This proposal aims to develop a mouse model to study the effects of pre- and post-natal exposure to marijuana on high-level (executive) cognitive functions. Marijuana is by far the most commonly used illicit drug and reports indicate that its use continues during the perinatal period. Recent studies indicate that preteenage children exposed prenatally to this drug demonstrate impairments on those cognitive processes (executive functions) typically associated with the prefrontal cortex. The premise of this proposal is that a mouse model of marijuana-induced cognitive dysfunction is needed to explore systematically the precise nature of the cognitive impairment and to identify the action of the drug on brain chemistry in the prefrontal cortex that underlies this impairment. The series of proposed experiments encompasses the following specific aims: I. To document alterations in executive function in mice exposed prenatally to D9-tetrahydrocannabinol (THC). The performance of mice exposed prenatally to D9-THC will be assessed on the following tasks: A. Motor inhibition. Behavioral paradigms developed for the study and analysis of motor inhibition in the rat will be modified for use with the mouse. Motor inhibition was selected for scrutiny because it is considered to be a core component of executive function associated with the prefrontal cortex. B. Integration and planning. Behavioral paradigms developed for the study and analysis of how associations are combined and of the rules used to solve instrumental discrimination tasks in rats will be modified for use with the mouse. This approach will be complemented by one that exploits the natural talent of the mouse to represent its location in three-dimensional space and to plan routes from its nest to foraging sites. II. To document alterations in endocannabinoid signalling systems A. Changes in cannabinoid receptors: density and affinity assessed by radioligand binding B. Changes in cannabinoid receptor signal transduction: G-protein stimulation by cannabinoid agonists C. Changes in endocannabinoid levels: -Measurements of anandamide and 2-arachidonylglycerol in dissected brain regions using liquid chromatography/mass spectrometry (LC/MS).
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