Psychotropic Effects of Cannabis Components on the Mesolimbic Dopaminergic System

The two most abundant phytochemical compounds in cannabis are cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC). THC is the primary psychoactive component of cannabis and is a partial CB1 receptor (CB1R) agonist. THC is believed to be responsible for the motivational and dependence-producing effects of cannabis and causes psychotomimetic and affective processing disturbances. Conversely, CBD, is non-psychoactive, acts as a 5-HT1A receptor agonist, antagonizes CB1Rs, and possesses both anti-psychotic and anxiolytic properties. The neural substrate believed to be responsible for many of the effects of cannabis is the dopaminergic, mesolimbic reward pathway which is responsible for the regulation of cognition and emotion. Specifically, the shell region of the nucleus accumbens (NASh) and the ventral tegmental area (VTA) are important brain areas involved in motivation, reward, aversion, and fear-related behavioural processing. Using a combination of behavioural, electrophysiology and molecular techniques, the first chapter evaluates the effects of direct infusions of CBD into the NASh. Intra-NASh CBD blocked the formation of fear memory through a 5-HT1A-dependent mechanism by functionally modulating the activity of neuronal activity dynamics directly in the VTA. In the second chapter, we examined the effects of THC in either the anterior NASh (aNASh), known as the “hedonic hotspot”, or posterior NASh, known to be involved in aversion. We demonstrate that aNASh THC produced rewarding behavioural effects and modulated reward salience through a µ-opioid-receptor-dependent mechanism, whereas THC in the pNASh produced aversive behavioural effects through a k-opioid-receptor-dependent mechanism. ICV infusions of THC caused aNASh MSN activity to decrease and increased the power of ɣ-oscillations on the local field potential but caused pNASh increased MSN activity and decreased the power of ɣ-oscillations on the local field potential. Finally, in the third chapter, we provide a characterization of how THC differentially regulates fear-related memory formation and cognitive processing via distinct Akt-dependent vs. GSK3-dependent signaling pathways, in the aNASh vs. pNASh, respectively. Together, these data provide a novel neuronal, molecular, behavioural and anatomical characterization of the effects of CBD and THC directly within the mesolimbic circuitry and reveals critical new insights into the mechanisms by which THC and CBD regulate affective and cognitive behaviours