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At the heart of homeostatic theory is the idea that explicit or implicit behavioral demands placed on physiological systems are required for the biological detection of homeostatic disturbances. The detection of drug-induced disturbances is required to drive the development of all systemic tolerance, both associative and nonassociative (i.e., both forms of tolerance are behaviorally contingent). A wide range of findings ranging from morphine-induced analgesia to ethanol-induced hyposexuality shows that contingent tolerance is pervasive and may be universal. The theory also stipulates that behavioral demands placed on the target system will govern the loss of both associative and nonassociative tolerance (physiological). The present formulation integrates contingent, associative, and nonassociative tolerance and drug-opposite withdrawal reactions within a unified theory.

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...

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Previous research indicated shared neurochemical substrates for gambling and psychostimulant reward. This suggests that dopamine substrates may directly govern the reinforcement process in pathological gambling. To investigate this issue, the present study assessed the effects of the relatively selective dopamine D2 antagonist, haloperidol (3 mg, oral) on responses to actual gambling (15 min on a slot machine) in 20 non-comorbid pathological gamblers and 18 non-gambler controls in a placebo-controlled, double-blind, counterbalanced design. In gamblers, haloperidol significantly increased self-reported rewarding effects of gambling, post-game priming of desire to gamble, facilitation of reading speed to Gambling words, and gambling-induced elevation in blood pressure. In controls, haloperidol augmented gambling-induced elevation in blood pressure, but had no effect on other indices. The findings provide direct experimental evidence that the D2 substrate modulates gambling reinforcement in pathological gamblers.

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To assess the effectiveness of a pharmacological cue as a conditional stimulus in the Pavlovian model of drug tolerance, two groups of Wistar rats received equal numbers of IP injections of a low and a high dose of alcohol. One group (Paired) received a low dose (0.8 g/kg) of alcohol followed 60 min later by the high dose (2.5 g/kg). Another group (Unpaired) received the low and high doses on an unpaired basis. When tested for tolerance to the hypothermic effect of the high dose of alcohol, only the Paired group showed tolerance, and only if the low dose preceded the high. When a saline injection preceded the high dose injection, the Paired group showed a loss of tolerance. The Paired group also showed a compensatory hyperthermia following the low dose injection. Animals from the Paired group that received repeated administrations of the low dose followed by saline, showed a significant extinction effect as compared with animals that received repeated saline injections only. These findings support the Pavlovian model of conditional tolerance, extending the realm of effective conditional stimuli to include a low dose of a drug.