Effects of Naltrexone and Fluoxetine on Alcohol Self-Administration and Reinstatement of Alcohol Seeking Induced by Priming Injections of Alcohol and Exposure to Stress

Abstract

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...

Persistent effects of acute stress on fear and drug-seeking in a novel model of the comorbidity between post-traumatic stress disorder and addiction

“…When footshocks were massed closely together within the selfadministration context, there was reinstatement, but this was not specific to the active lever, which is consistent with findings that shocks evoke general activity both during and soon after their presentation (Fanselow 1982). Although other studies have documented shock-induced reinstatement, the specificity of this effect to the drug-seeking lever is not always clear (see Shaham et al 1998;Lê et al 1999;Liu and Weiss 2002;McFarland et al 2004).…”

Conceptual framework for the etiology of alcoholism: a ?kindling?/stress hypothesis

“…3). The ability of stress to increase alcohol seeking (Lê et al 1998(Lê et al , 1999(Lê et al , 2000Weiss 2002a, 2003;Martin-Fardon et al 2000) is consistent with stress enhancing the probability of relapse and furthering alcohol abuse. Further, the risk of relapse in alcoholics is reportedly increased by stress (Brown et al 1990(Brown et al , 1995Pohorecky 1991;Sinha 2001), with anxiety during abstinence being a predictor of endstate drinking (Kushner et al 1994(Kushner et al , 2000(Kushner et al , 2001Sloan et al 2003;Willinger et al 2002).…”

“…Utilization of the sucrose-fading procedure to obtain reliable bar pressing for ingestion of alcohol is a popular apvproach to investigate alcohol drinking (Brown et al 1998;Ciccocioppo et al 2004;Lê et al 1999Lê et al , 2003Rogowski et al 2003;Roberts et al 1996;Samson 1986;Valdez et al 2002;Weiss et al 1993). However, while extended absence from bar pressing increased intake when alcohol was restored in some investigations (i.e., similar to alcohol deprivation; Heyser et al 1997;Hölter et al 1997;McKinzie et al 1998), Samson and Chappell (2001) found no effect of deprivation on intake using a limited access operant procedure.…”

“…Likewise, stress can increase alcohol-seeking behavior (Lê et al 1998(Lê et al , 1999(Lê et al , 2000Weiss 2002b, 2003;Martin-Fardon et al 2000;Weiss et al 2001). In fact, stress is a more powerful stimulus for alcohol seeking than "priming" doses of alcohol (Lê et al 1998).…”

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

“…Furthermore, we do not know whether the small oral priming dose of ethanol alone could have reinstated responding, or whether the environmental cues associated with ethanol availability and the orosensory properties of ethanol acted additively to induce reinstatement. In this context, it is worth noting that although contingent or injected ethanol have been previously reported to reinstate ethanol responding, this effect shows high variability and inconsistency (Chiamulera et al, 1995;Lê et al, 1998Lê et al, , 1999Vosler et al, 2001;Lê and Shaham, 2002).…”