolescence emerges as a critical phase in development. In the present review, we focus on recent neurobiological characterization of adolescent rats and mice. As for vulnerability to addictive behaviour, nicotine exposure during adolescence dose-dependently down-regulated levels of AMPA GluR2/3 subunits in the striatum, suggesting a reduced neurobehavioural plasticity in adult subjects. Comparable exposure during adulthood had opposite effects. It was found consistently that exposure to nicotine during adolescence, but not similar exposure in the post-adolescent period, increased the expression of specific subunits of the acetylcholine receptor in adult rats, thus enhancing the reinforcing efficacy of nicotine in a self-administration paradigm. The present data identified a specific age-window, characterized by long-term effects on behavioural and neurochemical indexes, of vulnerability. With respect to potential therapeutic approaches in ADHD, we studied the adolescent spontaneously-hypertensive-rat (SHR) in an intolerance-to-delay operant-behaviour paradigm. The model was further validated by the finding that impulsivity was reduced by chronic methylphenidate administration. Impulsive SHR animals were characterized by reduced cannabinoid CB1 receptor density in the prefrontal cortex. Interestingly, an acute cannabinoid agonist increased levels of self-control behaviour in these animals. The present data suggest that pharmacological modulation of the cannabinoid system might improve some behavioural anomalies seen in ADHD. In conclusion, modelling the adolescent phase in rats and mice appears to be useful for the investigation of determinants of vulnerability to addiction and to other early-onset neuropsychiatric disorders.
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PMID:Windows of vulnerability to psychopathology and therapeutic strategy in the adolescent rodent model. 1534 57

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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