The alcohol deprivation effect is a temporary increase in the intake of, or preference for, ethanol after a period of deprivation that may result from persistent changes in key limbic regions thought to regulate alcohol drinking, such as the nucleus accumbens. The present study tested the hypothesis that chronic alcohol drinking under continuous 24-h free-choice conditions alters dopamine and serotonin neurotransmission in the nucleus accumbens and that these alterations persist in the absence of alcohol. Using the no-net-flux microdialysis method, the steady-state extracellular concentration (point of no-netflux) for dopamine was approximately 25% higher in the adult female alcohol-preferring P rats given prior access to 10% ethanol, even after 2 weeks of ethanol abstinence, compared with the P rats gives access only to water. However, the extracellular concentration of serotonin was approximately 35% lower in animals given 8 weeks of continuous access to ethanol compared with water controls and animals deprived of ethanol for 2 weeks. The effect of local perfusion with 100 M sulpiride (D 2 receptor antagonist) and 35 M 1-(m-chlorophenyl)-biguanide (5-hydroxytryptamine 3 receptor agonist) on dopamine overflow were reduced approximately 33% in both groups of ethanol-exposed P rats compared with water controls. Freechoice alcohol drinking by P rats alters dopamine and serotonin neurotransmission in the nucleus accumbens, and many of these effects persist for at least 2 weeks in the absence of ethanol, suggesting that these underlying persistent changes may be in part responsible for increased ethanol drinking observed in the alcohol-deprivation effect.

This article represents the proceedings of a symposium at the 2003 annual meeting of the Research Society on Alcoholism in Fort Lauderdale, FL. The organizers and chairs were William J. McBride and David M. Lovinger. The presentations were (1) Mechanisms of alcohol potentiation of 5-HT3 receptor function, by David M. Lovinger and Tina Machu; (2) Chronic alcohol drinking alters 5-HT3 receptors regulating the mesolimbic dopamine system, by Richard J. Thielen; (3) 5-HT3 receptors in the VTA regulate alcohol drinking and the reinforcing effects of alcohol, by Zachary A. Rodd and James M. Murphy; and (4) Ondansetron as a treatment for "biological" alcoholism, by John D. Roache and Bankole A. Johnson.

The results of the microdialysis experiments suggest that periadolescent ethanol drinking by P rats increases basal DA neurotransmission (as indicated by higher DA clearance while maintaining the same extracellular DA concentrations) and prolongs the response of DA neurotransmission to ethanol.

The objectives of the present study were to examine (a) the effects of activating serotonin-3 (5-HT 3 ) receptors on dopamine (DA) release in the anterior and posterior ventral tegmental area (VTA) of Wistar rats; and (b) determine if there are differences in 5-HT 3 -stimulated DA release in the VTA between alcohol-preferring (P) and Wistar rats. Local perfusion with the 5-HT 3 agonist 1-(mchlorophenyl)-biguanide (CPBG) in the anterior and posterior VTA stimulated DA release in the both regions. The CPBG-stimulated increase in extracellular DA levels was significantly higher in the posterior than anterior VTA of Wistar rats. The basal extracellular DA levels were not significantly different between the anterior and posterior VTA of Wistar rats. However, the basal extracellular DA levels were significantly higher in the posterior VTA of Wistar rats than P rats. Local perfusion of CPBG into posterior VTA stimulated somatodendritic DA release significantly more in the P than Wistar rat. Overall, the results indicate that there may be a heterogeneous distribution of functional 5-HT 3 receptors within the VTA with higher numbers in the posterior than anterior VTA, and that, compared to 5-HT 3 receptors in Wistar rats, 5-HT 3 receptors in the posterior VTA of P rats may be more responsive to stimulation.

Abstract:The objective of the present study was to examine the involvement of serotonin 5-HT 2 receptors within the rat nucleus accumbens (Acc) in the regulation of dopamine (DA) release using in vivo microdialysis. Perfusion with the 5-HT 2 agonist (ϩ)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), at concentrations of 25-250 M, through microdialysis probes located in the posterior Acc increased extracellular DA levels to a maximum of 200% of baseline. DOI-induced increases in the extracellular levels of DA were Ca 2ϩ dependent and were inhibited by co-perfusion with the 5-HT 2 antagonist LY-53,857. DOI enhancement of the extracellular concentrations of DA was observed when probes were implanted in the Acc core and shell regions posterior to anteroposterior ϩ1.2 mm from bregma, whereas a small reduction in the extracellular levels of DA was observed in the anterior Acc. There were no differences between core and shell subdivisions within either the anterior or the posterior Acc. These results suggest that activation of 5-HT 2 receptors within the posterior, but not anterior, Acc stimulates DA release, indicating rostral-caudal differences in the interactions of 5-HT with DA systems in the Acc. Key Words: Microdialysis-Dopamine releaseSerotonin 5-HT 2 receptors-(ϩ)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane -LY-53,857. J. Neurochem. 75, 1625-1633 (2000).The mesolimbic dopamine (DA) pathway from the ventral tegmental area (VTA) to the nucleus accumbens (Acc) is involved in mediating many different motivated behaviors, including cocaine, morphine, and alcohol reinforcement (for review, see Di Chiara, 1995). In addition to the rich DA innervation, serotonergic (5-HT) terminals originating in the dorsal raphe nucleus (DRN) also project to the Acc (Azmitia and Segal, 1978;Li et al., 1989;. Moreover, ϳ20% of 5-HT-immunoreactive terminals in the shell and core of the rat Acc are in direct apposition to catecholamine afferents . This suggests that 5-HT could influence the release of DA in this brain region and may be important in DAcontrolled physiological and behavioral events. There also appear to be rostral-caudal differences in 5-HT fiber densities within the Acc, with significantly greater densities in the middle and posterior portions of the Acc than in the anterior subregion (Zhou et al., 1991).Several studies have shown that activation of the DRN 5-HT system or local 5-HT receptors facilitates DA release in the Acc. Yoshimoto and McBride (1992) reported that activating and inhibiting the DRN 5-HT system produced corresponding increases and decreases in the release of 5-HT and DA in the Acc. Electrical stimulation of the DRN enhanced DA release in the Acc but reduced extracellular levels of DA in the striatum (De Deurwaerdere and Spampinato, 1999). Furthermore, activation of 5-HT 3 receptors by local perfusion with 5-HT 3 agonists increased the extracellular levels of DA in the Acc (Chen et al., 1991;Campbell and McBride, 1995). In addition, Parsons and Justice (1993) have shown that local perfusion of 5...