Gerald A. Tolliver

Effect of dopamine agonists and antagonists on ethanol-reinforced behavior: The involvement of the nucleus accumbens

Rats initiated to self-administer 10% ethanol (v/v) in an operant situation using the sucrose-substitution technique received bilateral n. accumbens or caudate nucleus microinjections of d-amphetamine (4, 10, and 20 micrograms/brain), quinpirole (4 micrograms/brain), and/or raclopride (0.1, 0.5, and 1.0 micrograms/brain). Only microinjections into the n. accumbens produced changes in rate and pattern of responding. With d-amphetamine, an increase in total responding and a slowing of initial response rate was seen, whereas with raclopride administration a dose-related decrease in total responding was observed with no alteration in momentary response rates. Drug-dependent behavioral rate and pattern differences suggest that DA activity in the n. accumbens influences ethanol reinforced behavior.

Alcohol Self‐Administration: Role of Mesolimbic Dopamine

It appears clear that ethanol reinforcement, like that of many abused drugs, utilizes the mesolimbic DA pathways. From the data presented on microinjection of DA agonists and antagonists, it would seem that only part of the regulatory process controlling ethanol drinking is directly involved with this pathway. Once drinking has begun, the DA antagonist raclopride results in a rapid termination of drinking. This appears to be a blocking effect of what may be conditioned reinforcement resulting from prior ethanol reinforcement initiation procedures. Microinjection of the DA agonists d-amphetamine and quinpirole prolonged drinking, with little signs of normal termination apparent in the 30-min session in many animals. This appeared to be the result of interference with normal termination processes. While it remains to be demonstrated that oral ethanol consumption results in the release of DA in the nucleus accumbens, evidence from prior work and the present studies support a role for the mesolimbic DA system in ethanol reinforcement.

Oral ethanol reinforcement in the rat: Effect of the partial inverse benzodiazepine agonist RO15-4513☆

The partial inverse benzodiazepine agonist RO15-4513 has been found to reverse the sedating and anti-conflict effects of acute ethanol administration. In non-food or fluid-deprived rats, orally self-administering 10% ethanol in an operant situation, RO15-4513 resulted in a dose-dependent suppression on ethanol intake. Doses of 0.3, 1.0 and 3.0 mg/kg suppressed responding from approximately 25% to 60% respectively. A dose of 0.1 mg/kg had no significant effect upon responding. These findings were discussed in terms of the potential independence of brain mechanisms related to ethanol reinforcement and sedation.

Ethanol preference following the sucrose-fading initiation procedure

Lever responding maintained with ethanol reinforcement at concentrations up to 20% (v/v) was initiated in non-food and -water deprived rats via a sucrose-fading procedure. Home cage two-bottle preference tests between water and 10% ethanol were conducted before (pre) and after (post) the ethanol initiation procedure to determine the effect of initial ethanol preference on ethanol initiation and of initiation on later ethanol preference. Initial preference testing found that the rats could be divided into two groups, animals with low ethanol preference scores (preference below 25%) and those with moderate ethanol preference scores (preference between 25% and 50%). All animals were successfully initiated with the sucrose-fading procedure to lever press with ethanol reinforcement. Following initiation, home cage preference was markedly increased for the initially low-preferring rats (from 12% to 43%), while moderate-preferring rats showed only slight increases (from 37% to 47%). The shift in ethanol preference was discussed in terms of the relation between ethanol preference and behavioral history.

Ethanol reinforced responding in the rat: a concurrent analysis using sucrose as the alternate choice.

Rats were trained on a two lever concurrent schedule of reinforcement (Fixed Ratio 8 Fixed Ratio 8) with ethanol (5% v/v) and water as the two available fluids. After establishing baseline responding patterns, various concentrations of sucrose (0.05% to 5.0% w/v) were substituted for the water in an ascending series. When water was the alternative fluid, ethanol responding predominated. With increasing sucrose concentration, percent ethanol responding decreased. At sucrose concentrations between 1.00% and 1.25% approximately half of the total responses per session were for each substance. This change in relative responding for the two fluids occurred as a result of increased total responding and not as a result of decreased ethanol responses. When ethanol was paired with either a 3% or 5% sucrose concentration, ethanol responding decreased, with increased sucrose responding. However, when the number of responses required to obtain these sucrose solutions was greatly increased (Fixed Ratio 64), ethanol responding increased to levels of up to twice that of the water ethanol condition. This increased ethanol responding was found to remain in the following ethanol water session after the sucrose schedule manipulation.

Relation of ethanol self-administration to feeding and drinking in a nonrestricted access situation in rats initiated to self-administer ethanol using the sucrose-fading technique

Free-feeding male Long-Evans rats (N = 8) were initiated to self-administer 10% ethanol using a sucrose-fading procedure. Following initiation, they were placed into chambers which allowed for the continuous monitoring of feeding, water drinking and ethanol self-administration. All rats continued to daily self-administer ethanol in the continuous access situation. Ethanol drinking at certain times during the day appeared to be related to feeding bouts (prandial drinking). However, at other times, nonprandial ethanol self-administration occurred. These nonprandial ethanol drinking episodes, while not at levels of excessive ethanol intakes, were at levels well above water intake when water was substituted for ethanol. These findings suggest that ethanol intake in continuous access conditions is not solely a function of feeding behavior and that following initiation, ethanol-seeking behavior was maintained in a continuous access situation.

Antagonism of ethanol-reinforced behavior by the benzodiazepine inverse agonists Ro15-4513 and FG 7142: Relation to sucrose reinforcement

The partial inverse benzodiazepine agonist Ro15-4513 has been shown to antagonize many of ethanols actions, including the reduction of behavior reinforced with ethanol presentation. The studies reported here compared the effects of the Ro compound on sucrose reinforcement alone and concurrently available with ethanol reinforcement. Also, a second inverse agonist, FG 7142, was tested. The result indicated that ethanol reinforcement was more sensitive to the inverse agonists compared to sucrose reinforcement. This was seen as a graded effect upon ethanol responding at doses which failed to have any effect upon sucrose-reinforced behavior. The Ro compound was approximately three times more potent than the FG compound in suppressing ethanol-reinforced responding. Possible explanations for the greater sensitivity of ethanol reinforcement compared to sucrose reinforcement was discussed in terms of ethanols potential actions at the benzodiazepine-GABA receptor complex.

The influence of early postwearing ethanol exposure on oral self-administration behavior in the rat

The effects of three early ethanol home cage consumption procedures on the maintenance of operant lever responding reinforced by ethanol presentation were examined in the rat. Two groups of rats, 25 and 31 days of age, were exposed to 10% (v/v) ethanol as the only fluid in the home cage for 3 or 10 days. A third group, 31 days of age, were exposed to 10% ethanol or tap water for 24 h, with the fluid alternating daily for 18 days. All animals were subsequently trained to lever press using 10% ethanol reinforcement under a decreasing water restriction schedule. All three groups were found to have substantial ethanol consumption levels during the initial exposure in the home cage, ranging from 11.2 to 11.9 g/kg/day. The animals were all successfully trained to lever press in the operant chamber with ethanol as the reinforcer when limited to 15 ml/day of water in the home cage. The average number of reinforcements per day ranged from 29 to 43.5, yielding ethanol intakes from 1.06 to 1.97 g/kg in the 30-minute operant session. However, when 50 ml/day of water was available in the home cage, ethanol reinforcements were substantially reduced, with intakes which ranged from 0.14 to 0.18 g/kg/day. The data suggest that early exposure does not enhance ethanols reinforcing properties later in the animals life. These results were discussed in terms the effect of early ethanol exposure on later ethanol consumption and the role of ethanol initiation procedures in oral self-administration.

Ethanol drinking patterns in a continuous-access operant situation: Effects of ethanol concentration and response requirements ☆

Rats, initiated to self-administer ethanol with either a sucrose-substitution procedure or a secondary-conditioning procedure, were maintained in a continuous-access environmental system in which operant lever press responses were required to receive 10% ethanol and food reinforcement. Water available from a drinking tube was electronically monitored to detect licks. Total daily consumption and patterns of food, water, and ethanol responding were analyzed under conditions in which the concentration of ethanol presented as a reinforcer was either 10% or 20%, and the response requirement for ethanol reinforcement was either a fixed ratio 4 schedule or a fixed ratio 1 schedule. Either increasing the ethanol concentration or decreasing the response requirement resulted in an increase in total daily ethanol intake. There was no significant difference between initiation procedures. These results are similar to observations in studies using a limited-access operant situation. This increased ethanol intake resulted from a complex alteration in the daily ethanol drinking pattern. The greatest ethanol intakes were observed when both the ethanol concentration was increased and response requirement was decreased. This was predominantly the result of increasing the number of ethanol drinking bouts per day when the response requirement was decreased, and by decreasing individual bout size by less than half when the ethanol concentration was doubled. These studies indicate that concentration of the ethanol presented as the reinforcer and the response cost required for reinforcement are involved in regulating ethanol consumption in the continuous-access condition. Type of initiation did not appear to interact with these variables.

Effects of d-amphetamine injected into the nucleus accumbens on ethanol reinforced behavior

Rats, initiated to self-administer 10% (v/v) ethanol in an operant situation using the sucrose-fading procedure, received bilateral n. accumbens microinjections of d-amphetamine prior to operant sessions. Doses of 4 micrograms, 10 micrograms and 20 micrograms/brain were administered and some animals also received a 4 microgram/brain dose of LY171555. Three different effects were observed: increased, decreased and no change in total session responding. There was no clear relation between injection area in the n. accumbens and type of effect observed. For either an increase or decrease in total session responding, momentary response rates were decreased. Both d-amphetamine and LY171555 produced similar results. The data support the hypothesis that dopamine in the n. accumbens is involved with ethanol reinforced operant responding but in a complex manner.