Contribution of NMDA glutamate and nicotinic acetylcholine receptor mechanisms in the discrimination of ethanol–nicotine mixtures

Abstract

Ethanol and nicotine are commonly co-abused drugs, and the incidence of co-dependence is greater than would be expected based on the summed probability of dependence on each drug alone. Previous findings from our laboratory and others suggest that interactive mechanisms at the level of discriminative stimulus (SD) effects may contribute to this co-abuse phenomenon. Specifically, ethanol overshadows the nicotine SD whereas nicotine potentiates the stimulus salience of ethanol when the two drugs are conditioned as a drug mixture. The goal of the current study was to begin to delineate the pharmacological bases of these ethanol-nicotine interactions. Three groups of C57BL/6J mice were trained to discriminate 0.8 mg/kg nicotine + 0.5 g/kg ethanol (0.8N+0.5E), 0.8N+1.0E or 0.8N+2.0E. An NMDA receptor antagonist (MK-801) and three nACh receptor ligands were tested for their ability to generalize from or antagonize, respectively, the drug mixtures. MK-801 fully generalized from the 0.8N+1.0E and 0.8N+2.0E mixtures and partially generalized from 0.8N+0.5E. In contrast, nACh receptor ligands had minimal influence in blocking the perception of 0.8N+1.0E and 0.8N+2.0E mixtures, and only mecamylamine partially blocked 0.8N+0.5E. Reduced and enhanced contributions of nACh and NMDA receptors, respectively, in the discrimination of ethanol-nicotine mixtures may contribute to the overshadowing and potentiation phenomena previously observed.

The discriminative stimulus effects of a nicotine-ethanol compound in rats: Extinction with the parts differs from the whole.

“…Such responsiveness promoted by nicotine may have contributed to the elevation in response rates in the NE-S D but not NE-S Δ group and also to the response rate differences between N and E during acquisition in Exp 2 and 3. By contrast, Ford et al (2012, 2013) reported that the discriminative stimulus effects of E exceeded N; however that study was conducted with mice and required much higher doses of nicotine (0.4–1.2 mg) and ethanol (1.5 g) to show the effects. Clearly, more parametric analyses involving dose-response manipulations will explicate the relative contribution of N and E to the NE compound in future investigations using extinction training, as the lack of such evaluations was an obvious limitation of the present set of studies.…”

“…Gauvin and Holloway concluded that stimulus salience (i.e., overshadowing) likely plays a role in discrimination of drug mixtures and that the perception of the NE compound, as a whole, does not likely differ from each of the elements (i.e., the NE compound is not a unique cue that differs from its elements). Most recently, Ford, Davis, McCracken, and Grant (2013), and also see Ford, McCracken, Davis, Ryabinin, and Grant (2012), conducted systematic replications in mice but found evidence that EtOH overshadowed nicotine; the NMDA glutamate receptor was found to play a role. To date, these are the only reported studies evaluating the stimulus effects of the NE compound.…”

Role of mPFC and nucleus accumbens circuitry in modulation of a nicotine plus alcohol compound drug state

“…Given that individuals who use nicotine and alcohol regularly consume both together, the interoceptive effects are experienced together. It has previously been demonstrated by our lab and others that the combined nicotine and alcohol (N + A) interoceptive effects can be trained as a cue that predicts reward and represents a more complex cue than either the nicotine or alcohol components on their own . The present work seeks to build on these findings by exploring the role of two interconnected brain regions implicated in both associative learning (ie, drug discrimination) and drug‐seeking behavior: the medial prefrontal cortex (mPFC) and the nucleus accumbens core (AcbC).…”

The nicotine + alcohol interoceptive drug state: contribution of the components and effects of varenicline in rats

“…Moreover, given the frequency with which nicotine and alcohol are used in combination, it is important to consider that individuals often experience the interoceptive effects of both substances together (i.e., a unique compound interoceptive cue). Indeed, preclinical work using operant drug discrimination models has shown that a compound nicotine+alcohol interoceptive cue can serve as a discriminative stimulus to modulate behavior (Ford et al 2013; Ford et al 2012; Gauvin and Holloway 1993; Troisi et al 2013). …”