Neural Basis of Benzodiazepine Reward: Requirement for α2 Containing GABAA Receptors in the Nucleus Accumbens

Despite long-standing concerns regarding the abuse liability of benzodiazepines, the mechanisms underlying properties of benzodiazepines that may be relevant to abuse are still poorly understood. Earlier studies showed that compounds selective for a I containing GABA(A) receptors (alpha | GABA(A)Rs) are abused by humans and self-administered by animals, and that these receptors may underlie a preference for benzodiazepines as well as neuroplastic changes observed in the ventral tegmental area following benzodiazepine administration. There is some evidence, however, that even L-838, 417, a compound with antagonistic properties at alpha | GABA(A)Rs and agonistic properties at the other three benzodiazepine-sensitive GABAA receptor subtypes, is self-administered, and that the alpha 2GABA(A)Rs may have a role in benzodiazepine-induced reward enhancement. Using a two-bottle choice drinking paradigm to evaluate midazolam preference and an intracranial self-stimulation (ICSS) paradigm to evaluate the impact of midazolam on reward enhancement, we demonstrated that mice carrying a histidine-to-arginine point mutation in the alpha 2 subunit which renders it insensitive to benzodiazepines (alpha 2(HI0IR) mice) did not prefer midazolam and did not show midazolam-induced reward enhancement in 1CSS, in contrast to wild-type controls, suggesting that alpha 2GABA(A)R5 are necessary for the reward enhancing effects and preference for oral benzodiazepines. Through a viral-mediated knockdown of alpha 2GABA(A)R5 in the nucleus accumbens (NAc), we demonstrated that alpha 2 in the NAc is necessary forthe preference for midazolam. Findings imply that alpha 2GABAAR5 in the NAc are involved in at least some reward-related properties of benzodiazepines, which might partially underlie repeated drug-taking behavior.