Cannabinoid Tolerance Across Neurodevelopment: Disruption of Value-Driven Behavior and Prevention Through Physical Activity

University Of Colorado Denver, Aurora CO

Investigators

Abstract

Project Summary An illicit drug enterprise is currently duping United States citizens by marketing synthetic cannabinoids to them as a safe alternative to cannabis. Professionals and students are also drawn to these compounds to cheat conventional drug tests. Rather than a safe alternative, most synthetic cannabinoids are more dangerous than cannabis itself. Indeed, the primary psychoactive component of cannabis, a chemical called delta-9- tetrahydrocannabinol, only partially activates the primary cannabinoid receptor in the brain. In contrast, the most commonly abused class of synthetic cannabinoids fully activate this receptor. While we already know that this increased cannabinoid receptor activation can produce more substantial drug effects, the neurobehavioral consequences of repeated exposures remain unclear. This statement is particularly true across different stages of lifespan development and between sexes. Synthetic cannabinoids are one of the most commonly abused drugs amongst adolescents and cannabinoid abuse rates are at all-time highs across all age ranges, including senior citizens. Elucidating the neurobehavioral consequences of chronic synthetic cannabinoid exposure is necessary to validate and raise public awareness of the dangers posed by this harmful new class of drugs. Our preliminary data demonstrate that chronic exposure to synthetic cannabinoids renders them less effective at evoking dopamine release in adult rats. This finding is concerning because we have shown that dopamine- release events are necessary for adaptive behavior and resiliency. Because little is known regarding the effects of chronic cannabinoid abuse across the developmental lifespan, we will first test whether this form of neurochemical tolerance develops in both female and male early adolescent, adult, and aged rats. It is also essential to consider whether chronic cannabinoid exposure interferes with fundamental behaviors that allow us to thrive in society. Thus, we will use an innovative behavioral economics framework to assess whether the value female and male adult rats place on the pursuit of reward and the avoidance of harm changes following chronic synthetic cannabinoid exposure. We recently used this behavioral economics approach to show that dopamine value signals represent price and causally modify the price rats will pay for both reward and avoidance. Finally, we will investigate the interaction between chronic cannabinoid abuse and exercise. We will test whether a history of exercise protects against the development of neurochemical tolerance in female and male adult rats. Existing data reveal exercise creates a state of heightened dopamine release and that this neurobiological adaptation may protect against adverse events. The collection of these data will advance our understanding of the neurobiology of cannabinoid abuse in a manner that can be applied to improve individual and public health.