Pharmacological stress is required for the anti-alcohol effect of the α3β4* nAChR partial agonist AT-1001

Abstract

Alcohol and nicotine are often taken together. The mechanisms underlying this frequent co-abuse are not well known. Genetic and pharmacological evidence suggests that the nicotinic acetylcholine receptors (nAChRs) containing the α3 and β4 subunits play a role in alcohol as well as nicotine addiction. AT-1001 is a high affinity α3β4 nAChR partial agonist recently found to block nicotine self-administration and relapse-like behavior in rats. Here, to study the involvement of α3β4 nAChRs in the mechanisms that regulate alcohol abuse we evaluated the effects of AT-1001 on alcohol taking and seeking in Sprague-Dawley rats. AT-1001 reduced operant alcohol self-administration at the highest dose examined (3.0 mg/kg), an effect also observed for food self-administration. A dose of 1.5 mg/kg AT-1001, which had no effect on alcohol or food self-administration, essentially eliminated reinstatement of alcohol seeking induced by yohimbine (0.625 mg/kg) whereas, reinstatement induced by alcohol-associated cues was not altered, nor did AT-1001 induce reinstatement of extinguished self-administration on its own. Finally, AT-1001 showed an anxiolytic activity when measured in the presence or absence of yohimbine stress in the elevated plus maze paradigm. Together, these observations do not support a specific involvement of the α3β4 nAChR in mediating alcohol reward or cue-induced relapse to alcohol seeking but rather indicate that the α3β4 nAChR partial agonism may constitute an attractive approach for treating alcohol use disorders exacerbated by elevated stress response.

Varenicline decreases nicotine but not alcohol self-administration in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats

“…Testing sessions were conducted every 3–4 days. The day after the experiment, rats were allowed 1 day off and then a new baseline was established over the following 1 or 2 days (Cippitelli et al, 2015b). Data are expressed as mean ± S.E.M.…”

“…These well-documented anti-alcohol properties of varenicline seem to be dependent on the activation of α4 nAChRs (Hendrickson et al, 2010). In contrast, α7 (Kuzmin et al, 2009) and α3β4 nAChRs (Carnicella et al, 2010; Cippitelli et al, 2015b) may not be involved in alcohol reinforcement. Consistent with this literature, we have recently demonstrated the efficacy of varenicline in decreasing alcohol self-administration at doses that also decreased nicotine self-administraton in an operant co-administration paradigm (Cippitelli et al, 2015c).…”

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

“…Despite evidence that varenicline decreases alcohol intake (100,108,129), the effects on co-self-administration of nicotine and alcohol are not as clear (130,131). However, withdrawal from chronic concurrent exposure, which is more prolonged than withdrawal from either drug alone, can be attenuated by continued treatment with just one of the drugs (132).…”

The α3β4 nAChR partial agonist AT-1001 attenuates stress-induced reinstatement of nicotine seeking in a rat model of relapse and induces minimal withdrawal in dependent rats

“…Therefore, the present series of experiments were designed to investigate the efficacy of AT-1001 in stress-induced reinstatement of nicotine seeking behavior. We have previously shown that AT-1001 had anxiolytic activity in the elevated plus maze assay (EPM) in rats in the presence of a pharmacological stressor yohimbine [41]. Since AT-1001 decreased yohimbine’s anxiogenic effects in the elevated plus maze assay [41], we hypothesized that AT-1001 administration would block yohimbine stress-induced reinstatement of nicotine seeking.…”