Effects of GPR55 Receptor Blockade on Schedule-Induced Polydipsia in Rats

Abstract

Compulsivity, a tendency toward repetitive, habitual actions that are repeated despite adverse consequences, is a core trait of many psychiatric pathologies. Despite its prevalence and severity, there are few effective pharmacological interventions for compulsive symptoms. The schedule-induced polydipsia (SIP) rodent model, in which chronically food-restricted animals develop adjunct compulsive drinking behaviours, has been used to investigate neurochemical substrates of compulsion. Recently, drinking behaviour was associated with bi-directional gamma-aminobutyric acid (GABA) plasticity signalling between G-protein-coupled receptor 55 (GPR55) mediated GABA potentiation and cannabinoid type I receptor (CB1) mediated GABA depression, in the bed nucleus of the stria terminalis (BNST). Compulsive, high drinking was correlated with deficient GPR55 GABA signalling. This project investigated a potential causal link between deficient GPR55 signaling and the development of compulsive drinking. We hypothesized that antagonism of GPR55, using CID 16020046 (CID), would turn low-drinking rats into high drinkers. However, administration of CID did not significantly increase water intake in low-drinking rats. Further, there was no difference in CID-induced water intake between animals displaying low vs high drinking behaviour. Animals receiving the higher CID dose elicited a greater increase in CID-induced water intake, although marginal, compared to the lower dose, irrespective of drinking classification. This suggests dosing may have been too low for a sufficient amount of CID to reach its target in the brain. In addition, the targeting of one receptor may not have been sufficient to evoke detectable behavioural changes, as a wide range of receptors and signalling systems have been implicated in the development of compulsive phenotypes. Regardless, this project served as a useful starting point to investigate a causal link between GPR55/CB1 signalling and the development of compulsive behaviour.