TY - JOUR T1 - Reversal of prolonged dopamine inhibition of dopaminergic neurons of the ventral tegmental area JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.109.163931 SP - jpet.109.163931 AU - Sudarat Nimitvilai AU - Mark S. Brodie Y1 - 2010/01/01 UR - http://jpet.aspetjournals.org/content/early/2010/02/17/jpet.109.163931.abstract N2 - Drug abuse-induced plasticity of putative dopaminergic (pDAergic) ventral tegmental area (VTA) neurons may play an important role in changes in the mesocorticolimbic system that lead to the development of addiction. In the present study, extracellular recordings were used to examine time-dependent effects of dopamine (DA) on pDAergic VTA neurons in rat brain slices. Administration of DA (2.5-10 μM) for forty minutes resulted in inhibition followed by partial or full reversal of that inhibition. The reduced sensitivity to DA inhibition lasted 30-90 min after washout of the long-term dopamine administration. The inhibition reversal was not observed with 40 min administration of D2 agonist quinpirole (25-200 nM), so this phenomenon was not the result of desensitization induced solely by stimulation of D2 DA receptors. Inhibition reversal could be observed with the co-application of quinpirole and the D1/D5 agonist SKF38393, suggesting a D1/D5 mechanism for the reversal. Furthermore, D1/D5 antagonists given in the presence of prolonged DA exposure prevented the inhibition reversal. Application of 3 μM quinpirole caused desensitization to low quinpirole concentrations which was blocked by a D1/D5 antagonist. These data suggest that co-activation of D1/D5 receptors and D2 receptors in the VTA result in desensitization of autoinhibitory D2 receptors. Prolonged increases in pDAergic tone in the VTA, such as may occur in vivo with drugs of abuse, could reduce the regulation of firing by D2 dopamine receptor activation, producing long-term alteration in information processing related to reward and reinforcement.The American Society for Pharmacology and Experimental Therapeutics ER -