Benzodiazepine self-administration in humans and laboratory animals - implications for problems of long-term use and abuse

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.

Section: Introductionmentioning

confidence: 99%

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

Engin

Bakhurin

Smith

et al. 2014

“…Two types of inappropriate use of these drugs have brought about questions regarding their abuse potential over the years: Continued, long-term use beyond the therapeutic period often at higher doses than prescribed by patients and illicit use, often but not exclusively by polydrug abusers (Griffiths and Weerts, 1997;Malcolm, 2003;Salzman, 1998;Woods et al, 1992;O'Brien, 2005). Both types of misuse depend on the reinforcing effects of benzodiazepines (Griffiths and Weerts, 1997), making it necessary to understand the nature (eg, direct reward, enhancement of drug 'high' induced by other drug, relief of anxiety) and mechanisms (eg, receptor subtypes and brain regions involved in each component of the drug reinforcement effect) of benzodiazepine drug reinforcement. Here, we investigate the facilitation of brain-stimulation reward by benzodiazepines and receptor subtypes that are involved in this effect.…”

Section: Introductionmentioning

confidence: 99%

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

Reynolds

Engin

Tantillo

et al. 2012

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.

“…Atack, unpublished data). Benzodiazepines with relatively long durations of action typically are less robustly self-administered compared with short-acting drugs (Griffiths and Weerts, 1997;Platt and Rowlett, 2012).…”

Section: Introductionmentioning

confidence: 99%

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

Shinday

Sawyer

Fischer

et al. 2012

Benzodiazepines are prescribed widely but their utility is limited by unwanted side effects, including abuse potential. The mechanisms underlying the abuse-related effects of benzodiazepines are not well understood, although a1 subunit-containing GABA A receptors have been proposed to have a critical role. Here, we examine the reinforcing effects of several compounds that vary with respect to intrinsic efficacy at a2, a3, and a5 subunit-containing GABA A receptors but lack efficacy at a1 subunit-containing GABA A receptors ('a1-sparing compounds'): MRK-623 (functional selectivity for a2/a3 subunit-containing receptors), TPA023B (functional selectivity for a2/a3/a5 subunit-containing receptors), and TP003 (functional selectivity for a3 subunit-containing receptors). The reinforcing effects of the a1-sparing compounds were compared with those of the non-selective benzodiazepine receptor partial agonist MRK-696, and non-selective benzodiazepine receptor full agonists, midazolam and lorazepam, in rhesus monkeys trained to self-administer midazolam or cocaine, under a progressive-ratio schedule of intravenous (i.v.) drug injection. The a1-sparing compounds were self-administered significantly above vehicle levels in monkeys maintained under a midazolam baseline, but not under a cocaine baseline over the dose ranges tested. Importantly, TP003 had significant reinforcing effects, albeit at lower levels of self-administration than non-selective benzodiazepine receptor agonists. Together, these results suggest that a1 subunit-containing GABA A receptors may have a role in the reinforcing effects of benzodiazepine-type compounds in monkeys with a history of stimulant self-administration, whereas a3 subunit-containing GABA A receptors may be important mediators of the reinforcing effects of benzodiazepine-type compounds in animals with a history of sedative-anxiolytic/benzodiazepine self-administration.