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)

Cannabinoids represent one of the most commonly used hallucinogenic drug classes. In addition, cannabis use is a primary risk factor for schizophrenia in susceptible individuals and can potently modulate the emotional salience of sensory stimuli. We report that systemic activation or blockade of cannabinoid CB1 receptors modulates emotional associative learning and memory formation in a subpopulation of neurons in the mammalian medial prefrontal cortex (mPFC) that receives functional input from the basolateral amygdala (BLA). Using in vivo single-unit recordings in rats, we found that a CB1 receptor agonist potentiated the response of medial prefrontal cortical neurons to olfactory cues paired previously with a footshock, whereas this associative responding was prevented by a CB1 receptor antagonist. In an olfactory fear-conditioning procedure, CB1 agonist microinfusions into the mPFC enabled behavioral responses to olfactory cues paired with normally subthreshold footshock, whereas the antagonist completely blocked emotional learning. These results are the first demonstration that cannabinoid signaling in the mPFC can modulate the magnitude of neuronal emotional learning plasticity and memory formation through functional inputs from the BLA.
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PMID:Cannabinoids Potentiate Emotional Learning Plasticity in Neurons of the Medial Prefrontal Cortex through Basolateral Amygdala Inputs. 1677 33

We studied central cannabinoid CB1 receptors in a schizophrenic patient using the pyrazole derivative AM281 labelled with the positron-emitting nuclide iodine-124. A dynamic positron emission tomography (PET) acquisition with simultaneous blood sampling was performed up to 1.5 h post-injection. The classical Logan plot analysis was applied to generate a three-dimensional map of distribution volume (DV). The map was spatially normalised into the Montreal Neurological Institute stereotactic space. Using a volume of interest (VOI) template, mean values of DV were extracted from multiple grey matter regions and white matter (as a reference). As a measure of regional receptor availability, ratios of DV in grey matter to DV in white matter minus one (DVR-1) were calculated. The highest receptor binding was observed in the striatum and the pallidum (DVR-1: 0.35-0.37). Binding in basal ganglia regions was lower on the left than the right side. Moderately high binding was seen in the frontal cortex (0.22), the temporal cortex (0.18) and the cerebellum (0.15). In conclusion, 124I-AM281 PET can be used to reveal areas with prominent CB1 receptor binding. Nevertheless, limited image contrast and relatively high radiation exposure (physical half-life of 124I: 4 days) have to be taken into account. Asymmetric receptor binding may possibly reflect pathologic changes in schizophrenia.
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PMID:Feasibility of central cannabinoid CB1 receptor imaging with [124I]AM281 PET demonstrated in a schizophrenic patient. 1691 17

Cortical metabotropic glutamate receptors (mGluRs) seem to be involved in habituation of simple stimulus-bound behaviors (e.g., habituation to acoustic startle or odor-elicited orienting response). Habituation deficits may contribute to the cognitive symptoms of schizophrenia. In the present study, male NMRI mice were injected with mGluR2/3 antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid (LY-341495) 30 min before being placed into novel arenas for automatic motor activity recording (2-h sessions). Administration of LY-341495 (1-10 mg/kg s.c.) dose-dependently prevented the habituation of the locomotor activity. Effects of LY-341495 (10 mg/kg) were fully and dose-dependently reversed by i.p. administration of haloperidol (0.03-0.3 mg/kg), clozapine (1-10 mg/kg), risperidone (0.01-0.1 mg/kg), olanzapine (0.3-3 mg/kg), aripiprazole (1-10 mg/kg), and sulpiride (3-30 mg/kg), each of which was given 15 min before the test. Effects of antipsychotic drugs were observed at the dose levels that did not affect spontaneous motor activity. LY-341495-induced delayed hyperactivity was also partially attenuated by lithium (50-200 mg/kg), amisulpride (1-10 mg/kg), and the selective dopamine D3 antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011A; 3-30 mg/kg). Application of diazepam, imipramine, or several agonists and/or antagonists acting at various receptors that are thought to be relevant for antipsychotic treatment [e.g., 5-hydroxytryptamine (5-HT)(2A), 5-HT(3), and 5-HT(6) antagonists; 5-HT(1A) agonist; D4 antagonist; CB1 antagonist; ampakines; and glycine transporter inhibitor) had no appreciable effects. Thus, behavioral deficits induced by mGluR2/3 blockade (such as delayed motor hyperactivity) are selectively reversed by clinically used antipsychotic drugs.
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PMID:Habituation deficits induced by metabotropic glutamate receptors 2/3 receptor blockade in mice: reversal by antipsychotic drugs. 1713 47

The contribution of the endocannabinoid system to dopamine-mediated disorganized behavior in schizophrenia is discussed. We used a model of concurrent stimulation of dopamine D1 and D2 receptors to evaluate the role of this system in dopamine-mediated stereotypies measured in a hole-board test. Pretreatment with the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 1 mg/kg) potentiated stereotyped behavior induced by coadministration of the dopamine D1 receptor agonist SKF 38393 (0.05, 0.1 and 1 mg/kg) and the dopamine D2 receptor agonist quinpirole (0.25 mg/kg). Thus, the endocannabinoid system acts as a brake for abnormal behavior associated with dopaminergic overactivation.
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PMID:Cannabinoid CB1 receptor antagonism markedly increases dopamine receptor-mediated stereotypies. 1729 87

Clinical and laboratory findings suggest that cannabinoids and their receptors are implicated in schizophrenia. The role of cannabinoids in schizophrenia remains however poorly understood, as data are often contradictory. The primary aim of this study was to investigate whether the cannabinoid CB1 receptor antagonists rimonabant and AM251 are able to reverse deficits of sensorimotor gating induced by phencyclidine and to mimic the 'atypical' antipsychotic profile of clozapine. The prepulse inhibition (PPI) of the startle reflex was used to measure deficits of sensorimotor gating. PPI-disruptive effects of phencyclidine and their antagonism by rimonabant, AM251, and clozapine were studied in rats. The effects of rimonabant were carefully examined taking into account dose ranges, vehicle, and route of administration. We also examined the ability of rimonabant to reduce the PPI-disruptive effects of dizocilpine and apomorphine. Rimonabant as well as AM251 significantly counteracted the phencyclidine-disruptive model of PPI, comparable to the restoring effect of clozapine; no augmentation effect was observed with rimonabant and clozapine as cotreatment. Rimonabant also significantly attenuated the PPI disruptive effects of dizocilpine and apomorphine. Taken together, our results indicate that CB1 receptor antagonists do produce 'atypical' antipsychotic profile mimicking that of clozapine in the phencyclidine disruption of sensorimotor gating. Our findings further suggest that CB1 receptor antagonism may be involved in restoring disturbed interactions between the activity of the endocannabinoid system and glutamate neurotransmitter system implied in schizophrenia.
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PMID:Cannabinoid receptor antagonists counteract sensorimotor gating deficits in the phencyclidine model of psychosis. 1729 6

Recent epidemiological studies and advances in understanding of brain cannabinoid function have renewed interest in the long-recognized association between cannabinoids and psychosis. This chapter presents evidence supporting and refuting the association between cannabinoids and psychosis. Cannabinoids can induce acute transient psychotic symptoms or an acute psychosis in some individuals. What makes some individuals vulnerable to cannabinoid-related psychosis is unclear. Also clear is that cannabinoids can also exacerbate psychosis in individuals with an established psychotic disorder, and these exacerbations may last beyond the period of intoxication. Less clear is whether cannabis causes a persistent de novo psychosis. The available evidence meets many but not all the criteria for causality, including dose-response, temporality, direction, specificity, and biological plausibility. On the other hand, the large majority of individuals exposed to cannabinoids do not experience psychosis or develop schizophrenia and the rates of schizophrenia have not increased commensurate with the increase in rates of cannabis use. Similar to smoking and lung cancer, it is more likely that cannabis exposure is a component cause that interacts with other factors, for example, genetic risk, to "cause" schizophrenia. Nevertheless, in the absence of known causes of schizophrenia, the role of component causes such as cannabis exposure (exogenous hypothesis) is important and warrants further study. There is also tantalizing evidence from postmortem, neurochemical, and genetic studies suggesting CB1 receptor dysfunction (endogenous hypothesis) in schizophrenia that warrants further investigation. Further work is necessary to identify those factors that place individuals at higher risk for cannabinoid-related psychosis, to identify the biological mechanisms underlying the risks and to further study whether CB1 receptor dysfunction contributes to the pathophysiology of psychotic disorders.
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PMID:Cannabinoids and psychosis. 1734 65

Substance abuse is the most prevalent comorbid psychiatric condition associated with schizophrenia. Cannabis is a drug frequently used for schizophrenic patients. In the last decades the endocannabinoid system and their endogenous ligands have been discovered. Endogenous cannabinoids act in the brain on cannabinoid CB1 receptor. On the other hand this system may be involved in several brain functions through neuromodulation dopaminergic and other neurotransmitter system involved in schizophrenic and substance abuse disorders. Advances of genetic research have addressed the focus on the search of candidate genes for both disorders. In this review we have summarized the studies published about the CNR1 gene on schizophrenia and substance abuse disorders.
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PMID:[Endocannabinoid system and CNR1 gene polymorphisms in schizophrenia and addictive disorders]. 1740 83

The endocannabinoid system (ECS) plays an important and not yet fully understood role in hypothalamic and peripheral regulation of food intake, obesity, and metabolism. Two frequent single nucleotide polymorphisms (snp) have been identified in members of the ECS: the 1359 G/A variant in the cannabinoid receptor 1 ( CB1) and the P129T polymorphism in fatty acid amide hydrolase ( FAAH), a key degradation enzyme of endocannabinoids. -While for the 1359 G/A variant an association has been shown only with psychiatric diseases such as drug-abusing schizophrenia, the P129T polymorphism has recently been proved to be correlated to a higher body mass index (BMI) in a group of black and white Americans. However, no knowledge exists as to whether these variants affect the outcome of a low fat diet in obese subjects. Therefore, we genotyped a group of 451 obese and dyslipidaemic participants and observed the biometric and metabolic outcome of a 6 week low fat diet. While no significance was seen for the 1359 G/A variant, carriers of the P129T mutation in FAAH had a significantly greater decrease in triglycerides and total cholesterol as compared to wild type. The reason for our findings remains to be elucidated, however, a hepatic downregulation of endocannabinoid tone may contribute to the observed outcome in studied subjects.
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PMID:Genetic variation in two proteins of the endocannabinoid system and their influence on body mass index and metabolism under low fat diet. 1753 84

Schizophrenia is one of the most common psychiatric disorders. There is a growing body of evidence associating dysregulation of the endogenous cannabinoid system with the pathogenesis of schizophrenia. In order to test the hypothesis that mutations in the central cannabinoid receptor-1 (CNR1) gene confer susceptibility to the development of schizophrenia, we performed an association study in a group of 104 German patients with schizophrenia and 140 healthy controls, using three polymorphisms within and flanking the coding exon of CNR1 (rs6454674, rs1049353, AL136096). In addition, we analyzed the whole coding region of the CNR1 gene of 50 of the patients by capillary sequencing to detect rare mutations. Our adequately powered study failed to reveal a statistically significant segregation of CNR1 polymorphisms to the diseased or control group. Furthermore, capillary sequencing of CNR1 in a subgroup of study subjects did not show any non-synonymous mutations predicting malfunction of CNR1 in patients with schizophrenia. In conclusion, we could not detect a statistically significant association between mutations in the CNR1 gene and the predisposition to develop schizophrenia. However, further studies are necessary to unravel the relationship between mutations in the CNR1 gene and the genetic susceptibility for the manifestation of certain subtypes or schizophrenia i.e. the predominance of negative or positive symptoms or as predictors of the clinical course.
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PMID:No association of CNR1 gene variations with susceptibility to schizophrenia. 1788 Nov 26

Rearing rats in isolation has been shown to produce behavioral and neurochemical alterations similar to those observed in psychoses such as schizophrenia. Also, a dysregulation in both the endocannabinoid and dopaminergic systems has been implicated in schizophrenia. The aim of this study was to determine if there are differences in CB1 receptor and fatty acid amide hydrolase (FAAH) protein expression, as well as D2 dopamine receptor expression in different brain regions in rats reared in different environmental conditions. Twenty-one-day-old male Sprague-Dawley rats were either reared in individual cages (isolated rats) or in group cages of six per cage (group-housed rats) for 8 weeks. Quantitative fluorescence immunohistochemistry was performed on brain slices using antibodies specific to the CB1 or D2 receptor, or the enzyme FAAH. Raising rats in isolation led to a significant decrease in CB1 receptor expression in the caudate putamen and the amygdala, a significant increase in FAAH expression in the caudate putamen and the nucleus accumbens core and shell, and no significant change in D2 receptor expression in any region studied. These results indicate that the endocannabinoid system is altered in an animal model of aspects of psychosis. This implies that rearing rats under different housing conditions may provide new insight into the role of the endocannabinoid system in the development of psychoses.
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PMID:Effect of social isolation on CB1 and D2 receptor and fatty acid amide hydrolase expression in rats. 1808 30


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