Abstract
Opiate-induced motor sensitization refers to the progressive and enduring motor response that develops after intermittent drug administration, and results from neuroadaptive changes in ventral tegmental area (VTA) and nucleus accumbens (NAc) neurons. Repeated activation of μ-opioid receptors localized on γ-aminobutyric acid (GABA) neurons in the VTA enhances dopaminergic cell activity and stimulates dopamine release in the nucleus accumbens. We hypothesize that GABAB receptor agonist treatment in the VTA blocks morphine-induced motor stimulation, motor sensitization, and accumbal Fos immunoreactivity by inhibiting the activation of dopaminergic neurons. First, C57BL/6 mice were coadministered a single subcutaneous injection of morphine with intra-VTA baclofen, a GABAB receptor agonist. Baclofen produced a dose-dependent inhibition of opiate-induced motor stimulation that was attenuated by 2-hydroxysaclofen, a GABAB receptor antagonist. Next, morphine was administered on days 1, 3, 5, and 9 and mice demonstrated sensitization to its motor stimulant effects and concomitant induction of Fos immunoreactivity in the NAc shell (NAcS) but not NAc core. Intra-VTA baclofen administered during morphine pretreatment blocked the acquisition of morphine-induced motor sensitization and Fos activation in the NAcS. Intra-VTA baclofen administered only on day 9 blocked the expression of morphine-induced motor sensitization and Fos activation in the NAcS. A linear relationship was found between morphine-induced motor activity and accumbal Fos in single- and repeated-dose treatment groups. In conclusion, GABAB receptor stimulation in the VTA blocked opiate-induced motor stimulation and motor sensitization by inhibiting the activation of NAcS neurons. GABAB receptor agonists may be useful pharmacological treatments in altering the behavioral effects of opiates.
Footnotes
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This work was supported by a Merit Review Grant from the Department of Veterans Affairs (to G.B.K.) and by National Institute on Alcohol Abuse and Alcoholism T32 Grant AA07549 (to K.A.L.-M.). This manuscript is based upon the dissertation (2002) of K.A.L.-M. under the mentorship of Dr. Marian Goldsmith (University of Rhode Island) and G.B.K. (Brown University).
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DOI: 10.1124/jpet.103.058412.
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ABBREVIATIONS: VTA, ventral tegmental area; NAc, nucleus accumbens; PFC, prefrontal cortex; aCSF, artificial cerebral spinal fluid; PBS, phosphate-buffered saline; NAcS, nucleus accumbens shell; NAcC, nucleus accumbens core; ANOVA, analysis of variance; SNK, Student-Newman-Keuls; V, vehicle; M, morphine; B, baclofen.
- Received August 19, 2003.
- Accepted October 16, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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