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.
The stimulation of alcohol intake induced by nicotine treatment and the suppression of alcohol intake induced by mecamylamine provide evidence for the involvement of nicotinic receptors in alcohol consumption and/or self-administration. The failure of DHbetaE to reduce alcohol consumption, however, suggests that ethanol-nicotine interaction is mediated by other nicotinic receptor subtypes rather than alpha4beta2 receptor subtype, or that mecamylamine acts through a nonnicotinic mechanism.
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...
The experience of interacting with pups causes long-term changes in mothers' brains that mediate long-term changes in maternal behavior. As little as 1 hr of pup experience postpartum results in enhanced maternal responses to pups 10 days later. This experiment investigated the effects of lesions in multiple neural sites that have been implicated either in the actual expression of maternal behavior or in learning and memory within other behavioral contexts on the initiation and the long-term experience-based retention of maternal behavior. Electrolytic lesions were performed either before or after a 1-hr or 24-hr maternal experience. Rats sustaining lesions of the nucleus accumbens (NACC), whether administered before parturition and experience or immediately after a brief experience, failed to show a maternal experience effect. NACC lesions sustained 24 hr after a maternal experience did not disrupt long-term retention of the maternal behavior.
The onset of maternal behavior is characterized by the action of certain hormones, neuropeptides and neurotransmitters and a concomitant increase in the expression of c-Fos in the medial preoptic area (MPOA) but the signaling events that lie between have not been characterized. Because several of these hormones, neuropeptides and neurotransmitters function by activating Ca(2+)/calmodulin (CaM) mediated signaling pathways, many of which can lead to c-Fos expression, the goal of the current work was to identify calmodulin binding proteins (CaMBPs) or specific CaM-dependent phosphoproteins that might be involved. Probing of SDS-PAGE gels of extracts from the hippocampus, parietal cortex, basolateral amygdala and MPOA with recombinant (35)S-VU1-calmodulin (CaM) revealed 30 Ca(2+)-dependent and 4-6 Ca(2+)-independent CaMBPs. Statistically significant maternal behavior-related decreases in four Ca(2+)-dependent CaMBPs ( approximately 31 kDa, 50% decrease; approximately 33 kDa, 32%; approximately 50 kDa, 35%; approximately 60 kDa, 33%) were observed specifically in the MPOA. Numerous proteins were phosphorylated in a Ca(2+) CaM-dependent manner with two (MWs approximately 61 Da, approximately 58 kDa) showing a lack of phosphophorylation only in the MPOA. The selective decrease in CaMBPs coupled with the absence of CaM-dependent phosphoproteins implies that changes in Ca(2+)/CaM-mediated signaling may mediate some of the MPOA-specific processes during the onset of maternal behavior in the rat.
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