Maintenance Of Ethanol Self-administration Research Articles

Pregnenolone and Ganaxolone Reduce Operant Ethanol Self‐Administration in Alcohol‐Preferring P Rats

Neuroactive steroids modulate ethanol intake in several self-administration models with variable effects. The purpose of this work was to examine the effects of the long-acting synthetic GABAergic neurosteroid ganaxolone and the endogenous neurosteroid pregnenolone, a precursor of all GABAergic neuroactive steroids, on the maintenance of ethanol self-administration in an animal model of elevated drinking-the alcohol-preferring (P) rats. P rats were trained to self-administer ethanol (15% v/v) versus water on a concurrent schedule of reinforcement, and the effects of ganaxolone (0 to 30 mg/kg, subcutaneous [SC]) and pregnenolone (0 to 75 mg/kg, intraperitoneal [IP]) were evaluated on the maintenance of ethanol self-administration. After completion of self-administration testing, doses of the neuroactive steroids that altered ethanol self-administration were assessed on spontaneous locomotor activity. Finally, the effect of pregnenolone administration on cerebral cortical levels of the GABAergic neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone, 3α,5α-THP) was determined in both ethanol-experienced and ethanol-inexperienced P rats because pregnenolone is a precursor of these steroids. Ganaxolone produced a dose-dependent biphasic effect on ethanol reinforcement, as the lowest dose (1 mg/kg) increased and the highest dose (30 mg/kg) decreased ethanol-reinforced responding. However, the highest ganaxolone dose also produced a nonspecific reduction in locomotor activity. Pregnenolone treatment significantly reduced ethanol self-administration (50 and 75 mg/kg), without altering locomotor activity. Pregnenolone (50 mg/kg) produced a significant increase in cerebral cortical allopregnanolone levels. This increase was observed in the self-administration trained animals, but not in ethanol-naïve P rats. These results indicate that pregnenolone dose-dependently reduces operant ethanol self-administration in P rats without locomotor impairment, suggesting that it may have potential as a novel therapeutic for reducing chronic alcohol drinking in individuals that abuse alcohol.

Effects of mGlu1-receptor blockade on ethanol self-administration in inbred alcohol-preferring rats

The Group I family of metabotropic glutamate receptors includes subtype 1 (mGlu1) and subtype 5 (mGlu5) receptors. This family of receptors has generated interest as potential targets for different areas of therapeutic development, including intervention for alcohol and drug abuse. Most of this interest is driven by findings showing involvement of mGlu5 receptors in the regulation of drug self-administration; however, studies examining the role of mGlu1 receptors in drug self-administration are limited. The purpose of this work was to examine the role of mGlu1-receptor antagonism in the maintenance of ethanol self-administration and the self-administration of an alternate nondrug reward, sucrose. Male alcohol-preferring inbred rats were trained to self-administer ethanol (15% vol/vol) versus water on a concurrent schedule of reinforcement, and the effect of the mGlu1-receptor antagonist JNJ16259685 (0.1–1.0 mg/kg intraperitoneal [IP]) was evaluated on self-administration. The rats were then trained to self-administer sucrose (0.4% wt/vol) versus water, and the same dose range of JNJ16259685 was tested. Locomotor activity was tested in a separate assessment to evaluate potential nonspecific motor effects of the antagonist. Ethanol self-administration was dose dependently reduced by JNJ16259685. This reduction was likely due to a motor impairment as the lowest effective dose (0.1 mg/kg) significantly reduced locomotor behavior. Sucrose self-administration was reduced by the highest JNJ16259685 dose (1.0 mg/kg), and this reduction was also likely due to a motor impairment. Interestingly, ethanol self-administration was more sensitive to mGlu1-receptor antagonism than sucrose self-administration as lower JNJ16259685 doses reduced ethanol-reinforced responding and motor behavior. Together, these results suggest that mGlu1 receptors do not play a specific role in modulating ethanol self-administration or the self-administration of an alternate nondrug reward (i.e., sucrose).

The mGluR5 antagonist MPEP selectively inhibits the onset and maintenance of ethanol self-administration in C57BL/6J mice

The mGluR5 antagonist MPEP selectively inhibits the onset and maintenance of ethanol self-administration in C57BL/6J mice

The mGluR5 antagonist MPEP selectively inhibits the onset and maintenance of ethanol self-administration in C57BL/6J mice

Many of the biochemical, physiological, and behavioral effects of ethanol are known to be mediated by ionotropic glutamate receptors. Emerging evidence implicates metabotropic glutamate receptors (mGluRs) in the biobehavioral effects of ethanol and other drugs of abuse, but there is little information regarding the role of mGluRs in the reinforcing effects of ethanol. Male C57BL/6J mice were trained to lever-press on a concurrent fixed ratio 1 schedule of ethanol (10% v/v) vs water reinforcement during 16-h sessions. Effects of mGluR1, mGluR2/3, and mGluR5 antagonists were then tested on parameters of ethanol self-administration behavior. The mGluR5 antagonist MPEP (1-10 mg/kg, i.p.) dose-dependently reduced ethanol-reinforced responding but had no effect on concurrent water-reinforced responding. Analysis of the temporal pattern of responding showed that MPEP reduced ethanol-reinforced responding during peak periods of behavior occurring during the early hours of the dark cycle. Further analysis showed that MPEP reduced the number of ethanol response bouts and bout-response rate. MPEP also produced a 13-fold delay in ethanol response onset (i.e., latency to the first response) with no corresponding effect on water response latency or locomotor activity. The mGluR1 antagonist CPCCOEt (1-10 mg/kg, i.p.) or the mGluR2/3 antagonist LY 341495 (1-30 mg/kg, i.p.) failed to alter ethanol- or water-reinforced responding. These data indicate that mGlu5 receptors selectively regulate the onset and maintenance of ethanol self-administration in a manner that is consistent with reduction in ethanol's reinforcement function.

Devaluation of ethanol reinforcement

Postingestive CNS pharmacologic effects of ethanol are often assumed to provide the major stimuli for development and maintenance of ethanol self-administration in rats. However, there is little direct evidence to support this assumption. In all procedures that have been used to initiate ethanol intake in rats, some type of taste adaptation or taste conditioning could account for the increased and maintained ethanol intake. Thus, it remains critical to demonstrate that increased ethanol intake is related to postingestive CNS actions of ethanol, and not to a positive shift in the hedonic taste value of the solution. Two experiments were performed to examine this question. In both studies, rats were trained to self-administer 20% ethanol by using a sucrose-substitution initiation procedure. The rats were required to press a lever 25 or 30 times to gain access to 20% ethanol for 20 min from a sipper tube. Once initiated, extinction sessions were used to determine the strength of ethanol seeking by measuring the number of lever presses that occurred in 20 min with no presentation of the ethanol solution. After initial training, the rats were split into two groups: one that received pairings of a gavage of ethanol (1 g/kg), followed after 10 min by a lithium chloride (LiCl) injection (paired group), and one that also received ethanol gavage and LiCl injections, but separated by 24 h (unpaired group). This pairing of postingestive effects with the illness induced by LiCl injection has been shown to devalue other food and fluid reinforcers. In Experiment 1, the rats received four pairings, one after the other with no behavioral testing between. In Experiment 2, the rats received three pairings and were tested for devaluation after each pairing. Results from both experiments showed significant decreases in seeking behavior in both groups, but seeking behavior was decreased significantly greater in the paired group, even though neither group had access to ethanol during the extinction testing periods. In Experiment 1, when ethanol became available after the devaluation procedure, the pattern of intake in the paired group was unchanged early in the sipper tube availability period, supporting the suggestion that the devaluation effect was not mediated by taste stimuli. These findings support the assumption that postingestive effects contribute to the reinforcement produced by self-administered ethanol in rats.

Effects of adolescent ethanol exposure on ethanol consumption in adult rats

Ethanol exposure during early development could predispose an individual to increased ethanol consumption. Given the high prevalence of adolescent ethanol abuse, it is important to assess the potential impact of adolescent ethanol exposure on the development of alcohol drinking. The following study was designed to assess the initiation of ethanol consumption in adult rats after exposure to ethanol vapors during adolescence. Male Sprague–Dawley rats ( n = 23) were exposed to ethanol vapor for 12 h per day for 10 consecutive days between postnatal days 30 and 40. Ethanol vapor exposure maintained blood ethanol levels averaging 250 mg/dl. All rats were subsequently trained to self-administer ethanol after a 52-day withdrawal period. When ethanol consumption was assessed in the adult rats (>3 months old) there were no significant differences in initiation or maintenance of ethanol self-administration between ethanol-exposed and control rats. In addition, there were no group differences in the ability of a noise stressor presented before the drinking session to transiently decrease ethanol intake. Overall, these findings indicate that forced exposure to ethanol vapor during adolescence does not seem to be sufficient to alter initiation or maintenance of limited-access ethanol self-administration.

Naltrexone Suppresses Ethanol Intake in 6‐Hydroxydopamine–Treated Rats

The suppressive effect of opioid antagonists, such as naltrexone, on ethanol intake has been suggested to be based on the interference with ethanol-induced stimulation of dopamine release in the nucleus accumbens. The aim of this study was to determine whether reduction of dopamine innervation to the nucleus accumbens with the neurotoxin 6-hydroxydopamine (6-OHDA) alters naltrexone-induced suppression of ethanol consumption. Because the mesolimbic dopaminergic neurons have also been implicated in ethanol reinforcement, the effects of 6-OHDA on the maintenance and acquisition of ethanol intake were also studied. To damage accumbal terminals of the mesolimbic dopamine neurons, alcohol-preferring Alko Alcohol (AA) rats were given bilateral injections of 6-OHDA or vehicle into the nucleus accumbens after pretreatment with desipramine and pargyline. The effect of the lesion on the acquisition or maintenance of ethanol self-administration was studied in animals having continual access to ethanol solution (10% v/v) and water. Subsequently the effect of naltrexone on ethanol consumption was determined. Naltrexone (0.03-3.0 mg/kg subcutaneously) suppressed ethanol consumption in a dose-dependent manner both in 6-OHDA-treated and control animals given a daily 90-min access to ethanol solution. When the rats had continual access to ethanol, there was a clear day-to-day decline in ethanol intake during the first 5 days of the 7-day naltrexone treatment (10 mg/kg subcutaneously). 6-OHDA treatment had no effect on either the acquisition or maintenance of ethanol self-administration. Postmortem analysis of the brain dopamine content revealed approximately 92% depletion of dopamine in the nucleus accumbens of the 6-OHDA-treated rats. The suppressive effect of naltrexone does not depend on naltrexone's interaction with dopaminergic terminals in the nucleus accumbens. Furthermore, the role of the mesolimbic dopamine pathway is probably not central either in the acquisition or maintenance of ethanol self-administration in alcohol-preferring AA rats.

Induction and Maintenance of Ethanol Self-Administration in Cynomolgus Monkeys (Macaca fascicularis): Long-Term Characterization of Sex and Individual Differences

Induction and Maintenance of Ethanol Self-Administration in Cynomolgus Monkeys (Macaca fascicularis): Long-Term Characterization of Sex and Individual Differences

GABAergic Transmission in the Nucleus Accumbens Is Involved in the Termination of Ethanol Self‐Administration in Rats

Long-Evans rats (n = 12) were trained to lever-press on a fixed-ratio 4 schedule of reinforcement with ethanol (10% v/v) presented as the reinforcer. After implantation of bilateral stainless-steel guide cannulae aimed at the nucleus accumbens, site-specific microinjections of muscimol (1-30 ng) and bicuculline (1-10 ng) were tested for effects on ethanol-reinforced responding. Baseline response patterns were characterized by initial high rates that terminated abruptly after approximately 20 min. Muscimol administration in the nucleus accumbens decreased the total number of ethanol-reinforced responses and obtained reinforcers. Bicuculline also decreased ethanol-reinforced responses and reinforcers at the highest dose tested. When a dose of bicuculline (1 ng) that was ineffective by itself was coadministered with an effective dose of muscimol (10 ng), the muscimol-induced decreases in responding were blocked. Analysis of response patterns showed that muscimol decreased ethanol self-administration by terminating responding, normally lasting 20 min, after approximately 10 min with no changes in local response rate. Bicuculline decreased total responding by producing parallel, but nonsignificant, changes in time course and response rate. These data suggest that GABAergic transmission in the nucleus accumbens is involved in the termination, but not the onset or maintenance of ethanol self-administration. The specificity of this effect gives emphasis to the importance of measuring behavioral parameters, as well as products of behavior (such as intake volume) in the study of ethanol self-administration.

Induction and maintenance of ethanol self-administration without food deprivation in the rat

Rats were trained to lick at a drinking tube containing 5% ethanol to obtain access to a 0.1-ml dipper containing 20% sucrose. Following 20 of these drinking sessions, a lever press response was shaped and maintained with ethanol presentation in the dipper. This induction procedure resulted in rats responding on a FR 8 schedule of reinforcement to receive 40% (v/v) ethanol. Ethanol intakes over 0.5 g/kg in 30 min were obtained when ethanol concentrations over 10% were available. These intakes frequently resulted in blood ethanol levels over 100 mg ethanol/dl blood. This contingent sucrose induction procedure did not use food deprivation at any time. It is suggested that this procedure can be used to investigate the processes involved with the initiation of ethanol as a reinforcer independent of food restriction procedures.