Herman H. Samson

Neurobiology of alcohol abuse

Excessive consumption of beverage alcohol (ethanol) is a major health concern worldwide. Understanding the mechanisms by which ethanol affects neural functioning, after both acute and chronic exposure, has become a major goal in the study of alcoholism. With such an understanding, we should be able to institute more effective treatments and preventative measures for alcohol abuse problems. Recent studies have found, contrary to earlier assumptions, that ethanol has selective, dose-dependent effects on various neurotransmitter systems within the CNS. These effects are observed at all levels of analysis, from molecular to behavioral. This review by Herman Samson and Adron Harris covers these recent findings, with the intent of generating questions that will focus further research efforts.

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.

Oral ethanol self-administration in the rat: Effect of naloxone

Rats responding on a two lever concurrent for ethanol and water, were injected with 5, 10, or 20 mg/kg naloxone hydrochloride 30 min prior to a 30 min session. Only the 20 mg/kg dose had any effect, a decrease in responding for ethanol of up to 50% compared to saline control injection sessions. There were no systematic effects upon water responding. An additional study using sucrose and water as the fluid concurrently available failed to find any effects of naloxone on sucrose responding at the same doses. The effect upon ethanol responding was found not to resemble a pattern of extinction, but rather was best described as a general overall reduction in responding. The relation of these findings to the direct involvement of the endogenous opiate system in ethanol reinforcement is discussed.

Haloperidol and apomorphine effects on ethanol reinforcement in free feeding rats.

Free feeding male Long Evans rats were trained to lever press on a Fixed Ratio 8 schedule for 10% ethanol reinforcement. Mean ethanol intake in 30-minute sessions was 0.38 g/kg. Subcutaneous apomorphine (APO: 0.025 to 0.5 mg/kg) and haloperidol (HAL: 0.005 to 0.0625 mg/kg) administered 15 minutes before sessions dose-dependently reduced responding, but only APO reduced momentary response rates. Low doses of HAL reduced the effect of 0.3 but not 0.05 mg/kg APO. When the rats were food-restricted, control response rates decreased, and APO (0.025 and 0.05 mg/kg) had no further effect. Results were discussed in terms of dopamine involvement in the mechanism of ethanol reinforcement.

Dopamine Activity in the Nucleus Accumbens During Consummatory Phases of Oral Ethanol Self-Administration

UNLABELLED BACKGROUND This present study was designed to clarify the role of dopamine in the nucleus accumbens during operant ethanol self-administration by separating bar pressing (ethanol seeking) from ethanol consumption. Furthermore, we sought to define the relationship between ethanol in the brain and the accumbal dopamine response after oral self-administration of ethanol. METHODS Two separate groups of male Long-Evans rats were trained to bar press with 10% ethanol or water. Rats were trained to elicit an escalating number of bar presses across daily sessions before gaining access to the drinking solution for 20 min. Microdialysis was performed before (during a waiting period), during, and after bar pressing and drinking. A handling control group was included, but did not receive training. RESULTS A significant increase in dopamine occurred during placement of the rats into the operant chamber in trained rats and handling controls. The lever-pressing period did not produce an increase in dialysate dopamine. Accumbal dopamine was increased in the first 5 min of ethanol, but not water, consumption. Ethanol appeared in the dialysate sample following ethanol availability, and peak concentrations were reached at 10 min. Most of the ethanol and water consumption occurred within 5 min of fluid access. The probes were distributed in the core (32%), shell (32%), and core plus shell (36%) regions of the nucleus accumbens. CONCLUSIONS The enhancement of dopamine during transfer into the operant chamber does not depend on anticipation or operant training with ethanol or water reinforcement. Furthermore, the difference between the time course of accumbal dopamine and ethanol in dialysates suggests that the dopamine response is not solely due to pharmacological effects of ethanol. The dopamine response may be associated with the stimulus properties of ethanol presentation, which would be strongest during consumption.

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.

Specific decreases in ethanol- but not water-reinforced responding produced by the 5-HT3 antagonist ICS 205-930

The serotonin 5-HT3 antagonist ICS 205-930 has been shown to block the discriminative stimulus properties of ethanol and decrease voluntary intake, suggesting a possible role for 5-HT3 systems in the reinforcing effects of ethanol. ICS 205-930 (0.56, 1.0, 3.0, 10.0, and 17.0 mg/kg i.p.) was examined on ethanol and water self-administration in an operant paradigm. Following a sucrose-fading procedure, two groups of nondeprived rats responded on either a concurrent fixed ratio 4 schedule for ethanol (10% v/v) and water (CONC FR4 FR4), or a single FR4 schedule for ethanol (10% v/v). ICS 205-930 dose-dependently decreased ethanol-reinforced responding in the concurrent condition without decreasing water-reinforced responding, suggesting a specific effect on ethanol. Ethanol-reinforced responding was also dose-dependently decreased in the single FR4 condition, but the dose effect curve was shifted to the left. These data support the conclusions that 5-HT3 systems may play a specific role in ethanol self-administration that is independent of general appetitive and motor processes, and that 5-HT3 antagonists may have therapeutic efficacy in the treatment of alcohol abuse when multiple reinforcers are available.

Microinjections of dopamine agonists in the nucleus accumbens increase ethanol-reinforced responding.

Long-Evans rats (N = 3) were trained to lever press on a fixed-ratio 4 (FR 4) schedule with ethanol (10% v/v) presented as the reinforcer. Each rat received a total of six bilateral nucleus accumbens microinjections, one per week. They were tested with one physiological saline control, three 20.0-microgram/brain d-amphetamine, and two 6.0-microgram/brain quinpirole injections given 10 min prior to operant sessions. Ethanol-reinforced responding terminated after approximately 10 min during control sessions. Microinjections of the D2 agonist quinpirole and the nonspecific dopamine (DA) agonist d-amphetamine increased total responding but produced slowed response rates that continued for 45-60 min. The slowed response rate produced by d-amphetamine resulted in a peak increase in interresponse times (IRTs) between 8-10 s, whereas quinpirole increased IRTs in the 14- to 16-s range, indicating that nonspecific DA activation resulted in higher rates of ethanol-reinforced responding than specific D2 activation although both drugs decreased local response rates. These data indicate that the amount and temporal extent of ethanol-reinforced responding are increased by microinjections of DA agonists in the nucleus accumbens and support the hypothesis that DA activity in this region is involved in the regulation of ethanol-reinforced responding.

Effect of pimozide on home cage ethanol drinking in the rat: dependence on drinking session length.

A stimulus-fading procedure was used to initiate ethanol drinking in free-feeding Long Evans rats. During daily half-hour drinking sessions in the home cage, a combination of sucrose and ethanol was first presented to the rats; gradually the sucrose concentration was reduced and the ethanol concentration increased until after 7 weeks the rats were drinking 10% ethanol with no sucrose. After stabilization of intake, either pimozide (PIM, 0.25, 0.50 and 1.00 mg/kg) was injected 4 h before drinking sessions or (d)-amphetamine (DEX, 0.25 and 0.50 mg/kg) was injected 15 min before sessions. The 0.50 and 1.00 mg/kg PIM doses and the 0.50 DEX dose significantly reduced intake compared to vehicle injections. In the second part of the experiment, the rats were given 24-h access to 10% ethanol and water in a two-bottle choice procedure. In this condition, 0.50 mg/kg PIM failed to reduce intake compared to vehicle. The critical difference between the two procedures seems to be that with the 30-min sessions, PIM injections were timed to have their maximal effect during testing. With 24-h sessions, decreases in intake produced by PIM could have been compensated for by increases after the drug had worn off. The hypothesis that dopamine is necessary for ethanol reinforcement receives support from the PIM effect on the 30-min sessions. The DEX effect extends the generality of our previous finding that DEX reduces ethanol-reinforced lever pressing in free-feeding rats.