Featured Finding Figure
Cannabis use is associated with both impaired cognitive functions, including working memory, and an increased risk of schizophrenia. In addition, schizophrenia is characterized by impairments in working memory that are due, at least in part, to reduced GABA neurotransmission in the dorsolateral prefrontal cortex (DLPFC). The cannabinoid 1 receptor (CB1R) is highly expressed in the DLPFC, is contained in the axon terminals of a subpopulation of CCK-containing, perisomatic-targeting GABA neurons, and when activated, suppresses the release of GABA. In order to determine the potential relationship between CB1 receptor signaling and altered GABA neurotransmission in schizophrenia, we evaluated CB1 receptor mRNA and protein expression in the DLPFC from 23 pairs of schizophrenia and age-, sex-, and postmortem interval-matched comparison subjects. CB1 mRNA levels (panels A, B), assessed by in situ hybridization, were significantly 15% lower in the subjects with schizophrenia. Similarly, CB1 protein, assessed by radioimmunocytochemistry (RICC; panels C, D) and standard immunocytochemistry, was significantly decreased by 12% and 14%, respectively. Importantly, the within-pair percent change in CB1 RICC in the subjects with schizophrenia strongly correlated with the within-pair percent change in CB1 mRNA expression, indicating that changes in CB1 protein paralleled the changes in CB1 mRNA (panel E). CB1 mRNA expression was not changed in the DLPFC of monkeys chronically exposed to haloperidol or olanzapine, and neither CB1 mRNA or protein levels were affected by potential confounding factors in the subjects with schizophrenia. Finally, differences in CB1 mRNA levels were significantly correlated with those in glutamic acid decarboxylase (GAD67) and cholecystokinin (CCK) mRNA levels in the same subjects with schizophrenia. This combination of findings suggests the testable hypothesis that reduced CB1R mRNA and protein in schizophrenia represent a compensatory mechanism to increase GABA transmission from perisomatic-targeting CCK interneurons with impaired GABA synthesis (panel F).
Eggan SM, Hashimoto T, Lewis DA: Reduced cortical cannabinoid 1 receptor mRNA and protein expression in schizophrenia. Arch Gen Psychiatry 65: 772-784, 2008.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
3811 O'Hara Street, Biomedical Science Tower W1654
Pittsburgh, Pennsylvania 15213-2593
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