Abstract
The GABAergic system is the primary inhibitory regulator of the mesolimbic dopamine system, mediating both natural and drug-induced reward behaviours. The GABAB agonist, baclofen, has been postulated as a potential anti-addiction treatment. However, clinical studies have revealed conflicting results and both anti- and pro-rewarding effects of GABAB system activation have been reported. Thus, a deeper and more refined understanding of GABAB receptor pharmacology is needed. GABAB receptors are obligate heterodimers of GABAB(1) and GABAB(2) subunits and further GABAB(1) subunit isoforms are GABAB(1a) and GABAB(1b). While presynaptic GABAB receptors are likely to contain the GABAB(1a) isoform, postsynaptic GABAB receptors are composed of the GABAB(1b) isoform. Using mice lacking in GABAB(1a) (1a KO) and GABAB(1b) (1b KO) isoforms, we tested the hypothesis that the GABAB receptor isoforms differentially modulate psychomotor and reward behaviours of cocaine and morphine, alcohol intake and social behaviours via distinct neurochemical mechanism. We therefore examined cocaine- and morphine-induced locomotion stimulation, sensitisation and conditioned place preference (CPP) as well as alcohol intake. The 3-chambered box was utilised to investigate social behaviours. Cocaine and morphine enhanced the locomotor activity in 1a KO mice but not in 1b KO and WT mice. However, cocaine- and morphine-induced CPP was unaffected by either isoform deletion. Conversely, while WT and 1a KO mice extinguished alcohol preference during withdrawal, this was not seen in 1b KO mice. Finally, 1a KO mice exhibited higher social novelty preference and striatal oxytocin receptor levels compared to WT and 1b KO mice. These results reveal that presynaptic preferring GABAB(1a) receptors selectively modulate the psychomotor effects of cocaine and morphine as well as social novelty, most likely by inhibiting dopaminergic transmission. Conversely, the postsynaptic GABAB(1b) receptors may play a larger role in alcohol addiction. We conclude that targeting GABAB receptor isoforms may constitute an effective approach to drug addiction treatment