The escalation in recreational use of marijuana by today?s teenagers is a major health concern, because of the increased risk for psychiatric disorders in individuals who abuse marijuana during adolescence. The psychiatric symptoms include abnormalities in cognitive functions that are mediated largely through the prefrontal cortex (PFC) and associated limbic brain regions. Both pyramidal cells and interneurons in the PFC express cannabinoid-1 receptors (CB1Rs) that are activated by endocannabinoids and by ?9-tetrahydro- cannabinol (?9-THC), the major psychoactive compound in marijuana. Chronic activation of these receptors by ?9-THC downregulates the endocannabinoid system that is a key regulator of experience-dependent learning in the still immature PFC of adolescence. This learning is triggered by calcium influx through glutamatergic NMDA receptors comprised of subunits that are physically and functionally coupled to dopamine D1-like receptors (D1Rs). Pyramidal cells expressing D1Rs are among the PFC neurons most implicated in controlling subcortical brain networks that drive cognitive, social, and attentional functions that are often dysfunctional in psychiatric patients. These neurons are activated not only through Gs-coupled D1Rs and NMDA receptors, but also through Gq/ii-coupled M1 muscarinic acetylcholine receptors (M1Rs) that provoke calcium release from IP3-operated intracellular stores and also mediate endocannabinoid-dependent inhibition. However, there is a major gap in knowledge of the extent to which adolescent abuse of marijuana produces changes in the availability and functionality of these receptors in PFC neurons, which culminate in cognitive or social dysfunctions in adulthood. The proposed studies will test the Central Hypothesis that adult behavioral dysfunctions resulting from chronic adolescent administration of ?9-THC are maintained by persistent suppression of NMDA/D1R and M1R/IP3 receptor systems that mediate the influx and intracellular release of calcium in dopamine-regulated prefrontal cortical neurons. The research will be conducted in male and female C57BL/6J mice that are available in wild-type and mutant forms that can be used for determining potentially critical sex-specific differences in the deleterious effects of adolescent marijuana, which are not directly assessable in humans. The first two Specific Aims will assess the potentially deleterious impact of chronic adolescent administration of ?9-THC on the functional expression of ionotropic (NMDA) glutamate receptors and muscarinic (M1) acetylcholine receptors in D1R-containing output neurons within the adult PFC.
Specific Aim 3 will assess the functional relevance of observed THC-induced changes in these receptor systems by examining whether they are accompanied by (1) depression of intracellular Ca2+ and (2) behavioral dysfunctions recapitulated by genetic or pharmacological disruption of NMDA/D1 or M1R/IP3 signaling in the prefrontal cortex. Together, this research will identify molecular targets useful for treating and/or preventing the adverse neurobehavioral abnormalities resulting from marijuana abuse during adolescence.
Working memory deficits and social dysfunctions that often occur in adults who abuse marijuana during adolescence may reflect yet undisclosed abnormalities in dopamine-regulated glutamatergic and cholinergic receptor systems in the prefrontal cortex. In this grant proposal, a multidisciplinary approach will be used to test the hypothesized contribution of altered functional expression of these receptors and their downstream signaling molecules to behavioral dysfunctions in adult mice receiving chronic adolescent administration of ?9- tetrahydrocannabinol (THC), the primary psychoactive compound in marijuana. This approach is not feasible in humans, but has important implications for understanding and treating or preventing the many cognitive dysfunctions, which are escalating because of the increased recreational use of marijuana by today?s teenagers.
