58.2 Adolescent Cannabis use, Cortical Circuitry and Schizophrenia

Abstract

Background: Schizophrenia is associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC) which is manifest as alterations in working memory. Working memory depends on the coordinated activity of glutamatergic pyramidal cells and parvalbumin-containing, GABAergic basket cells in DLPFC layer 3. Both of these cell types are innervated by cholecystokinin-containing GABAergic neurons whose terminals contain very high levels of the cannabinoid 1 receptor (CB1R). These findings suggest that altered cannabinoid signaling, especially when this circuitry is being refined during adolescence, could contribute to DLPFC dysfunction and working memory impairments in schizophrenia. Furthermore, given the emerging evidence that DLPFC dysfunction may be upstream of the subcortical hyperdopaminergia associated with psychosis, adolescent cannabis use could lead to both the cognitive and positive symptoms of schizophrenia. Methods: To test these ideas, we conducted three sets of studies. First, we evaluated the integrity of the endocannabinoid system in the postmortem DLPFC from subjects with schizophrenia and comparison subjects. Second, we studied the impact of repeated exposure to exogenous cannabinoids during adolescence on the maturation of working memory performance in macaque monkeys. Third, we examined the cumulative effects of marijuana use on subclinical psychotic symptoms in 1,009 adolescent boys. Results: In the DLPFC of subjects with schizophrenia, our findings are consistent with elevated metabolism of the major endocannabinoid 2-arachidonylglycerol (2-AG), greater CB1R receptor binding and lower levels of CB1R mRNA and protein. In adolescent monkeys, repeated exposure to Δ9-tetrahydrocannabinol (THC) blunted the trajectory of accuracy improvements in spatial working memory but did not alter other cognitive functions that mature earlier. These effects were more marked and more persistent in male than in female monkeys. For each year that adolescent boys engaged in regular marijuana use, their expected odds of experiencing subsequent subclinical paranoia or hallucinations rose by 133% and 92%, respectively. Conclusion: Alterations of the endocannabinoid system in the DLPFC of subjects with schizophrenia may reflect a developmental disturbance that makes these individuals more vulnerable to the adverse effects of repeated cannabis use during adolescence on working memory maturation and reality testing. Apparent sex differences in sensitivity to exogenous cannabinoids may contribute to the tendency for schizophrenia to have an earlier age of onset, greater prevalence and more severe course in males.