The orphan receptor GPR3 modulates the early phases of cocaine reinforcement.

Background And Purpose: The modulatory activity of the orphan receptor GPR3 in the brain has been related to the control of emotional behaviours. Limbic structures that express GPR3 have been associated with the effects of drug abuse.

Experimental Approach: The role of GPR3 in different cocaine-elicited behaviours including locomotor activity, behavioural sensitization, conditioned place preference (CPP) and intravenous self-administration was evaluated in Gpr3-/- mice and their Gpr3+/+ littermates. Cocaine-induced dopamine release in the nucleus accumbens was also evaluated to elucidate the effect of Gpr3 deletion on extracellular levels of dopamine.

Key Results: Gpr3-/- mice exhibited higher rewarding responses in the CPP paradigm. Gpr3-/- mice self-administered more cocaine, especially during the first days of training. No differences were found between genotypes regarding behavioural sensitization and the maximal effort required to obtain a cocaine infusion. Non-contingent priming injections of cocaine before operant training eliminated enhanced cocaine self-administration in Gpr3-/- mice. Extracellular levels of dopamine in the nucleus accumbens induced by cocaine did not differ between genotypes.

Conclusions And Implications: The increased responsiveness of Gpr3-/- mice to the acute locomotor effects of cocaine and the inconsistency to further increase this effect reflected an 'already maximally sensitized' basal state. Enhanced responsiveness of Gpr3-/- mice to cocaine reward and to early phases of reinforcement suggests that an initial alteration increased vulnerability to this type of drug abuse. Overall, altered signalling pathways of GPR3 could contribute to the neurobiological substrate involved in developing addiction to cocaine.