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Reversal of prolonged dopamine inhibition of dopaminergic neurons of the ventral tegmental area.
J Pharmacol Exp Ther 2010; 333(2):555-63JP

Abstract

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 microM) for 40 min resulted in inhibition followed by partial or full reversal of that inhibition. The reduced sensitivity to DA inhibition lasted 30 to 90 min after washout of the long-term dopamine administration. The inhibition reversal was not observed with 40-min administration of the 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 coapplication of quinpirole and the D1/D5 agonist SKF38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide], 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 microM quinpirole caused desensitization to low quinpirole concentrations that was blocked by a D1/D5 antagonist. These data suggest that coactivation of D1/D5 receptors and D2 receptors in the VTA results in desensitization of autoinhibitory D2 receptors. Prolonged increases in pDAergic tone in the VTA that 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.

Authors+Show Affiliations

Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois 60612-7342, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

20164301

Citation

Nimitvilai, Sudarat, and Mark S. Brodie. "Reversal of Prolonged Dopamine Inhibition of Dopaminergic Neurons of the Ventral Tegmental Area." The Journal of Pharmacology and Experimental Therapeutics, vol. 333, no. 2, 2010, pp. 555-63.
Nimitvilai S, Brodie MS. Reversal of prolonged dopamine inhibition of dopaminergic neurons of the ventral tegmental area. J Pharmacol Exp Ther. 2010;333(2):555-63.
Nimitvilai, S., & Brodie, M. S. (2010). Reversal of prolonged dopamine inhibition of dopaminergic neurons of the ventral tegmental area. The Journal of Pharmacology and Experimental Therapeutics, 333(2), pp. 555-63. doi:10.1124/jpet.109.163931.
Nimitvilai S, Brodie MS. Reversal of Prolonged Dopamine Inhibition of Dopaminergic Neurons of the Ventral Tegmental Area. J Pharmacol Exp Ther. 2010;333(2):555-63. PubMed PMID: 20164301.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reversal of prolonged dopamine inhibition of dopaminergic neurons of the ventral tegmental area. AU - Nimitvilai,Sudarat, AU - Brodie,Mark S, Y1 - 2010/02/17/ PY - 2010/2/19/entrez PY - 2010/2/19/pubmed PY - 2010/5/11/medline SP - 555 EP - 63 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 333 IS - 2 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 microM) for 40 min resulted in inhibition followed by partial or full reversal of that inhibition. The reduced sensitivity to DA inhibition lasted 30 to 90 min after washout of the long-term dopamine administration. The inhibition reversal was not observed with 40-min administration of the 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 coapplication of quinpirole and the D1/D5 agonist SKF38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide], 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 microM quinpirole caused desensitization to low quinpirole concentrations that was blocked by a D1/D5 antagonist. These data suggest that coactivation of D1/D5 receptors and D2 receptors in the VTA results in desensitization of autoinhibitory D2 receptors. Prolonged increases in pDAergic tone in the VTA that 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/20164301/Reversal_of_prolonged_dopamine_inhibition_of_dopaminergic_neurons_of_the_ventral_tegmental_area_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=20164301 DB - PRIME DP - Unbound Medicine ER -