GABAB(1) Receptor Subtypes Differentially Modulate Locomotor Properties of Cocaine

L Rojo Gonzalez, P Zanos, P Georgiou, A Bailey, Y Chen. Univeristy of Surrey, Surrey, UK

Introduction : GABAB receptors are GPCRs regulating several neurotransmitter systems via its pre- and post- synaptic receptor subtypes, GABAB1a and GABAB1b respectively. In the last decade, there has been a substantial amount of pre-clinical and clinical evidence supporting a role of GABAB receptors in the modulation of addictive processes. Several studies suggest that baclofen, a GABAB agonist, has beneficial effects in the treatment of cocaine addiction. However, the precise role of the different subtypes of GABAB receptor in cocaine-induced behavioural effects is still poorly understood. Here, we aimed to define the roles of these receptor subtypes in the modulation of the rewarding, locomotor and behavioural sensitization effects of cocaine.

Methods : Locomotor-stimulation effects of cocaine in wild type (WT), GABAB1a (1a-/-) and GABAB1b (1b-/-) knockout mice were assessed following a 5-day escalating-dose cocaine administration paradigm (10-30mg/kg, i.p./day). We also examined the rewarding and behavioural sensitization properties of cocaine (20mg/kg, i.p.) using the conditioned place preference (CPP) paradigm. Immunohistochemical localisation of GABAB1a and GABAB1b and autoradiographic binding of dopamine D2 receptors in brains of WT and 1a-/- and 1b-/- mice were also investigated.

Results : Interestingly, only the 1a-/- mice manifested a significant increase in locomotor activity across all cocaine doses (i.e., 10mg/kg p<0.05, 15mg/kg p<0.001, 20mg/kg p<0.001, 25mg/kg p<0.001 and 30mg/kg p<0.01; two-way ANOVA followed by Tuckey’s multiple comparisons) compared to their respective saline controls. In contrast, a moderate increase in locomotor activity was observed following 15mg/kg and 20mg/kg cocaine in the 1b-/- mice (p<0.05), while WT mice did not show any cocaine-induced hyper-locomotion in any of the doses (p<0.05). Moreover, while cocaine administration induced a significant CPP in all three genotypes, only the 1a-/- mice showed behavioural sensitization to the acute locomotor enhancing effects of cocaine (20 mg/kg, i.p./day; day 2 compared to day 6; p<0.001; one-way ANOVA; n=11-12/genotype). Notably, striatal D2 receptor binding was significantly lower in the 1a-/- mice compared to WT (p<0.001; n=3/genotype; one-way ANOVA) and 1b-/- mice (p<0.05; n=3/genotype). In addition, while GABAB1 immonoreactivity was significantly reduced in the striatum of both the 1a-/- (p<0.001) and 1b-/- (p<0.01) compared to WT mice, GABAB2 was only reduced in the 1a-/- compared to both WT and 1b-/- (p<0.01).

Conclusion : Together, these data highlight a differential regulatory role for GABAB receptor subtypes in the rewarding and locomotor-inducing properties of cocaine. Specifically, this study suggests an important role of GABAB1a, but not GABAB1b, in the locomotor and behavioural sensitization effects of cocaine. These discrepancies might involve a possible interaction between the GABAB1a with the D2 receptors in the striatum to regulate psychostimulant-induced behaviours.