NEURONAL ADAPTATIONS IN THE NUCLEUS ACCUMBENS CORE UNDER ACUTE AND CHRONIC EXPOSURE TO CANNABINOIDS

Abstract

Cannabis, known as marijuana, is the most commonly used illicit drug in the United States, but we have limited knowledge about its effects on the brain, particularly the reward circuitry. Cannabinoids, the psychoactive ingredient of cannabis, activate cannabinoid receptors in the mesolimbic area, resulting in increased dopamine transmission in the nucleus accumbens (NAc). This effect is believed to enhance goal-directed behavioral responses, including the motivation to obtain natural and drug rewards, but NAc signaling under cannabinoid exposure remain largely unknown. To address this gap, this dissertation work examines two main signaling changes in the NAc core: neuronal activities and dopamine dynamics.

Since cannabis derivatives are usually used for a prolonged time, ongoing changes in the NAc core were investigated in response to acute and repeated exposure of cannabinoids. Therefore, in Experiment 1, NAc neuronal signaling was obtained on initial and repeated exposure (seven daily injections) of a cannabinoid receptor agonist, CP55,940 (0.2 mg/kg or 0.4 mg/kg) in male Sprague-Dawley rats using an in vivo electrophysiology technique. The overall effect of CP55,940 on CB1/2 receptor activation acutely inhibited NAc neuron activity and reduced correlated neuronal activity/burst firing, and these effects lasted for the seven days of injections. This result suggests that cannabinoids reduce neuronal signaling and disrupt functional communication in the NAc core for a prolonged period. However, cannabinoid increased the theta power of local field potentials after acute CP55,940 injection but repeated treatment failed to maintain this effect.

In Experiment 2, the electrically evoked dopamine overflow was collected using fast scan cyclic voltammetry (FSCV). Using kinetic analysis, dopamine release and reuptake were assessed immediately following one or seven daily injections of CP55,940 (0.2 mg/kg, i.p.) or a vehicle. A single injection of CP55,940 increased the stimulation-evoked dopamine concentration without altering dopamine reuptake. However, repeated CP55,940 exposure led to a similar level of dopamine concentration as the chronic vehicle treatment.

The sustained neuronal signaling but altered dopamine dynamics in the NAc core after repeated cannabinoid exposure suggest separate mechanisms in the development of tolerance. As the present results indicate, altered signaling of the NAc core could provide evidence of changes in motivational states that, in turn, may play a role in changing reward-related behaviors.