Nicotine‐induced molecular alterations are modulated by GABA_B receptor activity

Abstract

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 GABA B 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 α4β2, α4β2nAChRs) 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, α4β2nAChRs 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 GABA B 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.

The GABAB Receptor—Structure, Ligand Binding and Drug Development

“…The stimulation of GABA B -R by baclofen is linked to a reduction in addiction-related behavior towards substances such as nicotine, cocaine and alcohol in animal models [79,84]. Drugs of abuse stimulate the mesolimbic system in the brain that controls the release of the reward-associated neurotransmitter dopamine [85]. A recent study showed that the rewarding effect of nicotine was reduced in animals pre-treated with baclofen [85].…”

“…Drugs of abuse stimulate the mesolimbic system in the brain that controls the release of the reward-associated neurotransmitter dopamine [85]. A recent study showed that the rewarding effect of nicotine was reduced in animals pre-treated with baclofen [85]. Nicotine stimulates the nicotine acetylcholine receptors (nAchRs) located on GABAergic, glutamatergic and dopaminergic neurons, which causes release of dopamine.…”

In Silico Methods for the Discovery of Orthosteric GABAB Receptor Compounds

“…The GABA B -R is linked to a variety of neurological and neuropsychiatric disorders including memory and learning deficits, addiction, epilepsy, anxiety and depression, and is an interesting target for drug intervention [15,16,17,18]. However, at present, the agonist baclofen (β-(4-chloro-phenyl)GABA) is the only marketed drug targeting the GABA B -R. Baclofen is used as a muscle relaxant and antispastic agent to treat muscle spasticity and other muscle symptoms caused by e.g., multiple sclerosis [19,20].…”

Differential Nicotinic Modulation of Glutamatergic and GABAergic VTA Microcircuits

“…Such a speculative mechanism would have to be activity independent, though, since our experiments with nicotine were performed in the continued presence of TTX. Prolonged exposure of VTA slices to nicotine could induce glutamate, GABA, and/or endocannabinoid release that could then act on mGluR, GABA B , or CB1 G-protein-coupled receptors to attenuate optical activation of VGluT2 + or Gad2 + fibers (Merrill et al, 2015; Han et al, 2017; Varani et al, 2018). It is very unlikely, however, that nicotine suppresses release by interfering with a stimulatory action of endogenous ACh.…”