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.

Summary Schedules of intermittent food delivery induce excessive fluid intake, termed schedule-induced polydipsia (SIP), and hypothalamic-pituitary-adrenal (HPA) axis activation is important for the expression and maintenance of this adjunctive behavior. Previous work has focused of examining the relationship between water intake and plasma corticosterone (CORT) in rats at a single or a limited range of fixed time (FT) intervals. However, little remains known regarding SIP and the corresponding stress response 1) across the bitonic function that epitomizes adjunctive behavior, 2) when ethanol is the available fluid, and 3) when a species other than rat or multiple strains are studied. Here we report the findings from ethanol-preferring C57BL/6J (B6) and non-preferring DBA/2J (D2) mice serially exposed to progressively larger FT intervals (0 → 60 min) and given access to either water or a 5% v/v ethanol solution. Following 2 weeks of experience with each schedule, blood samples were collected at the conclusion of the last 60-min session to evaluate CORT and the blood ethanol concentration (BEC) achieved. While both strains exhibited a bitonic function of ethanol intake and BEC that peaked at or near a 5-min interval, only D2 mice showed a similar response with water. In contrast, CORT levels rose monotonically with incremental increases in the FT interval regardless of the strain examined or fluid type offered, indicating that glucocorticoid release likely reflects the aversive aspects of increasing intervals between reinforcement rather than engagement in adjunctive behavior. These findings also caution against the use of a single intensity stressor to evaluate the relationship between stress and ethanol intake, as the magnitude of stress appears to affect ethanol consumption in a non-linear fashion.

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.

Past studies have suggested that progesterone-derived ovarian hormones contribute to the discriminative stimulus effects of ethanol, particularly via progesterone metabolites that have activity at γ-aminobutyric acid type A (GABAA) receptors. It is unknown whether loss of ovarian hormones in women, for example, after menopause, may be associated with altered receptor mediation of the effects of ethanol. The current study measured the substitution of allopregnanolone, pregnanolone, pentobarbital, midazolam, dizocilpine, TFMPP, and RU 24969 in female sham and ovariectomized (OVX) rats trained to discriminate 1.0 g/kg ethanol from water. The groups did not differ in the substitution of GABAA-positive modulators (barbiturates, benzodiazepines, neuroactive steroids) or the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine. Similarly, blood-ethanol concentration (BEC) did not differ between the groups, and plasma adrenocorticotropic hormone (ACTH), progesterone, pregnenolone, and deoxycorticosterone (DOC) were unchanged 30 min after administration of 1.0 g/kg ethanol or water. However, substitution of neuroactive steroids and RU 24969, a 5-HT1A/1B receptor agonist, was lower than observed in previous studies of male rats, and TFMPP substitution was decreased in OVX rats. Ovarian hormones appear to contribute to 5-HT receptor mediation of the discriminative stimulus effects of ethanol in rats.

Cholinergic transmission modulates several aspects of stimulant abuse, including initial exposure, transition to dependence, and relapse risk. The goals of the current work were to 1) establish methamphetamine (MA) as a discriminative stimulus (SD) in mice, 2) assess the ability of M1‐ or M1/M4‐active compounds to generalize from or block the SD effects of MA, and 3) evaluate the nACh receptor subtypes underlying the MA‐like SD effects of nicotine. Sixteen male C57BL/6J mice were trained to discriminate 1 mg/kg MA (i.p.) from saline on a FR‐12 schedule. Following acquisition (41 ± 3 sessions), substitution testing revealed that the M1/M4‐preferrring agonist xanomeline and the M1‐preferring agonist n‐desmethylclozapine were perceived as saline‐like whereas the non‐selective antagonist scopolamine and the M1‐preferring antagonists trihexyphenidyl and dicyclomine exhibited low partial substitution for MA. Pretreatments were administered 10‐min prior to MA during blocking tests, and it was observed that dicyclomine producing a leftward shift in the MA dose‐response curve whereas xanomeline resulted in a non‐significant rightward shift. Nicotine partially generalized (50%) from MA in mice, and pretreatment with the nACh antagonists mecamylamine and DHβE as well as the partial agonist varenicline completely blocked the MA‐like SD effects of nicotine. Supported by DA018165, AA016849 and OD011092.