Hooked on benzodiazepines: GABAA receptor subtypes and addiction

Abstract

Benzodiazepines are widely used clinically to treat anxiety and insomnia. They also induce muscle relaxation, control epileptic seizures, and can provoke amnesia. Moreover, benzodiazepines are often abused after chronic clinical treatment but also for recreational purposes. Within weeks, tolerance to the pharmacological effects can develop, in addition to dependence and even addiction in vulnerable individuals. Here, we review recent observations from animal models regarding the cellular and molecular basis that may underlie the addictive properties of benzodiazepines. These data reveal how benzodiazepines, acting through specific GABAA receptor subtypes, activate midbrain dopamine neurons and how this may hijack the mesolimbic reward system. Such findings have important implications for the future design of benzodiazepines with reduced or even absent addiction liability.

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

“…As described above, recent work has implicated a1 subunit-containing GABA A receptors on GABAergic interneurons in the VTA as key mediators of the reinforcing effects of benzodiazepines (Heikkinen et al, 2009;Tan et al, 2010Tan et al, , 2011. In this regard, benzodiazepines would increase inhibition of these neurons, thus relieving their tonic inhibition of DA neurons (Tan et al, 2010(Tan et al, , 2011, and resulting in the hallmark DA increase observed with other (near zero efficacy at a1 subunit-containing receptors, ie, 'a1-sparing'; partial agonist at a2, a3, and a5 subunit-containing receptors) under the same conditions as described for panel a.…”

“…In this regard, benzodiazepines would increase inhibition of these neurons, thus relieving their tonic inhibition of DA neurons (Tan et al, 2010(Tan et al, , 2011, and resulting in the hallmark DA increase observed with other (near zero efficacy at a1 subunit-containing receptors, ie, 'a1-sparing'; partial agonist at a2, a3, and a5 subunit-containing receptors) under the same conditions as described for panel a. (c) Self-administration of MRK-623 (near zero efficacy at a1 subunit-containing receptors, ie, 'a1-sparing'; highest efficacy at a2, a3 subunit-containing receptors) under the same conditions as described for panel a.…”

“…Benzodiazepines potentiate the effects of the neurotransmitter g-aminobutyric acid (GABA) via positive allosteric modulation at the g-aminobutyric acid type A (GABA A ) receptor. GABA A receptors are heteropentameric chloride ion channels assembled in a typical stoichiometry of 2 a, 2 b, and 1 g subunits; conventional benzodiazepines bind to GABA A receptors containing a1, a2, a3, or a5 subunits (a1GABA A , a2GABA A , a3GABA A , or a5GABA A receptors, respectively; Rudolph and Knoflach, 2011;Tan et al, 2011). Previous studies have shown localization of a1GABA A receptors on inhibitory interneurons that synapse with DA neurons in the ventral tegmental area (VTA; Heikkinen et al, 2009;Tan et al, 2010) while a3GABA A receptors are expressed at lower levels on the DA neurons themselves (Fritschy and Mohler, 1995;Ciccarelli et al, 2012).…”

Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro

“…Moreover, animals and humans treated for prolonged period of time with drugs acting as full positive modulators of GABA action at GABA A receptors developed tolerance characterized by a decreased ability of the drug to produce its pharmacological effect. Although it appears that allosteric uncoupling could explain the development of tolerance, the molecular mechanisms are rather more complex [15,17] .…”

“…Moreover, the observed changes are not substantially different from those detected after prolonged exposure of these cells to high doses of the classical benzodiazepine, diazepam [14] . Despite of many studies, the molecular mechanisms involved in the development of tolerance to the actions of benzodiazepines remain unknown [15][16][17] . The aim of our study was to explore the molecular mechanisms induced by zolpidem treatment using radioligand binding assays.…”