The endocannabinoid system (ECS) plays a key modulatory role during synaptic plasticity and homeostatic processes in the brain and has an important role in the neurobiological processes underlying drug addiction. Impaired endocannabinoid (eCB) signaling contributes to dysregulated synaptic plasticity, increased stress responsivity, and craving that propel addiction. Basal levels of eCBs and eCB-Ls differ in specific brain regions and the ECS is upregulated in certain disorders as indicated by an “autoprotective” increased endogenous release of those molecules. Such increases have been observed in different mouse models. For example, traumatic brain injury (TBI) elicited substantial increases in N-oleoyl glycine (OlGly) in the insular cortex of mice and chronic administration of synthetic OlGly ameliorates the behavioral alterations associated with TBI. Therefore, we hypothesized that boosting the ECS exogenously will exert beneficial neuroprotective effects against drug-induced behaviors. Our overarching aim in the current study is to explore whether boosting the ECS in a region-specific manner will attenuate or reverse drug- induced addictive behaviors and to reveal the underlying molecular mechanism. To address our hypothesis, we will pursue the following aims: I. We will determine the levels of selective eCBs and eCB-Ls in the reward system following chronic drug administration. II. We will examine the behavioral consequence of differential exogenous administration of selective eCB-Ls in cocaine or morphine-induced behaviors. III. We will examine the behavioral consequence and region specificity of selective eCB-Ls on alcohol addiction using EtOH self-administration, and finally IV. We will explore the molecular mechanism underlying OlGly and OlAla action.

Supervisor: Prof. Rami Yaka