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NEUROPHARMACOLOGY

Suppressed Prolactin Response to Dynorphin A_1–13 in Methadone-Maintained Versus Control Subjects

The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York

Dynorphin A_1–13, a shortened sequence of the natural peptide dynorphin A_1–17, is a primarily -opioid receptor-preferring peptide. Previously, we showed that dynorphin A_1–13 administered to normal volunteers causes a prompt dose-dependent elevation in serum prolactin that may reflect a reduction in tuberoinfundibular dopaminergic tone. This study was conducted to determine whether tuberoinfundibular dopaminergic tone is reduced in methadone-maintained patients. Eight former heroin addicts on stable-dose methadone maintenance with no ongoing drug or alcohol abuse or dependence and 15 normal volunteer controls with no history of drug or alcohol dependence received dynorphin A_1–13 intravenously at doses of 120 µg/kg and 500 µg/kg. Studies began one hour before methadone dosing to avoid the expected increase in prolactin that coincides with peak plasma levels of methadone. After intravenous dynorphin A_1–13, a dose-response increase in serum prolactin, which peaked within 20 min, was observed in both groups. There was no difference in prolactin between the two groups at baseline or following a placebo. The prolactin response to each dose of dynorphin A_1–13 was significantly lower in the methadone-maintained volunteers compared with the controls. These results suggest that tuberoinfundibular dopaminergic tone is altered in methadone-maintained subjects. It is unknown whether altered dopaminergic tone existed before opiate addiction, is a result of heroin addiction, or is reflective of methadone maintenance. Whether methadone-maintained subjects also have decreased dopaminergic response to dynorphin and other -opioid receptor ligands in mesolimbic-mesocortical and nigrostriatal dopaminergic systems cannot be determined from this study.

Address correspondence to: Gavin Bart, The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, Box 171, 1230 York Ave., New York, NY 10021-6399. E-mail bartg{at}rockefeller.edu

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