GABA(B) receptors are crucial modulators of the behavioural effects of drug abuse, and agonists and positive allosteric modulators show promise as pharmacological strategies for anti-addiction therapeutics. GABA(B) receptors are functional heterodimers of GABA(B1), and GABA(B2) subunits. The predominant neuronal GABA(B1) subunit isoforms are GABA(B1a) and GABA(B1b). Selective ablation of these isoforms in mice revealed differential behavioural responses in fear, cognition and stress sensitivity. However, the influence of the two GABA(B1) isoforms on responses to drugs of abuse is unclear. Therefore we examined the responses of GABA(B1) subunit isoform null mice to cocaine in acute locomotor activity and conditioned place preference (CPP) paradigms. During habituation for the acute locomotor activity assay, GABA(B1b)(-/-) mice showed higher levels of locomotor activity relative to wild-type (WT) and GABA(B1a)(-/-) mice, in accordance with previous studies. Acute cocaine (10 mg/kg) increased locomotor activity in habituated mice of all three genotypes, with GABA(B1a)(-/-) mice showing sustained hyperlocomotor responses 30 mm after cocaine relative to WT and GABA(B1b)(-/-) mice. No genotypes demonstrated a cocaine-induced place preference, however, GABA(B1a)(-/-) mice demonstrated enhanced locomotor sensitisation to chronic cocaine in the CPP paradigm in comparison to WT mice, whereas GABA(B1b)(-/-) mice failed to develop locomotor sensitisation, despite higher levels of basal locomotor activity. These findings indicate that GABABia and GABA(B1b) isoforms differentially regulate behavioural responses to cocaine, with deletion of GABABia enhancing cocaine-induced locomotor activity and deletion of GABA(B1b) protecting from cocaine-induced sensitisation. (C) 2015 Elsevier B.V. All rights reserved.