Neural bases for addictive properties of benzodiazepines

Abstract

Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behavior. The neural basis for the addictive nature of benzodiazepines however remains elusive. Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABAA receptors in nearby interneurons. Such disinhibition, which relies on α1-containing GABAARs expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Taken together, our data provide evidence that benzodiazepines share defining pharmacological features of addictive drugs through cell type-specific expression of α1-containing GABAARs in the ventral tegmental area. The data also suggest that subunitselective benzodiazepines sparing α1 may be devoid of addiction liability.

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

“…Supporting this, the a1-sparing compound, TPA023, was not self-administered by baboons up to doses that completely occupied benzodiazepine binding sites as measured via positron emission tomography (Ator et al, 2010). Moreover, mice with point mutations rendering the a1GABA A receptor insensitive to benzodiazepines did not show a preference for oral midazolam vs sucrose solutions, in contrast to wild-type mice (Tan et al, 2010). We have shown, however, that the a1-sparing compound, L-838,417, was reliably self-administered by rhesus monkeys (Rowlett et al, 2005), a finding clearly inconsistent with the hypothesis that a1GABA A receptors mediate the reinforcing effects of benzodiazepines.…”

“…Benzodiazepines decrease firing of these interneurons via a1GABA A receptors, resulting in a net effect of decreased activity, ie, 'disinhibition', of DA neurons. The ultimate outcome would be an increase in DA release in the nucleus accumbens (NAc; Tan et al, 2010;2011), although this effect has yet to be established for benzodiazepines (eg Finlay et al, 1992;Murai et al, 1994). If this hypothesis is correct, then compounds lacking activity at a1GABA A receptors (ie, 'a1-sparing compounds') should lack abuse potential (Tan et al, 2010;2011).…”

“…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). Benzodiazepines decrease firing of these interneurons via a1GABA A receptors, resulting in a net effect of decreased activity, ie, 'disinhibition', of DA neurons.…”

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

“…Instead, they represent an imperative initial step that triggers synaptic changes in addiction if the use of drug becomes chronic. Furthermore, it has been shown that benzodiazepine-induced changes in synaptic plasticity depend on α1-containing GABA A receptors because the observed changes are abolished in α1-H101R knock-in mice [19] . In our model, a single dose of zolpidem and short-term intermittent zolpidem treatment did not induce molecular changes at GABA A receptors regarding receptor number and GABA potentiation.…”

“…Recent studies have provided evidence that benzodiazepines share the pharmacological profile of addictive drugs through cell-type specific expression of α1-containing GABA A receptors [13,14,19] . Non-benzodiazepine zolpidem acts selectively at α1 subunit-containing GABA A receptors and is considered to be devoid of addiction liability.…”