Nicotine-induced molecular alterations are modulated by GABA(B) receptor activity

作者：Varani Andres P; Pedron Valeria T; Aon Amira J; Hocht Christian; Acosta Gabriela B; Bettler Bernhard; Balerio Graciela N^*

来源：ADDICTION BIOLOGY, 2018, 23(1): 230-246.

DOI：10.1111/adb.12506

• c-Fos
• dopamine
• GABA(B) receptors
• nicotine
• nicotinic receptors
• reward

It has been demonstrated that GABA(B) receptors modulate nicotine (NIC) reward effect; nevertheless, the mechanism implicated is not well known. In this regard, we evaluated the involvement of GABA(B) receptors on the behavioral, neurochemical, biochemical and molecular alterations associated with the rewarding effects induced by NIC in mice, from a pharmacological and genetic approach. NIC-induced rewarding properties (0.5 mg/kg, subcutaneously, sc) were evaluated by conditioned place preference (CPP) paradigm. CPP has three phases: preconditioning, conditioning and postconditioning. GABA(B) receptor antagonist 2-hydroxysaclofen (0.25, 0.5 and 1 mg/kg; intraperitoneally, ip) or the GABAB receptor agonist baclofen (3 mg/kg; ip) was injected before NIC during the conditioning phase. GABA(B1) knockout (GABA(B1)KO) mice received NIC during the conditioning phase. Vehicle and wild-type controls were employed. Neurochemical (dopamine, serotonin and their metabolites), biochemical (nicotinic receptor alpha 4 beta 2, alpha 4 beta 2nAChRs) and molecular (c-Fos) alterations induced by NIC were analyzed after the postconditioning phase by high-performance liquid chromatography (HPLC), receptor-ligand binding assays and immunohistochemistry, respectively, in nucleus accumbens (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, alpha 4 beta 2nAChRs density in VTA and c-Fos expression in Acb shell (AcbSh), VTA and PFC. We showed that behavioral, neurochemical, biochemical and molecular alterations induced by NIC were prevented by baclofen. However, in 2-hydroxysaclofen pretreated and GABA(B1)KO mice, these alterations were potentiated, suggesting that GABAB receptor activity is necessary to control alterations induced by NIC-induced rewarding effects. Therefore, the present findings provided important contributions to the mechanisms implicated in NIC-induced rewarding effects.

• 出版日期2018-1