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Research indicates opioid antagonists can reduce alcohol drinking in rodents. However, tests examining the effects of opioid antagonists on ethanol seeking and relapse behavior have been limited. The present study examined the effects of two opioid antagonists on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats. Adult P rats were self-trained in two-lever operant chambers to self-administer 15% (vol/vol) ethanol on a fixed-ratio 5 (FR5) versus water on a FR1 concurrent schedule of reinforcement in daily 1-h sessions. After 10 weeks, rats underwent extinction training, followed by 2 weeks in their home cages. Rats were then returned to the operant chambers without ethanol or water to measure responses on the ethanol and water levers for four sessions. After a subsequent 2 weeks in the home cage, without access to ethanol, rats were returned to the operant chambers with ethanol and water available. Effects of antagonists on maintenance responding were tested after several weeks of daily 1-h sessions. Naltrexone (NAL; 1-10mg/kg, subcutaneously [s.c.]; n=8/dose), LY255582 (LY; 0.03-1mg/kg, s.c.; n=8/dose), or vehicle were injected 30min before the first session (in the absence of ethanol), following 2 weeks in their home cages, and for four consecutive sessions of ethanol self-administration under maintenance and relapse conditions. Both NAL and LY reduced responses on the ethanol lever without any fluids present, and ethanol self-administration under relapse and on-going drinking conditions, with LY being more potent than NAL. Both NAL and LY were less effective in reducing responding in the absence of ethanol than in reducing ethanol self-administration. Overall, the results indicate that the opioid system is involved in mediating ethanol seeking, and ethanol self-administration under relapse and on-going alcohol drinking, but that different neurocircuits may underlie these behaviors., (Published by Elsevier Inc.)

Previous research indicated that 5-HT(3) antagonists can reduce ethanol drinking in rats, but drinking conditions and other environmental manipulations influenced the efficacy of these antagonists. The current experiments were conducted to examine the effects of the 5-HT(3) antagonists MDL 72222 (MDL) or ICS 205-930 (ICS) on 24-h ethanol (10% v/v) consumption during acquisition, maintenance, and following a period of deprivation in selectively bred high alcohol-preferring (P) male rats. In an analysis of the acquisition of ethanol consumption, daily injections of MDL (1 mg/kg; s.c.) or ICS (1 or 5 mg/kg) were administered to separate groups of P rats during the initial 10 days of ethanol exposure. To examine the maintenance of ethanol drinking, these same groups of rats were allowed access to ethanol for 21 days with no pharmacological manipulations, and were then administered either saline or the 5-HT(3) antagonist. To examine the effects of a 5-HT(3) antagonist on relapse of ethanol drinking, another group of P rats was allowed access to ethanol for 6 weeks and was then deprived of ethanol for 3 weeks. Prior to ethanol reinstatement, rats were treated chronically (seven daily injections) or acutely with MDL (1 mg/kg), saline, or received no injections. MDL (1 mg/kg) and ICS (1 or 5 mg/kg) reduced ethanol intake during acquisition (60-80%) and during maintenance drinking (35-70%) in P rats pretreated with saline during acquisition. However, in rats pretreated with MDL or ICS during acquisition, there was a significant reduction in the effectiveness of either MDL or ICS to reduce ongoing ethanol drinking. Neither acute nor chronic treatment with 1 mg/kg MDL altered the 80% increase in ethanol consumption observed on the first day of reinstatement following a 3-week deprivation period. However, in a follow-up study, acute treatment with MDL (3 mg/kg) or ICS (5 mg/kg) did prevent the 80% increase in ethanol consumption observed on the first day of reinstatement. Overall, the results suggest that 5-HT(3) receptors are involved in the acquisition and maintenance of 24-h ethanol drinking, and that neuroadaptations may occur as a result of chronic treatment with 5-HT(3) antagonists, or during prolonged alcohol deprivation, which alter the involvement of these receptors in regulating alcohol drinking in the P rat.

Patterns of drinking and responding for ethanol (EtOH) and saccharin (SACC) were examined in the alcohol-preferring P rat using various limited-access paradigms. Adult female P rats (n = 10-20) were given 2-h access to EtOH (10-13% v/v) and SACC (0.0125% g/v) concurrently each day, or each solution individually on alternate days. Total 2-h SACC intake was significantly greater than EtOH under both concurrent (12+/-2 vs. 7+/-0.8 ml, p<0.05) and alternate-day access (18+/-1.6 vs. 10+/-0.5 ml) conditions. Under both conditions, however, EtOH intake (over 55% of the total) in the first 15 min was significantly greater than that of SACC (<25% of total). In an operant paradigm, total responding for EtOH (124+/-29) and SACC (114+/-7) under 2-h alternate-day conditions did not differ, but 65% of total EtOH responding occurred during the first 20 min versus less than 45% for SACC (p<0.05). Increasing response requirements (FR-1 to FR-5) did not significantly alter the total number of EtOH reinforcements, but decreased the total number of SACC reinforcements by approximately 50% (p<0.05). Increasing the EtOH concentration from 15% to 35% decreased the number of reinforcements approximately 50% but did not decrease the estimated g/kg EtOH intake. Increasing the SACC concentration from 0.0125% to 0.05%, however, nearly doubled the number of reinforcements. The greater preference for EtOH versus SACC during the initial part of the access period, together with the maintenance of EtOH intake in g/kg when the response requirements and the EtOH concentration were increased, suggests that EtOH intake is motivated by pharmacological consequences. Therefore, different motivational factors appear to underlie EtOH and SACC intake of the P rat. Furthermore, the pattern of EtOH intake and responding displayed by the P rat may be the result of a "bout-" or "binge-" like loss of control under restricted EtOH access conditions.

The densities of mu-opioid binding sites in the CNS of alcohol-naive adult male P and NP rats (N = 9 each line) were examined using quantitative autoradiography. Coronal sections (20 microm) were prepared from frozen brains and incubated in 5 nM [3H]DAMGO to label mu-opioid receptor sites. Nonspecific binding was determined in the presence of 1 microM DAMGO. The amount of [3H]DAMGO binding was (a) 20-25% higher in the olfactory tubercle, nucleus accumbens shell and core, and basolateral and lateral amygdaloid nuclei; (b) 15% higher in the lateral septal intermediate nucleus and caudate-putamen patches; and (c) 10-30% lower in the pyramidal and radiatum layers in the CA1 region of the anterior dorsal hippocampus, ventral dentate gyrus and CA1 pyramidal layer of the posterior hippocampus, and posterior medial cortical amygdaloid nucleus of the P compared to the NP rat. No line differences were found in any of the other regions examined (e.g., the cerebral cortical subregions and layers, thalamic nuclei, ventral tegmental area, ventral pallidum, lateral hypothalamus, other regions of the hippocampus, and several subcortical structures). The innate differences in the amount of binding to mu-opioid recognition sites in certain limbic structures, such as the nucleus accumbens, amygdala, and olfactory tubercle, of the P and NP lines may be factors contributing to their disparate alcohol drinking characteristics.

The effects of 5-HT3 receptor antagonists on ethanol intake were examined in the selectively bred alcohol-preferring P line of rats under continuous and limited access to 10% (v/v) ethanol with food and water ad lib. Single daily injections of either MDL 72222 (MDL) or ICS 205-930 (ICS) (0.01-3.0 mg/kg, SC) given 60 min before a 4-h scheduled access period for 4 consecutive days failed at all doses to alter the intake of a 10% (v/v) ethanol solution by P rats. However, multiple daily injections of either MDL (1-3 mg/kg, SC) or ICS (3.0 and 5.0 mg/kg, SC), given three times daily at 4-h intervals, significantly reduced ethanol intake under 24-h free-choice conditions on the first treatment day. Additionally, a single administration of 1.0 mg/kg MDL reduced 24-h free-choice ethanol intake by approximately 50% of control values and had no effect on 24-h saccharin intake. The effects of MDL were further examined in a 2-h schedule access paradigm in which rats received the access period at the same time every day (Fixed) or randomly during the dark cycle (Variable). Although 1.0 mg/kg MDL had little effect on ethanol drinking in the Fixed group, ethanol intake was reduced by 55% of control levels in the Variable group. Overall, the data indicate that drinking conditions influence the effectiveness of 5-HT3 antagonists to reduce ethanol consumption. Furthermore, the results suggest that conditions, associated with limited access ethanol drinking, markedly reduce the actions of 5-HT3 antagonists on ethanol intake.

The specific question was how prenatal and/or postnatal experience with ethanol influences cardiac and behavioral responses to the odor of ethanol on postnatal day (PD) 16. In each of two experiments, pregnant rats were given ethanol or water on gestational days 17-20. Offspring were exposed on PD12 to one of three conditions: intragastric administration of 6% ethanol, indirect exposure to ethanol from littermates, or no treatment. Results of Experiment 1 indicated that, regardless of prenatal ethanol exposure, 16-day-olds exposed on PD12 either directly or indirectly to ethanol expressed a greater increase in HR in response to ethanol odor than pups not postnatally exposed to ethanol. In Experiment 2, in which a lower ethanol dose was used postnatally, an interaction between pre- and postnatal ethanol exposure was observed; that is, pups exposed pre- and postnatally to ethanol showed the greatest increases in HR and the smallest increases in motor activity in response to ethanol odor. In both experiments motor activity was dissociated from increases in HR. The results are discussed in terms of what is learned, prenatally and postnatally, in association with the chemosensory properties of ethanol.

Neonatal alcohol exposure during the first 1-2 weeks of age is known to produce subsequent behavioral hyperactivity in rats. However, little is known about the effects of alcohol exposure during adolescence on subsequent adult behavior. In the present study, male and female P rats had free access to 10% alcohol during adolescence (3-8 weeks of age). After 8 days of abstinence, their behavior was evaluated in the cross-maze and in the inescapable slip funnel tests during the 10th week of age. Two-way ANOVAs revealed significant effects of alcohol drinking on several variables. Compared to alcohol-naive rats, the alcohol-exposed group started exploration earlier (3.5 +/- 0.3 vs. 5.4 +/- 0.7 s, p = 0.03) and made fewer defecations. In the slip funnel test, the alcohol group spent more time immobile (130 +/- 7 vs. 107 +/- 5 s, p = 0.01) and less time attempting to escape out of the funnel (11 +/- 2 vs. 28 +/- 5 s, p = 0.002) than the control group. Overall, the results suggest that the effects of alcohol drinking by P rats during adolescence on subsequent behavior are to reduce novelty-induced anxiety (cross-maze test) and lower response to stress induced by an inescapable situation (slip-funnel test).