Enhanced alcohol-seeking behavior by nicotine in the posterior ventral tegmental area of female alcohol-preferring (P) rats: modulation by serotonin-3 and nicotinic cholinergic receptors

Abstract

Rationale Alcohol and nicotine co-use can reciprocally promote self-administration and drug-craving/drug-seeking behaviors. To date, the neurocircuitry in which nicotine influences ethanol (EtOH) seeking has not been elucidated. Clinical and preclinical research has suggested that the activation of the mesolimbic dopamine system is involved in the promotion of drug seeking. Alcohol, nicotine, and serotonin-3 (5-HT3) receptors interact within the posterior ventral tegmental area (pVTA) to regulate drug reward. Recently, our laboratory has reported that systemic administration of nicotine can promote context-induced EtOH seeking. Objectives The goals of the current study were to (1) determine if microinjections of pharmacologically relevant levels of nicotine into the pVTA would enhance EtOH seeking, (2) determine if coadministration of nicotinic cholinergic receptor antagonist (nACh) or 5-HT3 receptor antagonists would block the ability of nicotine microinjected into the pVTA to promote EtOH seeking, and (3) determine if 5-HT3 receptors in the pVTA can modulate EtOH seeking. Results Nicotine (100 and 200 µM) microinjected into the pVTA enhanced EtOH seeking. Coinfusion with 200 µM mecamylamine (nACh antagonist) or 100 and 200 µM zacopride (5-HT3 receptor antagonist) blocked the observed nicotine enhancement of EtOH seeking. The data also indicated that microinjection of 1 µM CPBG (5-HT3 receptor agonist) promotes context-induced EtOH seeking; conversely microinjection of 100 and 200 µM zacopride alone reduced context-induced EtOH seeking. Conclusions Overall, the results show that nicotine-enhanced EtOH-seeking behavior is modulated by 5-HT3 and nACh receptors within the pVTA and that the 5-HT3 receptor system within pVTA may be a potential pharmacological target to inhibit EtOH-seeking behaviors.

Interactions between nicotine and drugs of abuse: a review of preclinical findings

“…Research has primarily focused on nAChRs in the mesolimbic DA system as crucial mediators of these effects, though glutamate [74], GABA [50], and serotonin [75] may also play important roles. While nAChRs are the main target of action for nicotine, they also appear to be involved in many of the abuse-related effects of alcohol (reviewed by [76,77]).…”

“…For example, injections of alcohol directly into the VTA increase NAcc DA levels, which is blocked by mecamylamine [94]. Further, nicotine administered directly into the posterior VTA [75] or the basal forebrain, which receives input from the VTA [95], increases alcohol seeking in rats. VTA activation also increases extracellular DA in the NAcc shell, and combinations of nicotine + alcohol administered directly into the VTA produce an additive effect on DA levels in this region [96].…”

Mechanisms and genetic factors underlying co-use of nicotine and alcohol or other drugs of abuse

“…Alcohol preferring rats will self-administer combined ethanol and nicotine directly into the pVTA at concentrations that do not support individual self-administration (127), while combinations of oral nicotine and ethanol are self-administered at levels similar to ethanol alone (121). Furthermore, microinfusion of nicotine into the pVTA of these rats will enhance ethanol self-administration, an effect that is blocked by antagonists for both nAChRs and 5-HT3 receptors (128). …”

The antero-posterior heterogeneity of the ventral tegmental area

“…The pVTA ethanol self-administration is also attenuated by the co-infusion of a 5HT 2A antagonist (R96544), but not by a 5HT 1B antagonist (GR55562) (Ding et al, 2009c). An intra-pVTA microinjection of nicotine can favor ethanol seeking, which is prevented by a nicotinic (mecamylamine) or 5-HT 3 receptor antagonist (zacopride) (Hauser et al, 2014). An intra-pVTA administration of the glutamate antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) also reduces ethanol-seeking, but without affecting ethanol intake (Czachowski et al, 2012).…”