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Cannabinoid CB1 Receptor: Role in Primate Prefrontal Circuitry and Schizophrenia

Eggan, Stephen Melford (2007) Cannabinoid CB1 Receptor: Role in Primate Prefrontal Circuitry and Schizophrenia. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Eggan, Stephen
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairLewis, David Alewisda@upmc.eduTNPLEWIS
Committee MemberAlger,
Committee MemberBradberry,
Committee MemberSibille,
Committee MemberCard, J. Patrickcard@bns.pitt.eduCARD
Committee MemberSesack, Susansesack@bns.pitt.eduSESACK
Date: 20 September 2007
Date Type: Completion
Defense Date: 19 July 2007
Approval Date: 20 September 2007
Submission Date: 8 August 2007
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Neuroscience
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: cannabinoids; cognition; human; immunocytochemistry; in situ hybridization; monkey; mRNA; parvalbumin; postmortem; protein; cortex; gamma oscillations
Other ID:, etd-08082007-161415
Date Deposited: 10 Nov 2011 19:58
Last Modified: 19 Dec 2016 14:37


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