Ethanol→Nicotine & Nicotine→Ethanol drug-sequence discriminations: Conditional stimulus control with two interoceptive drug elements in rats

Abstract

Self-administration of ethanol (E) and nicotine (N) occurs frequently in tandem orders (i.e., N→E vs. E→N) and thereby produces differing interoceptive profiles of subjective effects in humans. If the interoceptive stimulus characteristics of N→E differ from E→N, it is possible that such differences contribute to their co-dependence. The rationale for the present investigation was to determine whether ethanol, when preceded or followed by nicotine, produces different discriminative stimulus effects in rats. In two experiments, using a one-manipulandum operant drug discrimination procedure, rats were trained to discriminate temporal sequential administrations of ethanol (1.0 g/kg) that was followed or preceded by nicotine (0.3 mg/kg). Sessions alternated between food-reinforcement sessions on a variable interval 30-sec schedule (i.e., S^D) and non-reinforcement sessions (i.e., S^Δ). In Experiment 1, administrations of ethanol were followed or preceded by a 10-min interval of nicotine. Training sessions took place 10 min following the second drug injection. Four groups of rats were trained to discriminate only one sequence from sequential administrations of saline, and each drug sequence was counterbalanced across groups for their roles as S^D or S^Δ. There was robust stimulus control. N→E and E→N functioned equally well as S^D or S^Δ. Experiment 2 used two groups of rats. For one group, the E→N sequence functioned as the S^D and the N→E sequence functioned as the S^Δ. The drug sequences were counterbalanced for the other group. Brief non-reinforcement tests revealed significantly greater responding during the S^D sequence compared to the S^Δ sequence for both groups. These results suggest that different drug sequences of ethanol followed or preceded by nicotine established reliable discriminative stimulus control over operant responding, potentially because of characteristic differences in the overlapping pharmacokinetic profiles of the NE compound. The results are discussed in terms of: 1) conditional stimulus control among two interoceptive drug states; and 2) the clinical modulation of human alcohol consumption and tobacco smoking.

Keywords: Conditional drug discrimination; Drug sequence; Ethanol; Nicotine; Rats.

Figure 1.

Exp 1 acquisition training results for 16 rats trained to discriminate sequences of nicotine (N)→EtOH (E) from a saline (S)→saline (S) or sequences of EtOH→nicotine from a saline→saline sequence. For four rats (A) the N→E+ functioned as the S^D and occasioned 20-min sessions in which nose poking was food-reinforced on a VI-30” schedule; S→S- functioned as S^Δ and occasioned non-reinforcement sessions. The stimulus roles were reversed for the four rats assigned to the opposite condition (B). Four other rats (C) were assigned to the E→N S^D and S→S- S^Δ condition, and those roles were counterbalanced for the remaining four rats (D).

Figure 2.

5-min test results for the rats in Exp 1. For four rats (A) the N→E+ functioned as the S^D and S→S- functioned as S^Δ. The stimulus roles were reversed for four counterbalanced rats (B). Four rats were assigned to the E→N+ S^D and S→S- S^Δ (C) with four other rats counterbalancing the stimulus roles (D). Discrimination indices (% drug sequence responding) are noted above the drug sequence bars.

Figure 3.

Exp 2 acquisition training results for 16 rats trained to discriminate a sequences of nicotine (N)→EtOH (E) from a EtOH→nicotine. For eight rats, the N→E+ sequence functioned as S^D signaling 20-min food reinforced sessions and the E→N sequence functioned as the S^Δ (top graph). Eight other rats were assigned to the opposite contingencies in which the E→N+ sequence functioned as the S^D and the N→E- sequence functioned as the S^Δ (bottom graph).

Figure 4.

5-min non-reinforcement test results for Exp 2. For eight rats, the N→E+ sequence functioned as S^D signaling 20-min food reinforced sessions and the E→N sequence functioned as the S^Δ (left bars). Eight other rats were assigned to the opposite contingencies in which the E→N+ sequence functioned as the S^D and the N→E- sequence functioned as the S^Δ (right bars). Discrimination indices (% S^D responses) are displayed above each set of bars.