Discrimination of ethanol–nicotine drug mixtures in mice: dual interactive mechanisms of overshadowing and potentiation

Abstract

Rationale One possible basis for the proclivity of ethanol and nicotine co-abuse is an interaction between the discriminative stimulus (SD) effects of each drug. Objectives The current work sought to assess the discriminative control of ethanol and nicotine cues in mice trained with drug mixtures and to determine whether interactive mechanisms of overshadowing and potentiation occur. Methods Male C57BL/6J mice were trained to discriminate ethanol (1.5 g/kg) alone or ethanol plus nicotine (0.4, 0.8 or 1.2 mg/kg base) in experiment 1, and nicotine (0.8 mg/kg) alone or nicotine plus ethanol (0.5, 1.0 or 2.0 g/kg) in experiment 2. Stimulus generalization of the training mixtures to ethanol, nicotine and the drug combination were assessed. Results Ethanol (1.5 g/kg) retained discriminative control despite the inclusion of a progressively larger nicotine dose within the training mixtures in experiment 1. Although the nicotine SD was overshadowed by ethanol training doses > 0.5 g/kg in experiment 2, nicotine did potentiate the effects of low dose ethanol. Conclusions These findings are suggestive of dual mechanisms whereby ethanol (>0.5 g/kg) overshadows the SD effects of nicotine, and at lower doses (< 1 g/kg) the salience of ethanol’s SD effects is potentiated by nicotine. These mechanisms may contribute to the escalation of concurrent drinking and smoking in a binge-like fashion.

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

“…By contrast. Ford et al (2012Ford et al ( , 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.…”

“…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.…”

Ethanol-Nicotine Combinations Induces C-Fos Expression Within Stress And Reward-Related Circuitry

“…The mice were then returned to their home cage and fed their daily food diet, and remained in the procedural room for another 55 min before being transported to a separate procedural room where they were placed in a CO2 chamber. At 90 min total after initial treatment injection mice were euthanized (Ford et al, 2012). Normally, a perfusion of paraformaldehyde (PFA) is used to preserve the tissue and organs of the mouse, but in this particular procedure PFA was not used because it can prevent the primary antibody (c-Fos) from binding properly.…”

“…Once the mice were trained, the mice were divided into separate groups and given an intraperitoneal (i.p.) injection of either the saline, alcohol, or nicotine-alcohol combination (Ford et al, 2012). A double-14 alternation schedule of drug administration was used where saline (i.e., non-drug) was given two days in a row and then alcohol or both drugs for two days (saline, saline, drug, drug).…”

“…A double-14 alternation schedule of drug administration was used where saline (i.e., non-drug) was given two days in a row and then alcohol or both drugs for two days (saline, saline, drug, drug). Each group of mice were required to meet criteria for drug discrimination for three days prior to and including the final testing session, the last requirement that the mice needed to demonstrate criteria on the test session that day in order to be euthanized (see Ford et al, 2012 for additional details). To avoid disruptions in home cage environments, both mice (housed in pairs) were required to meet criteria on the same day.…”