Previous studies using a reinstatement procedure have found that acute reexposure to the self-administered drug and exposure to footshock stress reinstate heroin and cocaine seeking after prolonged drug-free periods. Here we tested whether these findings generalize to alcohol-taking behavior. Male rats were initially allowed to consume alcohol in a two-bottle choice procedure (water versus alcohol) for 30 min/day for 36 days. Rats were then trained for 60 min/day in operant chambers to press a lever for the drug (0.13 ml of 12% w/v of an alcohol solution) for up to 55 days. After stable drug-taking on a fixed-ratio-3 schedule of reinforcement was obtained, lever pressing for alcohol was extinguished by terminating drug delivery for 4-9 days. Reinstatement of drug seeking was then determined after non-contingent priming injections of alcohol (0.24 and 0.48 g/kg; given i.p. and orally) or exposure to intermittent footshock stress (5 and 15 min; 0.8 mA). Priming injections of alcohol produced a modest dose-dependent reinstatement of drug seeking, whereas footshock stress potently reinstated extinguished alcohol seeking. In contrast, similar parameters of footshock failed to reinstate extinguished sucrose-taking behavior in rats previously trained to lever press for sucrose pellets. These findings extend previous reports on reinstatement of cocaine and heroin seeking by a footshock stressor and by priming drug injections. It also appears that the reinstatement procedure provides an appropriate methodology to study relapse to alcohol-taking behavior in the drug-free state.

These data suggest that CRF contributes to stress-induced relapse to alcohol seeking via its actions on extra-hypothalamic sites. The present data, and previous data with heroin- and cocaine-trained rats, point to a general role of CRF in relapse to drugs induced by stressors.

We have recently shown that priming injections of alcohol and footshock stress reinstate alcohol seeking in drug-free rats. Here we tested whether naltrexone and fluoxetine, two drugs used in the treatment of alcohol dependence, would affect reinstatement of alcohol seeking induced by these events. We also determined the effects of these drugs on alcohol self-administration during the maintenance phase. Rats were trained to press a lever for a 12% w/v alcohol solution. After stable drug-taking behavior was obtained, lever pressing for alcohol was extinguished. Reinstatement of drug seeking was then determined after priming injections of alcohol (0.24-0.96 g/kg) Studies with laboratory rats have shown mu opioid antagonists and selective serotonin reuptake inhibitors (SSRIs) decrease alcohol self-administration in a number of experimental procedures (Amit et al. 1991; Herz 1997;Lê et al. 1996). The preferentially mu opioid receptor antagonist, naltrexone, and SSRI agents such as fluoxetine also have been shown to decrease relapse to alcohol in humans (Naranjo and Sellers 1989;O'Malley et al. 1992;Sellers et al. 1992;Volpicelli et al. 1992). It is important to note, however, that several studies failed to find that SSRIs decrease rates of relapse (Zernig et al. 1997). In addition, although naltrexone has been found to decrease rates of relapse in alcoholics, a high proportion of these individuals relapse to alcohol during nal- Received September 25, 1998; revised February 11, 1999; accepted February 15, 1999. 436 A.D. Lê et al. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 3 trexone treatment (Volpicelli et al. 1997). Thus, it appears that while drugs such as naltrexone and fluoxetine consistently decrease alcohol consumption in laboratory animals, their clinical efficacy in humans is more variable.One important difference between the studies with humans versus the studies with laboratory animals is that those with humans concentrated on the relapse phase, while those with rats were done during the maintenance phase of the addiction process. Consequently, data on the effect of fluoxetine and naltrexone on relapse to alcohol seeking in preclinical models do not exist. In the present study, therefore, we used a reinstatement procedure, an animal model of relapse (Carroll and Comer 1996;Stewart and de Wit 1987), to study the effect of fluoxetine and naltrexone on relapse to drug seeking induced by reexposure to alcohol and exposure to a footshock stressor. Acute reexposure to alcohol (Bigelow et al. 1977;de Wit 1996;de Wit and Chutuape 1993;Hodgson et al. 1979;Ludwig et al. 1974) and exposure to stress (Brown et al. 1995;Cooper et al. 1992;Hore 1971) are regarded as two important factors for provoking relapse in humans.We have recently modified the reinstatement method, previously used to study factors involved in relapse to opioid and stimulant drugs in rats and monkeys, in order to determine factors involved in relapse to alcohol seeking in rats (Lê et al. 1998). We found that priming injections of alc...

Rationale and objective: Alcohol and tobacco are often co-abused in humans and previous studies found that nicotine increases alcohol consumption in rats. Here, we studied whether nicotine would reinstate alcoholtaking behavior in drug-free rats and whether this effect would be enhanced by prior exposure to nicotine during alcohol self-administration training. Methods: Rats were trained to press a lever for alcohol (12% w/v, 1 h/day), and following stable alcohol intake groups of rats (n=11-12) were given daily vehicle or nicotine (0.2, 0.4 or 0.8 mg/kg, SC) injections just prior to the self-administration sessions for 10 days. Rats were then given 6 days of alcohol self-administration in the absence of nicotine and an additional 5-10 drug-free days during which lever presses were not reinforced (extinction). Subsequently, rats were tested for reinstatement of alcohol seeking following exposure to priming injections of vehicle or nicotine (0.4 mg/kg, SC). Results: Nicotine increased alcohol self-administration in a dose-and time-dependent manner over the 10-day period. Nicotine also reinstated alcohol seeking after extinction of the alcohol-reinforced behavior, and this effect was strongly enhanced by prior nicotine exposure. Conclusions: The present data extend previous studies on the effect of nicotine on alcohol selfadministration, and further indicate that nicotine is an effective stimulus for reinstatement of alcohol seeking during drug-free periods.