The cerebral cortex is involved in a huge diversity of function, ranging from sensory processing and motor coordination to perception, generation of language, aM other higher-order cognitive abilities. These varied processes rely on the function of pyramidal cells, which are responsible for connections between cortical areas as well as connections to subcortical structures. Pyramidal cell activity, in turn, is tightly controlled by distinct classes of GABAergic inhibitory interneurons, which innervate functionally segregated domains on pyramidal cells to regulate action potential timing, the efficacy of excitatory inputs, and synchronous activity. These interneurons fire at high rates in vivo and provide potent inhibition to pyramidal cells, thus regulation of this inhibitory tone is essential for proper cortical function. Recent anatomical and physiological data indicate that the cannabinoid system plays an important role in modulating GABAergic interneurons in the neocortex. The type 1 cannabinoid (CB 1) receptor is one of the most highly expressed G-protein coupled receptors in the forebrain, and mediates the effects of exogenous cannabinoids on cognitive, sensory, and motor processes. Endogenous cannabinoid ligands are synthesized and released from pyramidal neurons with a high degree of spatial and temporal specificity, and act at least in part by binding to receptors on the presynaptic terminals of interneurons to regulate GABA release. The specificity of the endogenous system suggests that the disruptive effects of exogenous cannabinoids on cognitive processes may result from the non-selective global activation of this system. The long-term objective of this research is to understand the physiological significance of endogenous cannabinoid signaling in the regulation of neocortical function. The specific goals of the proposed studies are to: 1) determine the impact of endogenous cannabinoids on cortical synaptic inhibition, 2) test the hypothesis that cannabinoids selectively modulate a particular functional class of inhibitory afferents to pyramidal cells, and 3) investigate the consequences of cannabinoid signaling for pyramidal cell activity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA016791-05
Application #
7225484
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Sorensen, Roger
Project Start
2003-08-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2010-04-30
Support Year
5
Fiscal Year
2007
Total Cost
$206,229
Indirect Cost
Name
University of Connecticut
Department
Pharmacology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030