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 μM) 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 μM 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.
Footnotes
This study was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Public Health Service Grants AA09125, AA05846].
Some of this work was presented previously: Nimitvilai S and Brodie MS (2008) Biphasic effects of dopamine on the firing rate of dopaminergic ventral tegmental area neurons: involvement of h-current; 2009 Nov 15–19; 2008 Neuroscience Meeting Planner. Program 727.4, Society for Neuroscience, Washington, DC.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.163931.
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ABBREVIATIONS:
- pDAergic
- putative dopaminergic
- DA
- dopamine
- VTA
- ventral tegmental area
- LTP
- long term potentiation
- SKF38393
- (±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide
- SCH39166
- (6aS-trans)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H-benzo[d]naphth[2,1-b]azepin-12-ol hydrobromide
- SCH23390
- (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride
- ANOVA
- analysis of variance
- aCSF
- artificial cerebrospinal fluid.
- Received November 16, 2009.
- Accepted February 16, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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