Alcohol and nicotine addiction are frequently co-morbid. The nicotinic acetylcholine receptors (nAChRs) are critical for both alcohol and nicotine addiction mechanisms, since nAChR drugs that reduce nicotine consumption have been shown to also reduce alcohol consumption. Sazetidine-A, a pre-clinical nAChR drug with agonist and desensitizing effects at α4β2 and α7 nAChRs, has been reported to reduce alcohol consumption and nicotine self-administration in rats when administered at high doses. However, this effect has not been replicated in mice. In this study, we examined the effect of sazetidine-A on alcohol and nicotine consumption in male and female mice utilizing voluntary oral consumption procedures previously developed in our lab. We found that sazetidine-A (1 mg/kg, i.p) reduced overnight alcohol consumption, but did not affect nicotine consumption when presented either alone or concurrently with alcohol. Sazetidine-A did not reduce water or saccharin consumption at any dose tested. In a chronic co-consumption experiment in which either alcohol or nicotine was re-introduced after one week of forced abstinence, sazetidine-A attenuated post-abstinence consumption of alcohol but not nicotine. Sazetidine-A also significantly reduced alcohol consumption in an acute, binge drinking-in-the-dark procedure. Finally, we tested the effect of sazetidine-A on alcohol withdrawal, and found that sazetidine-A significantly reduced handling-induced convulsions during alcohol withdrawal. Collectively, these data suggest a novel role for the nAChR targets of sazetidine-A in specifically mediating alcohol consumption, separate from the involvement of nAChRs in mediating nicotine consumption. Delineation of this pathway may provide insight into novel therapies for the treatment of alcohol use disorders.
Pavlovian conditioned approach behavior can be directed as much toward discrete cues as it is toward the environmental contexts in which those cues are encountered. The current experiments characterized a tendency of rats to approach object cues whose prior exposure had been paired with reward (conditioned object preference, COP). To demonstrate the phenomenon, rats were conditioned to associate cocaine or saline with two different objects. Rats acquired a preference, assessed using investigation times directed toward each object, for the cocaine-paired object following conditioning. Furthermore, high levels of object investigation during cocaine conditioning predicted stronger preferences for the cocaine-paired object in the test phase. Conditioned approach diminished across extinction but was reinstated through a priming injection of cocaine. To determine whether preferences are affected by reward value, rats were conditioned using three objects paired with 0, 5, or 20 mg/kg of cocaine. This produced object preferences in the post-test that scaled with cocaine dose used for conditioning. Finally, we explored whether contextual cues modulate expression of COP by testing rats for renewal of cocaine seeking. When conditioning was conducted in one context and extinction training in a second context, COP was renewed when the rats were retested in the original context. Thus, conditioned object preferences are readily acquired, easily measured, and amenable to a number of standard Pavlovian conditioning manipulations. This task promises to become a valuable addition to the panoply of behavioral tools available to test mechanisms underlying adaptive and maladaptive reward processing.
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