Teenage Brains on Pot: Adolescent Cannabinoid Exposure to Mice and Maturation of Cortical Functions

Abstract

Regular use of marijuana during adolescence -- but not adulthood -- permanently impairs cognitive functions, and significantly elevates the risk for developing severe psychiatric diseases, such as schizophrenia, in some users. This vulnerable adolescent period coincides with the emergence of synchronous, network activity in the neocortex, termed cortical oscillations, as well as the anatomical and physiological maturation of the neural networks, neurotransmitter systems, and the endocannabinoid (eCB) system that shape oscillations. Cortical oscillations are implicated in cognitive and sensory processing, and are abnormal in patients with schizophrenia, in which these functions are impaired. We therefore proposed a link between adolescent use of marijuana, and abnormal cortical network activity in adulthood. Specifically, we hypothesized that repeated cannabinoid administration to adolescent mice would permanently alter cortical oscillations and related cognitive behaviors in adult animals. We tested this hypothesis by administering cannabinoid receptor ligands to adolescent mice, and recording oscillations both in vitro from isolated cortical preparations, and in vivo from intact, behaving mice once they reached adulthood. We find that chronic cannabinoid exposure to adolescent, but not adult animals, persistently suppresses pharmacologically-evoked cortical oscillations in vitro, preferentially in rostral neocortical areas that are less developed at the time of drug exposure. In awake, behaving adult mice, chronic exposure to cannabinoids in adolescence attenuates pharmacologically-evoked cortical oscillations, impairs working memory, and alters oscillations associated with cognitive behaviors. We reveal that attenuation of cortical oscillations in adulthood by a shorter-period of cannabinoid exposure during early adolescence, or by chronic exposure to the primary active ingredient in marijuana, Δ9 THC, is mediated by the cannabinoid-1 receptor (CB1R), and can be reversed with a CB1R antagonist. However, chronic exposure to a more potent cannabinoid receptor agonist cannot be reversed by chronic exposure to cannabinoid receptor antagonists, as antagonists also persistently attenuate oscillations in adulthood when administered alone. These data support the hypothesis that marijuana use in adolescence persistently alters synchronous activity in cortical networks in adulthood, and serve as a novel link between early cannabis use and alterations in cortical network activity implicated in cognitive processing and psychiatric disease.