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)

Cannabis consumption may induce psychotic states in normal individuals, worsen psychotic symptoms of schizophrenic patients, and may facilitate precipitation of schizophrenia in vulnerable individuals. Recent studies provide additional biological and genetic evidence for the cannabinoid hypothesis of schizophrenia. Examinations using [3H]CP-55940 or [3H]SR141716A revealed that the density of CB1 receptors, a central type of cannabinoid receptor, is increased in subregions of the prefrontal cortex in schizophrenia. Anandamide, an endogenous cannabinoid, is also increased in the CSF in schizophrenia. A genetic study revealed that the CNR1 gene, which encodes CB1 receptors, is associated with schizophrenia, especially the hebephrenic type. Individuals with a 9-repeat allele of an AAT-repeat polymorphism of the gene may have a 2.3-fold higher susceptibility to schizophrenia. Recent findings consistently indicate that hyperactivity of the central cannabinoid system is involved in the pathogenesis of schizophrenia or the neural mechanisms of negative symptoms.
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PMID:New perspectives in the studies on endocannabinoid and cannabis: cannabinoid receptors and schizophrenia. 1561 77

Cannabinoids are the constituents of the marijuana plants. The central effects of exogenous cannabinoids are implicated in enhancing mood, altering emotional states, and interfering in the formation of short-term memory. Cannabinoid receptors are G protein-coupled receptors with seven transmembrane domains that are expressed on the cell surface with their binding domain exposed to the extracellular space. To date, two cannabinoid receptors have been cloned, CB1 and CB2. Recent evidence suggests that a third CB3 receptor is out there, waiting to be cloned. The endocannabinoids may represent the first members of a new classes of neuromodulators, that are not stored in cell vesicles, but rather synthesised by the cell on demand. The endogenous cannabinoid system could play a central role in several neuropsychiatric disorders and is also involved in other conditions such as pain, spasticity and neuroprotection. Implication of cannabinoid system in the pathogenesis and development of schizophrenia is also discussed.
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PMID:Cannabinoid receptors and their relationships with neuropsychiatric disorders. 1569 7

Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC50=18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID50: 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 microM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB1 receptors): it reversed the decrease in electrically evoked [3H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.
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PMID:Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. 1595 94

Antipsychotic drugs are effective in the treatment of cannabis-induced psychosis, but only clozapine appears effective in the treatment of comorbid schizophrenia and cannabis use. The unique effects of clozapine on cannabis use could, therefore, be due to an as yet unidentified interaction between clozapine and the endogenous cannabinoid system. To address this hypothesis, we used in situ radioligand binding and quantitative autoradiography with the selective cannabinoid CB1 receptor agonist, (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (side chain-2,3,4(N)-3H) ([3H]CP 55940) to measure the density of the CB1 receptor in frontal cortex, hippocampus, nucleus accumbens and striatum from rats treated with a variety of antipsychotic drugs. Clozapine significantly decreased [3H]CP 55940 binding in the nucleus accumbens compared with vehicle after 1 (35.0+/-14.0 vs. 71.2+/-8.5 fmol/mg estimated tissue equivalent (ete); P = 0.03) and 3 months (42.3+/-4.0 vs. 71.1+/-16.3 fmol/mg ete; P < 0.04) of treatment, an effect not observed with haloperidol, chlorpromazine or olanzapine. In rats treated with clozapine for 3 months and then left for 1 month without treatment, [3H]CP 55940 binding was not different in the nucleus accumbens (100.5+/-22.2 vs. 100.9+/-25.4 fmol/mg ete; P > 0.10). By contrast, there were significant increases in accumbal [3H]CP 55940 binding in rats treated with haloperidol (136.5+/-14.2 fmol/mg ete; P < 0.05), chlorpromazine (137.4+/-12.7 fmol/mg ete; P < 0.05) and olanzapine (144.7+/-10.1 fmol/mg ete; P < 0.01). These data indicate that in the nucleus accumbens clozapine differs from other antipsychotic drugs in its effects on [3H]CP 55940 binding. If these results can be extrapolated into humans, then this effect of clozapine on the CB1 receptor may be a mechanism that makes it uniquely effective in schizophrenia and comorbid cannabis use.
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PMID:Clozapine decreases [3H] CP 55940 binding to the cannabinoid 1 receptor in the rat nucleus accumbens. 1599 76

Clinical and laboratory findings suggest that cannabinoid signalling is implicated in schizophrenia. However, the interaction remains poorly understood, as data are often contradictory. Here we investigated wild-type (WT) and cannabinoid CB1 receptor-knockout (CB1-KO) mice in the phencyclidine-induced social withdrawal model of schizophrenia. N-methyl-D-aspartate (NMDA) antagonists (including phencyclidine) induce psychotic symptoms in humans, and are used to model schizophrenia in a variety of experimental conditions. In WTs, 5 mg/kg phencyclidine increased locomotion and stereotyped behaviours, and decreased social interactions. These changes are consistent with a schizophrenia-like effect. In CB1-KOs, phencyclidine decreased locomotion, enhanced ataxia and stereotypy more markedly than in WTs, but did not affect social interactions. Locomotion showed a significant negative correlation with both ataxia and stereotypy, suggesting that in CB1-KOs, the locomotor suppressive effect of phencyclidine was secondary to changes in these variables. Our findings demonstrate that CB1 gene disruption dramatically alters the behavioural effects of the NMDA antagonist phencyclidine, suggesting that the CB1 receptor is involved in schizophrenia. As social disruption and stereotypy respectively are believed to model negative and positive symptoms of schizophrenia, our findings tentatively suggest that cannabinoids are differentially involved in these two symptom categories. These findings require verification by experiments involving CB1 receptor blockers, as the genetic and pharmacological blockade of receptors may not always provide similar results.
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PMID:Cannabinoid CB1 receptor dependent effects of the NMDA antagonist phencyclidine in the social withdrawal model of schizophrenia. 1614 46

Owing to their agonist action on dopaminergic systems, cannabinoids may play a major role in substance dependency and schizophrenia. We examined the (AAT)n triplet repeat polymorphism nearby the CNR1 gene, which encodes human cannabinoid (CB1) receptor, in a male Afro-Caribbean population. The allelic and genotypic distributions were significantly different in non-schizophrenic cocaine dependents (n = 97), schizophrenic cocaine dependents (n = 45) and matched controls (n = 88) (P < 10(-4)). The frequency of the (AAT)12 repeat allele was increased in non-schizophrenic cocaine dependents and schizophrenic cocaine dependents vs controls (25.3 and 26.7 vs 5.7%) (P < 10(-4)). Our results support that the (AAT)n polymorphism nearby the CNR1 gene could be associated with predisposition to cocaine dependency.
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PMID:(AAT)n repeat in the cannabinoid receptor gene (CNR1): association with cocaine addiction in an African-Caribbean population. 1631 80

Retrograde synaptic signaling influences both short-term and long-term plasticity of the brain, in both excitatory and inhibitory synapses. During the last few years it has become apparent that the endogenous ligands for the cannabinoid CB1 receptor, the "endocannabinoids", fulfill an essential role in the brain as retrograde synaptic messengers, in a number of structures including the hippocampus, cerebellum and the limbic and mesocortical systems. This seminal discovery provides a cellular basis for the well known ubiquitous role of the endocannabinoids and their receptors (together, the "ECBR" system) in virtually all brain functions studied. This review will relate the anatomical distribution of the endocannabinoids and their CB1 receptors to functions of the ECBR system, as much as possible in light of the endocannabinoids as retrograde synaptic messengers. Functional implications of the high rates of co-localization with cholecystokinin (CCK), will also be considered. The most obvious function to be profoundly affected by the retrograde synaptic role of the endocannabinoids is memory. However, additional functions and dysfunctions such as reward and addiction, motor coordination, pain perception, feeding and appetite, coping with stress, schizophrenia and epilepsy will also be reviewed. Finally, the widespread presence of the ECBR system in the brain also lends a scientific basis for the development of cannabinoid-based medicines. The same ubiquity of the ECBR system however, should also be taken into consideration with respect to possible adverse side effects and addictive potential of such pharmaceutical developments.
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PMID:Endocannabinoids in the central nervous system: from neuronal networks to behavior. 1637 81

Delta-9-tetrahydrocannabinol (Delta9-THC) has profound effects on higher cognitive functions, and exposure to Delta9-THC has been associated with the appearance or exacerbation of the clinical features of schizophrenia. These actions appear to be mediated via the CB1 receptor, the principal cannabinoid receptor expressed in the brain. However, the distribution of the CB1 receptor in neocortical regions of the primate brain that mediate cognitive functions is not known. We therefore investigated the immunocytochemical localization of the CB1 receptor in the brains of macaque monkeys and humans using antibodies that specifically recognize the N- or C-terminus of the CB1 receptor. In monkeys, intense CB1 immunoreactivity was observed primarily in axons and boutons. Across neocortical regions of the monkey brain, CB1-immunoreactive (IR) axons exhibited considerable heterogeneity in density and laminar distribution. Neocortical association regions, such as the prefrontal and cingulate cortices, demonstrated a higher density, and exhibited a unique laminar pattern of CB1-IR axons, compared with primary sensory and motor cortices. Similar regional and laminar distributions of CB1-IR axons were also present in the human neocortex. CB1-IR axons had more prominent varicosities in human tissue, but this difference appeared to represent a postmortem effect as similar morphological features increased in unperfused monkey tissue as a function of postmortem interval. In electron microscopy studies of perfused monkey prefrontal cortex, CB1 immunoreactivity was predominantly found in axon terminals that exclusively formed symmetric synapses. The high density, distinctive laminar distribution, and localization to inhibitory terminals of CB1 receptors in primate higher-order association regions suggests that the CB1 receptor may play a critical role in the circuitry that subserves cognitive functions such as those that are disturbed in schizophrenia.
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PMID:Immunocytochemical distribution of the cannabinoid CB1 receptor in the primate neocortex: a regional and laminar analysis. 1646 63

Several clinical studies have shown that alterations in the cannabinoid system in the brain may be associated with schizophrenia. Although evidence points towards an antipsychotic potential for cannabinoid antagonists, experimental studies have shown inconsistent behavioural effects of cannabinoid ligands within and across species. The aim of the present study was to explore these contradictory findings in a non-human primate model, predictive of antipsychotic efficacy in humans. The effects of the cannabinoid CB1 receptor antagonist SR141716A and the CB1 receptor agonist CP55,940 were explored in an d-amphetamine-based Cebus monkey model of psychosis. The monkeys were sensitive to extrapyramidal side effects (EPS), and the side-effect profiles of the drugs were explored as well. SR141716A (0.1, 0.25, 0.375, 0.5 and 0.75 mg/kg) and CP55,940 (0.0025, 0.005 and 0.01 mg/kg) were administered by subcutaneous injection alone and in combination with d-amphetamine (0.25mg/kg). SR141716A (0.1-0.5mg/kg) reduced d-amphetamine-induced arousal, while CP55,940 had no significant effect upon d-amphetamine-induced behaviours. No EPS were observed with either of these compounds. These data suggest that cannabinoid CB1 antagonists such as SR141716A may have limited antipsychotic potential in man as to positive symptoms. SR141716A administered alone induced anxiolytic-like behaviour, whereas administration of CP55,940 alone showed anxiogenic properties.
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PMID:Effects of the cannabinoid CB1 receptor agonist CP55,940 and antagonist SR141716A on d-amphetamine-induced behaviours in Cebus monkeys. 1653 66

The posterior cingulate cortex (PCC) has recently been implicated in the pathophysiology of schizophrenia, through both animal and human studies. We have recently shown abnormal glutamate, GABA, and muscarinic receptor binding in the PCC in schizophrenia. In addition, there is evidence for an abnormal endogenous cannabinoid system in schizophrenia. The endogenous cannabinoid system, including CB1 receptors, is proposed to play a role in modulating neurotransmission via affecting the release of a variety of neurotransmitters, (e.g. GABA). In the present study, we used quantitative autoradiography to investigate the binding of [(3)H]CP-55940 to CB1 receptors in the PCC in schizophrenia subjects compared to controls. A significant 25% increase in CB1 binding was found in the superficial layers (layer I, II) of the PCC of schizophrenia subjects compared to controls, none of whom had recently used cannabis. There was no statistical difference in CB1 binding in the deeper layers (layers III-VI) between the two groups. There were no significant correlations between CB1 binding density and age, PMI, pH, brain weight, freezer storage time, or final recorded antipsychotic drug dose. These results show an increase in CB1 receptor density in the PCC in schizophrenia, and therefore provide support for a role of the endogenous cannabinoid system in schizophrenia.
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PMID:Increased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia. 1671 Jun 82


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