Differential Roles of GABAA Receptor Subtypes in Benzodiazepine-Induced Enhancement of Brain-Stimulation Reward

Abstract

Benzodiazepines such as diazepam are widely prescribed as anxiolytics and sleep aids. Continued use of benzodiazepines, however, can lead to addiction in vulnerable individuals. Here, we investigate the neural mechanisms of the behavioral effects of benzodiazepines using the intracranial self-stimulation (ICSS) test, a procedure with which the reward-enhancing effects of these drugs can be measured. Benzodiazepines bind nonselectively to several different GABA A receptor subtypes. To elucidate the a subunit(s) responsible for the reward-enhancing effects of benzodiazepines, we examined mice carrying a histidine-to-arginine point mutation in the a1, a2, or a3 subunit, which renders the targeted subunit nonresponsive to diazepam, other benzodiazepines and zolpidem. In wild-type and a1-pointmutated mice, diazepam caused a dose-dependent reduction in ICSS thresholds (reflecting a reward-enhancing effect) that is comparable to the reduction observed following cocaine administration. This effect was abolished in a2-and a3-point-mutant mice, suggesting that these subunits are necessary for the reward-enhancing action of diazepam. a2 Subunits appear to be particularly important, since diazepam increased ICSS thresholds (reflecting an aversive-like effect) in a2-point-mutant animals. Zolpidem, an a1-preferring benzodiazepine-site agonist, had no reward-enhancing effects in any genotype. Our findings implicate a2 and a3 subunit containing GABA A receptors as key mediators of the reward-related effects of benzodiazepines. This finding has important implications for the development of new medications that retain the therapeutic effects of benzodiazepines but lack abuse liability.

Reinforcing Effects Of Compounds Lacking Intrinsic Efficacy At α1 Subunit-Containing GABAA Receptor Subtypes in Midazolam- But Not Cocaine-Experienced Rhesus Monkeys

“…Under cocaine baseline conditions, our findings are consistent with the prediction advanced by Tan et al (2010) that a1-sparing compounds should be without reinforcing effects, possibly due to a lack of disinhibition of VTA dopaminergic neurons that innervate the NAc. In contrast, our findings that a1-sparing compounds have reinforcing effects under the midazolam baseline condition is more consistent with recent results reported by Reynolds et al (2012), in which the a1GABA A receptor appeared to have little role in benzodiazepine-induced enhancement of reward thresholds in an intra-cranial self-stimulation procedure.…”

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

“…In an earlier study, we showed that zolpidem did not cause reward enhancement in ICSS (Reynolds et al, 2012), whereas our current findings show that the a1GABA A Rs are required for the reward-enhancing actions of midazolam. This could be interpreted as the a1GABA A Rs being required, but not sufficient for, reward enhancement.…”

“…The ICSS paradigm is based on the operant response of the animals to brain stimulation and can be viewed as the animals' willingness to work to obtain a certain level of stimulation. Although animals will learn operant responses that elicit stimulation in a large number of different brain areas (Zacharko et al, 1990), the medial forebrain bundle was selected in the current study because of the relative lack of motor artifacts upon stimulation in this region, as well as for comparability to earlier studies from our laboratory using other benzodiazepines (Straub et al, 2010;Reynolds et al, 2012). Responding to lower stimulation frequencies after the administration of a drug than those that maintained responding previously is interpreted as 'reward enhancement', and is commonly observed after the administration of drugs of abuse (Wise, 1996).…”

“…All procedures were described in detail previously (Carlezon and Chartoff, 2007;Reynolds, 2012). Monopolar electrodes were implanted in the right medial forebrain bundle at the level of the lateral hypothalamus.…”

“…In addition, it has been reported that benzodiazepines lead to reward enhancement in intracranial self-stimulation (ICSS) studies in rodents (Olds, 1970;Straub et al, 2010). We have recently demonstrated that reward enhancement by diazepam was completely abolished and even led to aversive-like effects at doses that do not impair responding (as measured by maximal response rates) in a2(H101R) mice (Reynolds et al, 2012). Taken together, these findings suggest that although a1GA-BA A Rs are involved in the positively reinforcing effects of benzodiazepines, other subtypes, especially a2GABA A Rs, may also have a role.…”