Modulation of ethanol drinking-in-the-dark by mecamylamine and nicotinic acetylcholine receptor agonists in C57BL/6J mice

Abstract

Rationale-Recent reports describe a restricted access ethanol consumption paradigm where C57Bl/6J mice drink until intoxicated. Termed "drinking in the dark" (DID), this paradigm has been used as a model of binge drinking. Although neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in alcohol drinking in rats pre-trained to self-administer ethanol, their role in binge-like ethanol consumption is unknown.Objectives-To determine if nAChRs are involved in binge drinking as measured by the DID assay in C57Bl/6J mice.Methods-Adult male C57Bl/6J mice were injected i.p. with nicotinic receptor antagonists including mecamylamine, hexamethonium, dihydro-β erythroidine, and methyllycaconitine. Immediately following injection mice were presented with 20 % ethanol for 2 hours in the DID assay to measure ethanol consumption. Nicotinic agonists including cytisine and nicotine were also evaluated. The effects of mecamylamine and nicotine on ethanol-induced dopaminergic neuronal activation in the VTA were evaluated via immunohistochemistry.Results-Mecamylamine dose dependently reduced ethanol consumption; whereas the peripheral antagonist hexamethonium had no significant effect. Nicotinic agonists cytisine and nicotine reduced ethanol consumption. None of the effective nicotinic receptor drugs reduced sucrose drinking. Mecamylamine blocked ethanol activation of dopaminergic neurons while nicotine alone activated them without additional activation by ethanol.Conclusions-Neuronal nAChRs are involved in ethanol consumption in the DID paradigm. The effects of mecamylamine, nicotine, and cytisine on ethanol intake appear to be specific because they do not reduce sucrose drinking. Mecamylamine reduces alcohol consumption by blocking activation of dopaminergic neurons; whereas nicotinic agonists may activate the same reward pathway as alcohol.

Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence

“…Local injection of mecamylamine into the VTA reduces rat operant responding for EtOH and EtOH-associated cues, as well as consumption during relapse [19,20] . Mecamylamine delivered systemically reduces EtOH consumption in C57Bl/6J mice in restricted access EtOH consumption "drinking in the dark" (DID) paradigm [21] , a model of binge drinking, as well as in the two-bottle choice consumption assay [22] . More recently, it has been demonstrated that mecamylamine blocks EtOHmediated activation of VTA DAergic neurons in mouse midbrain slices [23] .…”

Nicotinic Ligands Modulate Ethanol-Induced Dopamine Function in Mice

“…It has been reported that partial agonists at ␣ 4 ␤ 2 nAChRs, in predicted free human brain concentrations, could desensitize the nAChRs followed by minimal activation, thereby generating a response similar to that of an . Pretreatment with cytisine reduces ethanol-induced DA and DOPAC content in ventral striatum either by its low intrinsic efficacy (partial agonist) or desensitization of nAChRs [26] . On the other hand, lobeline is a non-selective antagonist at nAChRs and reduces the ethanol-induced increase in DA and DOPAC content likely by functional blockade of nAChRs in VTA.…”

“…On the other hand, cytisine is a nicotinic alkaloid and a known partial agonist at ␣ 4 ␤ 2 and full agonist at ␣ 7 nAChRs [23,24] . Cytisine has shown potential as a smoking cessation treatment [25] , and cytisine or its derivatives have been found to inhibit ethanol intake and ethanol-seeking behavior in rodent models [21,26,27] . However, the neurochemical effects of cytisine on ethanol-induced DA function remain unknown.…”

The Role of Halogen Bonding in Crystal Structures of 3-Halogeno Cytisine Derivatives

“…These receptors have been identified as promising targets for the treatment of several neurological disorders, such as Parkinson's and Alzheimer's diseases, Tourette's syndrome, dyskinesias, schizophrenia, anxiety, attention deficit disorder, and pain [4][5][6]. Additionally, this natural compound was found to decrease nicotine-induced extra cellular dopamine release in the nucleus accumbens [7], and was shown to reduce ethanol drinking behaviors in mice or rats [8,9] and ethanol-induced dopamine and its metabolite [10]. Therefore, nicotinic ligands could be developed as potential therapeutic candidates for binge-like ethanol drinking and dependence in humans.…”