題目：ENDOGENOUS CANNABINOIDS AND THE PURSUIT OF REWARD
演講人：Joseph F. Cheer, Ph.D.
Professor of Anatomy
& Neurobiology and Psychiatry
University of Maryland School of Medicine
In the early stages of substance abuse, subjects receive a drug that is highly reinforcing and are thus likely to repeat the actions that led them to obtain it. This is termed positive reinforcement. However, in a minority of people who develop an addiction phenotype, negative reinforcement also causes a behavior to be repeated, but in this case, the action causes a bad feeling or situation to go away. The mesolimbic dopamine system, which is thought to generate a teaching signal, is involved in the selection of advantageous behavioral repertoires. This brain pathway is under control of endocannabinoid (eCBs), ubiquitous signaling molecules that bind to the same receptor targeted by marijuana (CB1) known to strengthen responses leading to the procurement of reward. Here, we investigate how eCBs modulate dopaminergic encoding of cues predicting either, appetitive stimuli, the avoidance of punishment or aversive outcomes. We find that disrupting eCB signaling by treating animals with a CB1 receptor antagonist dose-dependently decreased concentrations of dopamine release in the nucleus accumbens that were time-locked to a warning signal that predicts avoidance of punishment while simultaneously weakening shock avoidance behavior, effectively shifting the behavioral outcome from avoidance to escape. We further demonstrate, using directed mutagenesis approaches, that 2AG release from dopamine neurons in the midbrain is a canonical mechanism responsible for the pursuit of rewards. Together these data suggest that eCBs might modify distinct behavioral responses related to aversive stimuli by modulating conditioned mesolimbic dopamine release events. These findings suggest that therapies aimed at modifying tissue levels of eCBs may be used to prevent drug seeking driven by negative affective states.