The rewarding properties of cocaine and other addictive drugs have been extensively studied, but much less is known about these drugs'aversive properties. Numerous studies have found that even small or infrequent doses of cocaine and other drugs produce strong avoidance responses that can attenuate or prevent drug-seeking. Some of these responses may explain why some individuals do not progress to compulsive drug use despite the drugs'intense rewarding effects, but relatively little is known about these phenomena, in part because their underlying neural circuitry is not well understood. Recently, a sequentially linked series of brain regions has become increasingly well implicated in aversive behavior;this set of regions includes the entopeduncular nucleus (EPN), lateral habenula (LHb), and rostromedial tegmental nucleus (RMTg). Activations of these structures strongly inhibit dopamine neurons, and our recently published work and preliminary data implicate these regions in aversive responses to cocaine. We further posit that cocaine avoidance conditioning is driven by activation of these pathways at specific times and via specific dopamine receptor subtypes. Finally, we posit that individual variability in the functioning of these pathways may relate to individual differences in drug- seeking propensity. In testing these hypotheses, this project could further our understanding of the aversive properties of drugs and their variation between individuals, while also identifying novel targets for possible therapeutic modulation of drug-seeking behavior.
In addition to their extensively studied rewarding effects, cocaine and other abused drugs produce aversive conditioning effects that powerfully modulate drug-seeking, but in ways that are poorly understood. We propose that acute aversive responses to cocaine are mediated by specific pathways that link the basal ganglia with midbrain dopamine neurons via the lateral habenula and rostromedial tegmental nucleus. These pathways could present novel targets for addiction therapy and modulation of drug-seeking behavior.