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 noncompetitive NMDA receptor antagonist phencyclidine (PCP) and the neuronal cannabinoid receptor agonist delta9-tetrahydrocannabinol (THC) are two agents shown to have psychotomimetic properties in humans. Both drugs increase dopamine release and utilization in the prefrontal cortex, a brain region thought to be dysfunctional in schizophrenia. In the present series of studies, the effects of drugs acting at alpha-noradrenergic receptors on PCP- and THC-induced increases in prefrontal cortical and nucleus accumbens dopamine utilization in the rat were examined. Clonidine, an alpha2 noradrenergic receptor agonist, completely blocked the activation of mesoprefrontal dopamine system by THC or PCP. In addition, the alpha1 noradrenergic receptor antagonist prazosin blocked the PCP-induced increase in prefrontal cortical dopamine utilization. These data may provide new insights concerning pharmacological therapies for acute drug-induced psychoses and behavioral abnormalities in human PCP and THC abusers.
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PMID:Alpha-noradrenergic receptor modulation of the phencyclidine- and delta9-tetrahydrocannabinol-induced increases in dopamine utilization in rat prefrontal cortex. 941 14

It is now known that there are at least two types of cannabinoid receptors. These are CB1 receptors, present mainly on central and peripheral neurones, and CB2 receptors, present mainly on immune cells. Endogenous cannabinoid receptor agonists ('endocannabinoids') have also been identified. The discovery of this 'endogenous cannabinoid system' has led to the development of selective CB1 and CB2 receptor ligands and fueled renewed interest in the clinical potential of cannabinoids. Two cannabinoid CB1 receptor agonists are already used clinically, as antiemetics or as appetite stimulants. These are D 9 - tetrahydrocannabinol (THC) and nabilone. Other possible uses for CB1 receptor agonists include the suppression of muscle spasm/spasticity associated with multiple sclerosis or spinal cord injury, the relief of chronic pain and the management of glaucoma and bronchial asthma. CB1 receptor antagonists may also have clinical applications, e. g. as appetite suppressants and in the management of schizophrenia or disorders of cognition and memory. So too may CB2 receptor ligands and drugs that activate cannabinoid receptors indirectly by augmenting endocannabinoid levels at cannabinoid receptors. When taken orally, THC seems to undergo variable absorption and to have a narrow 'therapeutic window' (dose range in which it is effective without producing significant unwanted effects). This makes it difficult to predict an oral dose that will be both effective and tolerable to a patient and indicates a need for better cannabinoid formulations and modes of administration. For the therapeutic potential of cannabis or CB1 receptor agonists to be fully exploited, it will be important to establish objectively and conclusively (a) whether these agents have efficacy against selected symptoms that is of clinical significance and, if so, whether the benefits outweigh the risks, (b) whether cannabis has therapeutic advantages over individual cannabinoids, (c) whether there is a need for additional drug treatments to manage any of the disorders against which cannabinoids are effective, and (d) whether it will be possible to develop drugs that have reduced psychotropic activity and yet retain the ability to act through CB1 receptors to produce their sought-after effects.
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PMID:Cannabis and cannabinoids: pharmacology and rationale for clinical use. 1057 83

Schizophrenia is a devastating psychiatric disorder with a high prevalence worldwide. There is therefore a need for animal models allowing the development of new therapeutic interventions and reliable diagnostic tests. In the temporal domain, cannabinoid receptor gene (CB1) knockout mice exhibit behavioural alterations, which parallel symptoms in schizophrenia, cannabis intoxication and dopamine D2 activation. While a specific nucleotide homology between CB1 and D2 accounts for the pathophysiology, pre-inserted spirochaetal DNA on the polyadenylation signal of CB1 reveals the aetiology of schizophrenia. If, in analogy to thalassaemia, mutations occur within this 3' regulatory domain, the genetic expression of CB1 is disrupted and sequential information lost in time. CB1, previously unrecognized as a candidate gene, thus unifies the different aspects of schizophrenic psychosis: cannabis-induced model psychosis, disrupted information processing, spatio-temporal distortions and other psychotic symptoms, disturbed neuronal migration, schizophrenic brain disorder, familial transmission, and prenatal infection by Borrelia burgdorferi.
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PMID:Are cannabinoid receptor knockout mice animal models for schizophrenia? 1139 12

There has been considerable debate about the reasons for the association observed between cannabis use and psychosis in both clinical and general population samples. Among the hypotheses proposed to explain the association are the following: 1) common factors explain the co-occurrence; 2 cannabis causes psychosis that would not have occurred in the absence of cannabis use; 3) cannabis precipitates psychosis among persons who were vulnerable to developing the disorders; 4) cannabis use worsens or prolongs psychosis among those who have already developed the disorder; and 5) that persons with psychosis are more likely to become regular or problematic cannabis users than persons without psychosis. This article evaluates the evidence on each of these hypotheses, including recent research on the role of the cannabinoid receptor system in schizophrenia. The evidence suggests that common factors do not explain the comorbidity between cannabis use and psychosis, and it is unlikely that cannabis use causes psychosis among persons who would otherwise not have developed the disorder. The evidence is more consistent with the hypotheses that cannabis use may precipitate psychosis among vulnerable individuals, increase the risk of relapse among those who have already developed the disorder, and may be more likely to lead to dependence in persons with schizophrenia.
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PMID:Cannabis and psychosis. 1200 81

There are at least two types of cannabinoid receptors, CB(1) and CB(2), both coupled to G proteins. CB(1) receptors exist primarily on central and peripheral neurons, one of their functions being to modulate neurotransmitter release. CB(2) receptors are present mainly on immune cells. Their roles are proving more difficult to establish but seem to include the modulation of cytokine release. Endogenous agonists for cannabinoid receptors (endocannabinoids) have also been discovered, the most important being arachidonoyl ethanolamide (anandamide), 2-arachidonoyl glycerol and 2-arachidonyl glyceryl ether. Other endocannabinoids and cannabinoid receptor types may also exist. Although anandamide can act through CB(1) and CB(2) receptors, it is also a vanilloid receptor agonist and some of its metabolites may possess yet other important modes of action. The discovery of the system of cannabinoid receptors and endocannabinoids that constitutes the "endocannabinoid system" has prompted the development of CB(1)- and CB(2)-selective agonists and antagonists/inverse agonists. CB(1)/CB(2) agonists are already used clinically, as anti-emetics or to stimulate appetite. Potential therapeutic uses of cannabinoid receptor agonists include the management of multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, vasodilation that accompanies advanced cirrhosis, and cancer. Following their release onto cannabinoid receptors, endocannabinoids are removed from the extracellular space by membrane transport and then degraded by intracellular enzymic hydrolysis. Inhibitors of both these processes have been developed. Such inhibitors have therapeutic potential as animal data suggest that released endocannabinoids mediate reductions both in inflammatory pain and in the spasticity and tremor of multiple sclerosis. So too have CB(1) receptor antagonists, for example for the suppression of appetite and the management of cognitive dysfunction or schizophrenia.
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PMID:Cannabinoid receptors and their ligands. 1205 30

Ontogenetic brain-asymmetry and its reversal in schizophrenia constitute special cases of a more fundamental principle of sensory-motor integration. Transmitted through an immature optical system, asymmetric inputs from the left visual field induce the infant's right hemispheric preference for lower spatial frequencies during early mother-child interaction. The emerging classical features of hemispheric specialisation later in life can be accounted for by a transformation law of the neuronal reference frames based on relativistic non-linear information processing. Accordingly, the asymmetric distributions of the cannabinoid receptor CB1 in the right basal ganglia and the left area of Wernicke reflect the preferences for lateralised posture, positioning, and speech. Epigenetic development of brain asymmetry thus unifies the different aspects related to cradling and breast-feeding, speech- and visuospatial processing, the dimensional conversion of spatiotemporal information and, in the case of a dysbalanced cannabinoid system, its psychotic reversal. The predicted right hemispheric shift and the inverse relationship between Kolmogorov entropy and its dimensional embedding (Shannon entropy) has ultimately been confirmed by non-linear EEG analysis of a fluoro-methyl-anadamide induced model psychosis splitting conscious from unconscious mental processes.
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PMID:The origin of brain asymmetry and its psychotic reversal. 1261 2

Recent advances in the understanding of brain cannabinoid receptor function have renewed interest in the association between cannabinoid compounds and psychosis. In a 3-day, double-blind, randomized, and counterbalanced study, the behavioral, cognitive, and endocrine effects of 0, 2.5, and 5 mg intravenous delta-9-tetrahydrocannabinol (Delta-9-THC) were characterized in 22 healthy individuals, who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder. Prospective safety data at 1, 3, and 6 months poststudy was also collected. Delta-9-THC (1) produced schizophrenia-like positive and negative symptoms; (2) altered perception; (3) increased anxiety; (4) produced euphoria; (5) disrupted immediate and delayed word recall, sparing recognition recall; (6) impaired performance on tests of distractibility, verbal fluency, and working memory (7) did not impair orientation; (8) increased plasma cortisol. These data indicate that Delta-9-THC produces a broad range of transient symptoms, behaviors, and cognitive deficits in healthy individuals that resemble some aspects of endogenous psychoses. These data warrant further study of whether brain cannabinoid receptor function contributes to the pathophysiology of psychotic disorders.
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PMID:The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. 1517 44

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

Recent longitudinal studies from Sweden, the Netherlands, New Zealand, and Israel report that cannabis use during childhood and adolescence doubles the risk of later appearance of psychosis or schizophrenia. These data have been interpreted as indicating that cannabis has a causal effect along the pathway to psychosis. In this paper, we will offer an alternative explanation of these data. Recent investigations of patients with schizophrenia found increased density of cannabinoid receptors in the dorso-lateral prefrontal cortex and the anterior cingulate cortex. Others reported higher levels of endogenous cannabinoids in the blood and cerebrospinal fluid of patients; these findings were independent of possible cannabis use. Several genetic studies have reported an association between genes encoding the cannabinoid receptor and schizophrenia. Thus, an alternative explanation of the association between cannabis use and schizophrenia might be that pathology of the cannabinoid system in schizophrenia patients is associated with both increased rates of cannabis use and increased risk for schizophrenia, without cannabis being a causal factor for schizophrenia.
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PMID:Interpreting the association between cannabis use and increased risk for schizophrenia. 1606 May 98

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


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