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

Abstract

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 a1-containing GABA A receptors (a1GABA 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 a1GABA A Rs and agonistic properties at the other three benzodiazepine-sensitive GABA A receptor subtypes, is self-administered, and that the a2GABA 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 a2 subunit which renders it insensitive to benzodiazepines (a2(H101R) mice) did not prefer midazolam and did not show midazolam-induced reward enhancement in ICSS, in contrast to wild-type controls, suggesting that a2GABA A Rs are necessary for the reward enhancing effects and preference for oral benzodiazepines. Through a viral-mediated knockdown of a2GABA A Rs in the nucleus accumbens (NAc), we demonstrated that a2 in the NAc is necessary for the preference for midazolam. Findings imply that a2GABA A Rs in the NAc are involved in at least some rewardrelated properties of benzodiazepines, which might partially underlie repeated drug-taking behavior.

A Pharmacogenetic ‘Restriction-of-Function’ Approach Reveals Evidence for Anxiolytic-Like Actions Mediated by α5-Containing GABAA Receptors in Mice

“…Compounds targeting α5-and/or α2-GABA A Rs should lack both the sedative (Rudolph et al, 1999) and addictive (Tan et al, 2010) properties of benzodiazepines, which have been attributed to the α1-GABA A Rs. Such compounds may provide additional value in the treatment of conditions such as anxious depression, as positive modulation of α2-GABA A Rs may enhance reward states (Engin et al, 2014;Reynolds et al, 2012) and positive modulation of α5-GABA A Rs might reduce cognitive problems commonly observed in psychiatric disorders, such as issues with memory interference and cognitive rigidity (Engin et al, 2015).…”

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…In general, ICSS is facilitated by barbiturates including phenobarbital and pentobarbital, although the magnitude of this facilitation is generally small relative to effects of stimulants like amphetamine (Reid et al, 1964;Seeger et al, 1981a;Bossert and Franklin, 2003). ICSS is also typically facilitated by benzodiazepines including midazolam, diazepam, and chlordiazepoxide (Olds, 1966;Ichimaru et al, 1985;Straub et al, 2010;Tracy et al, 2014;Engin et al, 2014). For example, Fig.…”

Pharmacological and antihyperalgesic properties of the novel α2/3 preferring GABA A receptor ligand MP-III-024

“…GABA A receptors containing α1 subunits (α1GABA A receptors) are located ubiquitously throughout the CNS, and have been implicated in the sedative effects of benzodiazepines as well as in effects related to physical dependence and abuse (Engin et al, 2014; Fischer et al, 2013; Mirza and Nielsen, 2006; Rudolph et al, 1999; Tan et al, 2010). In contrast, GABA A receptors containing α2 and α3 subunits (α2GABA A and α3GABA A receptors, respectively) are anatomically distributed in the cortex, limbic system and spinal cord (Rudolph and Knoflach, 2011) and have been associated with the anxiolytic effects of benzodiazepines (Fischer et al, 2010; Löw et al, 2000; McKernan et al, 2000; Rowlett et al, 2005).…”