A hypothalamus‐habenula circuit regulates psychomotor responses induced by cocaine

Abstract

AbstractAdministration of cocaine increases synaptic dopamine levels by blocking dopamine reuptake and leads to increased locomotor activity and compulsive drug‐seeking behaviour. It has been suggested that the lateral hypothalamus (LH) or lateral habenula (LHb) is involved in drug‐seeking behaviours. To explore the role of the LH and the LHb in cocaine‐induced psychomotor responses, we tested whether modulation of the LH or the LH‐LHb circuit affects cocaine‐induced locomotion. Cocaine‐induced locomotor activity and dopamine release were suppressed by the activation of the LH with 2‐[2,6‐difluoro‐4‐[[2‐[(phenylsulfonyl)amino]ethyl]thio]phenoxy]acetamide (PEPA), an AMPA receptor agonist. When the LH was inhibited by microinjection of a GABA receptor agonists mixture prior to cocaine injection, the cocaine's effects were enhanced. Furthermore, optogenetic activation of the LH‐LHb circuit attenuated the cocaine‐induced locomotion, while optogenetic inhibition of the LH‐LHb circuit increased it. In vivo extracellular recording found that the LH sent a glutamatergic projection to the LHb. These findings suggest that the LH glutamatergic projection to the LHb plays an active role in the modulation of cocaine‐induced psychomotor responses.