GABAB receptors involvement in behavioral, neurochemical, biochemical and molecular alterations induced by nicotine rewarding effect: Pharmacological and genetic approaches

VARANI ANDRÉS P.; PEDRÓN VALERIA T.; AON, AMIRA J.; HÖCHT CHRISTIAN; ACOSTA GABRIELA B.; BETTLER BERNHARD; BALERIO GRACIELA N.

ADDICTION BIOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2018 vol. 23 p. 230 - 246

1355-6215

It has been demonstrated that GABAB receptors modulate nicotine (NIC) reward effect, nevertheless the mechanism implicated is not well known. In this sense, we evaluated the involvement of GABAB receptors on the behavioral, neurochemical, biochemical and molecular alterations associated with the rewarding effect induced by NIC in mice, from a pharmacological and genetic approach. NIC-induced rewarding properties (0.5 mg/kg, sc) were evaluated by conditioned place preference (CPP) paradigm. CPP has three phases: pre-conditioning, conditioning and post-conditioning. GABAB receptor antagonist 2-OHsaclofen (SAC; 0.25, 0.5 and 1 mg/kg; ip) or the GABAB receptor agonist baclofen (BAC; 3 mg/kg; ip) was injected before NIC during the conditioning phase. GABAB1 knockout (GABAB1KO) mice received NIC during the conditioning phase. Neurochemical (dopamine, serotonin and their metabolites), biochemical (nicotinic receptor α4β2, α4β2nAChRs) and molecular (c-Fos) alterations induced by NIC were analyzed after the post-conditioning phase by HPLC, receptor-ligand binding assays and immunohistochemistry, respectively, in accumbens nucleus (Acb), prefrontal cortex (PFC)and ventral tegmental area (VTA). NIC induced rewarding effects in the CPP paradigm, and increased dopamine levels in Acb and PFC, α4β2nAChRs density in ATV and c-Fos expression in Acb Shell, ATV and PFC. Importantly, we showed that behavioral, neurochemical, biochemical and molecular alterations induced by NIC were prevented by BAC (3 mg/kg). However, in SAC-pretreated (1 mg/kg) and GABAB1KO mice these alterations were potentiated, suggesting that GABAB receptor activity is necessary to control alterations induced by NIC-induced rewarding effect. Therefore, GABAB receptor could be consider as a promising target to prevent the NIC-induced rewarding effect.