Abstract
The neuronal substrates underlying cocaine’s aversive properties are poorly understood. The habenulomesencephalic pathway, which connects the lateral habenula (LHb), an epithalamic structure, with the ventral tegmental area (VTA) and rostromedial tegmental nucleus (RMTg), has emerged as a key player in the aversive responses to many addictive drugs, including cocaine. This chapter focuses on recent advances in our understanding of the role of this neural circuit in the effects of cocaine, particularly aversion. Growing evidence highlights several new aspects of cocaine’s action: notably that aversion to cocaine is induced by potentiation of glutamatergic excitation of a subset of LHb neurons that projects to the RMTg, this potentiation being mediated by dopamine receptors and increased trafficking of AMPA-type glutamate receptors. Precise delineation of the neural circuits that mediate cocaine aversion will help the development of effective pharmacotherapy for the treatment of cocaine addiction and the prevention of relapse.