Differential Roles of GABAB1 Subunit Isoforms on Locomotor Responses to Acute and Repeated Administration of Cocaine

GABAB receptors are crucial modulators of the behavioural effects of drugs of abuse, and agonists and positive allosteric modulators show promise as a pharmacological strategies for anti-addiction therapeutics. GABAB receptors are heterodimers of GABAB1 and GABAB2 subunits. The predominant neuronal GABAB1 subunit isoforms are GABAB1a and GABAB1b. Selective ablation of these isoforms in mice revealed differential behavioural responses in fear, cognition and stress sensitivity. However, the influence of the two GABAB1 isoforms on responses to drugs of abuse has not been investigated. Therefore we examined the responses of GABAB1 subunit isoform null mice to acute and repeated administration of cocaine in locomotor and conditioned place preference (CPP) paradigms. During habituation in the locomotor activity assay, GABAB1b-/- mice showed higher levels of locomotor activity relative to wild-type (WT) and GABAB1a-/- mice, in accordance with previous studies. Acute cocaine (10 mg/kg) increased locomotor activity in habituated mice of all three genotypes, with GABAB1a-/- mice showing sustained hyperlocomotor responses 30 min after cocaine relative to WT and GABAB1b-/- mice. In the CPP paradigm, GABAB1a-/- mice demonstrated enhanced locomotor sensitisation to cocaine compared to WT mice, whereas GABAB1b-/- mice failed to develop locomotor sensitisation, despite higher levels of basal locomotor activity. These findings indicate that GABAB1a and GABAB1b isoforms differentially regulate behavioural responses to cocaine, with the GABAB1a isoform specifically modulating a heightened response to cocaine administration, and GABAB1b protection from sensitisation