Abstract
Previous studies in vivo have shown that salsolinol, the condensation product of acetaldehyde and dopamine, has properties that may contribute to alcohol abuse. Although opioid receptors, especially the μ-opioid receptors (MORs), may be involved, the cellular mechanisms mediating the effects of salsolinol have not been fully explored. In the current study, we used whole-cell patch-clamp recordings to examine the effects of salsolinol on dopamine neurons of the ventral tegmental area (VTA) in acute brain slices from Sprague-Dawley rats. Salsolinol (0.01–1 μM) dose-dependently and reversibly increased the ongoing firing of dopamine neurons; this effect was blocked by naltrexone, an antagonist of MORs, and gabazine, an antagonist of GABAA receptors. We further showed that salsolinol reduced the frequency without altering the amplitude of spontaneous GABAA receptor-mediated inhibitory postsynaptic currents in dopamine neurons. The salsolinol-induced reduction was blocked by both naltrexone and [d-Ala2,N-Me-Phe4,Gly5-ol]enkephalin, an agonist of MORs. Thus, salsolinol excites VTA-dopamine neurons indirectly by activating MORs, which inhibit GABA neurons in the VTA. This form of disinhibition seems to be a novel mechanism underlying the effects of salsolinol.
Footnotes
This work was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grants AA016964, AA016618] (to J.-H.Y.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- NAcc
- nucleus accumbens
- APV
- 2-amino-5-phosphono-valeric acid
- DAMGO
- [d-Ala2,N-Me-Phe4,Gly5-ol]enkephalin
- DNQX
- 6,7-dinitroquinoxaline-2,3-dione
- MOR
- μ-opioid receptor
- VTA
- ventral tegmental area
- p-VTA
- posterior VTA
- TTX
- tetrodotoxin
- ACSF
- artificial cerebrospinal fluid
- IPSC
- inhibitory postsynaptic current
- sIPSC
- spontaneous IPSC
- mIPSC
- miniature IPSC
- eIPSC
- evoked IPSC
- HPC
- hyperpolarizing current
- PPR
- paired-pulse ratio
- SAL
- salsolinol
- APs
- action potentials
- GABAR
- GABA receptor
- SR-95531
- 2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)pyridazinium bromide.
- Received August 16, 2011.
- Accepted December 22, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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