Deletion of the GABAA α2-subunit does not alter self administration of cocaine or reinstatement of cocaine seeking

C I Dixon,D N Stephens,B Halbout,S L King

doi:10.1007/s00213-014-3443-3

C I Dixon, D N Stephens + Show 2 more

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https://doi.org/10.1007/s00213-014-3443-3

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Abstract

RationaleGABAA receptors containing α2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the α2-subunit results in an absence of sensitisation to cocaine.ObjectiveWe investigated the reinforcing properties of cocaine in GABAA α2-subunit knockout (KO) mice using an intravenous self-administration procedure.Methodsα2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg).ResultsNo differences were found in acquisition of lever pressing for milk. All genotypes acquired self-administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose-dependent increase in lever pressing during the cue presentation, KO mice did not.ConclusionsDespite a reported absence of sensitisation, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the α2-subunit may be involved in modulating the “energising” aspect of cocaine’s effects on reward-seeking.

Highlights

GABA is the major inhibitory neurotransmitter in the mammalian brain but is often overlooked when considering the neurobiology of drug abuse
Within the nucleus accumbens (NAcc), a primary locus associated with integrating information relating to reward, 95 % of neurons are GABAergic medium spiny neurons (Taverna et al 2004) with the remainder consisting mostly of GABAergic interneurons (Kawaguchi 1993)
Instrumental responding for the milk solution did not differ among genotypes, with all mice performing a comparable number of active lever presses in the initial overnight training session (Fig. 1b; F(2,61)=1.918, p=0.156), the first daytime 90-min session (F(2,61)=0.327, p=0.723) and the last training session once criterion was reached (F(2,61)=2.017, p= 0.142)

Summary

Introduction

GABA is the major inhibitory neurotransmitter in the mammalian brain but is often overlooked when considering the neurobiology of drug abuse. It is important to consider how other reward-related neurotransmitter systems may interact with the inhibitory GABA neurons to mediate reward- and drug-related behaviour. Facilitation of GABAergic transmission reduces the expression and acquisition of cocaineconditioned place preference (CPP; Dewey et al 1998) and behavioural sensitisation (Filip et al 2006). Manipulations of Psychopharmacology (2014) 231:2695–2703 inhibitory transmission have, been shown on many occasions to attenuate addiction- and reward-related behaviours and suggest that GABA may participate in the underlying neurobiology

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