Increased vulnerability to nicotine self-administration and relapse in alcohol-naive offspring of rats selectively bred for high alcohol intake

Abstract

The prevalence of smoking in human alcoholics is substantially higher than in the general population, and results from twin studies suggest that a shared genetic vulnerability underlies alcohol and nicotine addiction. Here, we directly tested this hypothesis by examining nicotine-taking behavior in alcohol-naive offspring of alcohol-preferring (P) rats and alcohol-nonpreferring (NP) rats that had been selectively bred for high and low alcohol intake. The self-administration of intravenous nicotine (0.015-0.060 mg/kg per infusion) in P rats was more than twice than that of NP rats. Nicotine seeking induced by reexposure to nicotine cues in extinction tests was also substantially greater in P rats than in NP rats. In a subsequent relapse test, priming nicotine injections reinstated drug seeking in P rats but not NP rats. P rats also self-administered higher amounts of oral sucrose (1-20%) than NP rats, a finding consistent with previous reports. In contrast, self-administration of intravenous cocaine (0.1875-1.125 mg/kg per infusion) was remarkably similar in the P and NP rats; however, P-NP differences in cocaine seeking emerged in subsequent extinction and cocaine priming-induced reinstatement tests. In both cases, lever responding was higher in P rats than in NP rats. Thus, alcohol-naive offspring of rats genetically selected for high alcohol intake are highly susceptible to nicotine self-administration and relapse, and this susceptibility is not likely caused by general reward deficits in NP rats. The present findings provide experimental evidence for the hypothesis that a shared genetic determinant accounts for the co-abuse of nicotine and alcohol.

Figure 1.

Sucrose self-administration in P and NP rats. a, Mean ± SEM number of sucrose deliveries during the first 10 d of sucrose (10%) self-administration (0.19 ml per reward delivery) under an FR-1 reinforcement schedule (each lever press was reinforced). b, Mean ± SEM number of sucrose deliveries as a function of the sucrose concentration; data are from the concentration–response determination during days 11–22 of sucrose self-administration (3 d per dose). *Different from the NP group; p < 0.05 (Newman–Keuls post hoc test); n = 11 per line.

Figure 2.

Nicotine self-administration in P and NP rats. a, b, Mean ± SEM number of nicotine infusions and active lever responses during the first 24 d of nicotine self-administration (0.03 mg/kg per infusion) under FR-1, FR-2, and FR-5 reinforcement schedules. c, d, Mean ± SEM number of nicotine infusions and nicotine intake (milligrams per kilogram); data are from the dose–response determination during days 25–33 of nicotine self-administration training (3 d per dose). *Different from the NP group; p < 0.05 (Newman–Keuls post hoc test); n = 9–12 per line.

Figure 3.

Extinction and reinstatement of nicotine seeking in P and NP rats. a, Mean ± SEM number of responses on the previously active lever during the first seven sessions of the extinction phase. During this phase, lever responding led to saline infusions and the illumination of the cue light previously paired with nicotine infusions. b, Mean ± SEM number of responses on the previously active lever during the tests for reinstatement of nicotine seeking induced by priming injections of saline or nicotine (0.15 mg/kg, s.c). During the reinstatement tests, lever responding was not reinforced with nicotine. *Different from the NP group; p < 0.05; n = 9–12 per line.

Figure 4.

Cocaine self-administration in P and NP rats. a, b, Mean ± SEM number of cocaine infusions and active lever responses during the first 14 d of cocaine self-administration (0.75 mg/kg per infusion) under FR-1, FR-2, and FR-5 reinforcement schedules. c, d, Mean ± SEM number of cocaine infusions and cocaine intake (milligrams per kilogram); data are from the dose–response determination during days 15–22 of cocaine self-administration (2 d per dose; n = 9–11 per line).

Figure 5.

Extinction and reinstatement of cocaine seeking in P and NP rats. a, Mean ± SEM number of responses on the previously active lever during the first 14 sessions of the extinction phase. During this phase, lever responding led to saline infusions and the illumination of the cue light previously paired with cocaine infusions. b, Mean ± SEM number of responses on the previously active lever during the tests for reinstatement of cocaine seeking induced by priming injections of saline and cocaine (5 and 10 mg/kg, i.p.). c, Mean ± SEM number of responses on the previously active lever during the tests for reinstatement of cocaine seeking induced by priming injections of saline and nicotine (0.15 mg/kg, s.c.). During the reinstatement tests, lever responding was not reinforced with cocaine. *Different from the NP group; p < 0.05; n = 9–11 per line.