Abstract
To characterize the effects of morphine on serotonin (5-HT) in the central nervous system, we used microdialysis in freely behaving rats. Subcutaneous injection of morphine sulfate produced a dose-dependent increase in extracellular 5-HT in the dorsal raphe nucleus (DRN) and a forebrain site, the nucleus accumbens (NAcc). To determine the site of action for this effect, the opioid receptor antagonist naltrexone was infused into either the DRN or NAcc. Naltrexone infusion (300 μM) into the DRN but not the NAcc attenuated the increase in 5-HT elicited by systemic morphine (20 mg/kg). This suggests that morphine acts in the DRN to alter the activity of 5-HT neurons that project to NAcc. Consistent with this conclusion, infusion of the GABAA receptor antagonist bicuculline (100 μM) into the DRN but not the NAcc also blocked the effect of systemic morphine. Similarly, the effect of systemic morphine was blocked by infusion into the DRN of the GABAA receptor agonist muscimol (30 μM) and attenuated by the GABAB receptor agonist (±)-baclofen (100 μM). This provides evidence that morphine indirectly influences 5-HT release via opioid receptors on GABAergic neurons in the DRN. A new finding is that ionotropic glutamate receptor antagonists [kynurenate or a mixture of (±)-2-amino-5-phosphonopentanoic acid and 6,7-dinitro-quinoxaline-2,3-dione] infused in the DRN also attenuated the effect of systemic morphine. These results suggest that morphine acts on GABAergic and glutamatergic afferents to indirectly influence the activity of 5-HT neurons in the DRN. Understanding the details of this neural circuitry may provide new leads for treatment of opiate addiction.
Footnotes
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↵1 Current address: Department of Psychiatry, Harvard/VA Medical Center, 940 Belmont St., Brockton, MA 02301.
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This research was supported by National Institutes of Health Grants MH51080 (to S.B.A.) and DA14541 (to R.T.).
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DOI: 10.1124/jpet.102.038133
- Abbreviations:
- DRN
- dorsal raphe nucleus
- 5-HT
- 5-hydroxytryptamine, serotonin
- NAcc
- nucleus accumbens
- aCSF
- artificial cerebrospinal fluid
- ANOVA
- analysis of variance
- AP-5
- (±)-2-amino-5-phosphonopentanoic acid
- DNQX
- 6,7-dinitro-quinoxaline-2,3-dione
- AP
- anteroposterior
- ML
- mediolateral
- DV
- dorsoventral
- Received April 30, 2002.
- Accepted July 8, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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