GABAergic and glutamatergic afferents in the dorsal raphe nucleus mediate morphine-induced increases in serotonin efflux in the rat central nervous system.

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 microM) 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 GABA(A) receptor antagonist bicuculline (100 microM) 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 GABA(A) receptor agonist muscimol (30 microM) and attenuated by the GABA(B) receptor agonist (+/-)-baclofen (100 microM). 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.