Schizophrenia is a complex and devastating psychiatric disorder that creates a substantial emotional and economic burden on individuals with the illness, their families, and society. Understanding the causes and identifying the molecular alterations in the brain that underlie the pathophysiology of core clinical features of schizophrenia are central to the development of new therapeutic interventions. In particular, schizophrenia is characterized by impairments in working memory, which are thought to result from a deficit in GABA neurotransmission in the dorsolateral prefrontal cortex (DLPFC). Interestingly, exposure to cannabis has been associated with an increased risk for developing schizophrenia and cannabis use is associated with DLPFC-related working memory impairments similar to those observed in schizophrenia. The effects of cannabis are mediated by the brain cannabinoid 1 (CB1) receptor, which in the rodent, is heavily localized to certain inhibitory axon terminals and, when activated, inhibits GABA release. Here, we have investigated the anatomical distribution of the CB1 receptor in the primate brain and characterized the cellular localization and synaptic targets of the CB1 receptor in the primate DLPFC. In addition, we explored the potential relationship between CB1 receptor signaling and altered GABA neurotransmission in schizophrenia by evaluating CB1 receptor mRNA and protein expression in the DLPFC of subjects with schizophrenia. We found that CB1 receptors are highly expressed in the primate DLPFC and that CB1 receptors are localized in the terminals of the subtype of perisomatic-targeting GABA interneurons that contain the neuropeptide cholecystokinin (CCK). We found that CB1 mRNA and protein are reduced in schizophrenia, which may represent a compensatory mechanism to increase GABA transmission from perisomatic-targeting CCK neurons with impaired GABA synthesis. We conclude that reductions in the expression of the CB1 receptor mRNA and protein in CCK neurons represent a novel neuropathological entity in the DLPFC of individuals with schizophrenia. These findings suggest a novel drug target for the treatment of cognitive dysfunction in schizophrenia.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08082007-161415 |
| Date | 20 September 2007 |
| Creators | Eggan, Stephen Melford |
| Contributors | Susan Sesack, Ph.D., Charles Bradberry, Ph.D., Etienne Sibille, Ph.D., Bradley Alger, Ph.D., David A. Lewis, M.D., J. Patrick Card, Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-08082007-161415/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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