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Mu opioid receptor mRNA in nucleus accumbens is elevated following dopamine receptor activation
A V Azaryan1, B J Clock, B M Cox
1Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Abstract:
We have previously demonstrated that continuous cocaine treatment for three days induces a marked but transient increase in mu opioid receptor (MOR) mRNA in nucleus accumbens (n. acc.); SCH 23390 and eticlopride, selective antagonists of D1- and D2-like dopamine (DA) receptors, respectively, blocked this cocaine-induced upregulation of MOR mRNA in n. acc. suggesting involvement of both subfamilies of DA receptors in the effect of cocaine (1,2). In the present study the ability of the selective DA D3 receptor antagonist, nafadotride (3,4), to prevent the cocaine-induced upregulation of MOR mRNA in n. acc. has been examined. Also, regulation of MOR mRNA following chronic administration of the DA agonists, SKF 38393, R(+)-6-Bromo-APB hydrobromide, or bromocriptine, has been studied. Male Sprague-Dawley rats were treated for 3 days with saline, cocaine, the DA receptor agonists or antagonist delivered by osmotic minipump. Expression of MOR mRNA in n. acc. was estimated by quantitative competitive polymerase chain reaction (PCR) assays following reverse transcription. Nafadotride (1.0 mg/kg/day) prevented the cocaine-induced upregulation of MOR mRNA in n. acc. When administered alone, nafadotride did not change the expression of MOR mRNA. The levels of MOR mRNA were elevated in n. acc. after 3 days treatment with each of the DA agonists, SKF 38393 (4.0 mg/kg/day), R(+)-6-Bromo-APB hydrobromide (4.0 mg/kg/day), or bromocriptine (5.0 mg/kg/day). Thus, DA agonists mimick the effect of cocaine on the expression of MOR mRNA in n. acc. These data confirm the involvement of dopaminergic mechanisms in the mediation of cocaine effects, indicate the comparability of actions of indirect and direct DA agonists, and point to the usefulness of cocaine as a tool to expose interaction between dopaminergic and opioid systems. The results suggest that activation of more than one type of DA receptor is required for the increased expression of MOR mRNA.
Insights
Cocaine increases mu opioid receptor (MOR) mRNA in the nucleus accumbens, an effect blocked by D3 receptor antagonists. Dopamine agonists also increase MOR mRNA, suggesting multiple dopamine receptor types mediate this cocaine effect.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Previous studies showed continuous cocaine treatment upregulates mu opioid receptor (MOR) mRNA in the nucleus accumbens.
- This cocaine-induced effect is blocked by D1 and D2 dopamine receptor antagonists, indicating dopamine system involvement.
- The specific role of the dopamine D3 receptor and dopamine agonists in this regulation remained unclear.
Purpose of the Study:
- To investigate the effect of the selective dopamine D3 receptor antagonist, nafadotride, on cocaine-induced MOR mRNA upregulation.
- To examine MOR mRNA regulation following chronic administration of dopamine receptor agonists (SKF 38393, R(+)-6-Bromo-APB hydrobromide, bromocriptine).
Main Methods:
- Male Sprague-Dawley rats were treated with saline, cocaine, dopamine agonists, or nafadotride via osmotic minipump for three days.
- MOR mRNA expression in the nucleus accumbens was quantified using reverse transcription and competitive polymerase chain reaction (PCR).
Main Results:
- Nafadotride (1.0 mg/kg/day) prevented the cocaine-induced increase in MOR mRNA in the nucleus accumbens.
- Administered alone, nafadotride did not alter MOR mRNA expression.
- Treatment with dopamine agonists (SKF 38393, R(+)-6-Bromo-APB hydrobromide, or bromocriptine) elevated MOR mRNA levels in the nucleus accumbens.
Conclusions:
- Dopamine D3 receptor antagonism prevents cocaine-induced MOR mRNA upregulation, confirming dopaminergic involvement.
- Dopamine agonists mimic cocaine's effect on MOR mRNA expression, highlighting the comparability of indirect and direct dopamine agonists.
- The findings suggest that activation of multiple dopamine receptor types is necessary for increased MOR mRNA expression.