BACKGROUND: Extracellular dopamine (DA) levels in the nucleus accumbens (nAc) increase after ethanol (EtOH) administration in the rat, a response that may be involved in the positive reinforcing effects of EtOH. The mechanisms underlying this DA activation and how they relate to EtOH reinforcement remain to be elucidated, but recent data indicate that glycine receptors (GlyRs) in the nAc may be involved. Here this hypothesis was further challenged by examining the influence of bilateral accumbal application of glycine (a GlyR agonist), strychnine (a GlyR competitive antagonist), or Ringer on EtOH intake and preference, as well as on the concomitant DA output in the nAc, in EtOH high-preferring male Wistar rats. METHODS: EtOH high-preferring male Wistar rats [EtOH preference >60% during continuous access to a bottle of EtOH (6% v/v) and a bottle of water] were limited to drink 1 hr/day (limited access drinking). Thereafter, the animals were equipped bilaterally with microdialysis probes aimed at the mAc, and were subjected to in vivo microdialysis (coupled to high-pressure liquid chromatography with electrochemical detection) and reversed microdialysis (for drug application) during two experimental days (balanced study), during which the animals were allowed a choice between EtOH and water. RESULTS: The EtOH consumption in rats that were perfused with Ringer in the nAc was approximately 0.9 g/kg/hr and associated with a significant increase in extracellular accumbal DA levels. In a subpopulation of rats, bilateral accumbal glycine (100 microM) perfusion produced a significant increase in accumbal DA output and a decrease in EtOH preference and intake. In these glycine responders, the EtOH consumed (approximately 0.7 g/kg/hr) did not produce a further increase of DA levels. In other rats, bilateral glycine perfusion did not change the accumbal DA output, and voluntary EtOH intake was not altered. In these glycine nonresponders, EtOH tended to increase accumbal DA levels. Bilateral accumbal strychnine (20 microM) perfusion significantly decreased DA output in the nAc, and the DA levels remained decreased despite a statistically significant increase of EtOH intake. Finally, the increase in accumbal DA levels observed after EtOH consumption in Ringer-treated rats was significantly larger in glycine responders than in glycine nonresponders. CONCLUSIONS: The present findings suggest that glycine and strychnine alter extracellular DA levels in the nAc, probably via GlyR stimulation and blockade, respectively, and concomitantly glycine and strychnine reciprocally alter also EtOH consumption in EtOH high-preferring male Wistar rats. The possibility of developing selective GlyR agonists and/or antagonists should be explored. Such agents could prove of value in the treatment of alcoholism.
BACKGROUND: Extracellular dopamine (DA) levels in the nucleus accumbens (nAc) increase after ethanol (EtOH) administration in the rat, a response that may be involved in the positive reinforcing effects of EtOH. The mechanisms underlying this DA activation and how they relate to EtOH reinforcement remain to be elucidated, but recent data indicate that glycine receptors (GlyRs) in the nAc may be involved. Here this hypothesis was further challenged by examining the influence of bilateral accumbal application of glycine (a GlyR agonist), strychnine (a GlyR competitive antagonist), or Ringer on EtOH intake and preference, as well as on the concomitant DA output in the nAc, in EtOH high-preferring male Wistar rats. METHODS:EtOH high-preferring male Wistar rats [EtOH preference >60% during continuous access to a bottle of EtOH (6% v/v) and a bottle of water] were limited to drink 1 hr/day (limited access drinking). Thereafter, the animals were equipped bilaterally with microdialysis probes aimed at the mAc, and were subjected to in vivo microdialysis (coupled to high-pressure liquid chromatography with electrochemical detection) and reversed microdialysis (for drug application) during two experimental days (balanced study), during which the animals were allowed a choice between EtOH and water. RESULTS: The EtOH consumption in rats that were perfused with Ringer in the nAc was approximately 0.9 g/kg/hr and associated with a significant increase in extracellular accumbal DA levels. In a subpopulation of rats, bilateral accumbal glycine (100 microM) perfusion produced a significant increase in accumbal DA output and a decrease in EtOH preference and intake. In these glycine responders, the EtOH consumed (approximately 0.7 g/kg/hr) did not produce a further increase of DA levels. In other rats, bilateral glycine perfusion did not change the accumbal DA output, and voluntary EtOH intake was not altered. In these glycine nonresponders, EtOH tended to increase accumbal DA levels. Bilateral accumbal strychnine (20 microM) perfusion significantly decreased DA output in the nAc, and the DA levels remained decreased despite a statistically significant increase of EtOH intake. Finally, the increase in accumbal DA levels observed after EtOH consumption in Ringer-treated rats was significantly larger in glycine responders than in glycine nonresponders. CONCLUSIONS: The present findings suggest that glycine and strychnine alter extracellular DA levels in the nAc, probably via GlyR stimulation and blockade, respectively, and concomitantly glycine and strychnine reciprocally alter also EtOH consumption in EtOH high-preferring male Wistar rats. The possibility of developing selective GlyR agonists and/or antagonists should be explored. Such agents could prove of value in the treatment of alcoholism.
Authors: Gonzalo E Yevenes; Gustavo Moraga-Cid; Robert W Peoples; Günther Schmalzing; Luis G Aguayo Journal: Proc Natl Acad Sci U S A Date: 2008-12-12 Impact factor: 11.205
Authors: Braulio Muñoz; Scarlet Gallegos; Christian Peters; Pablo Murath; David M Lovinger; Gregg E Homanics; Luis G Aguayo Journal: Addict Biol Date: 2019-03-18 Impact factor: 4.280