Involvement of Brain Serotonin in the Prolactin- Releasing Effect of Opioid Peptides*

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Abstract
The role played by brain serotonin (5-HT) neurotransmission in mediating the PRL-releasing effect of enkephalins was investigated in the rat. Both MetG-enkephalin (Metenk) and (D-Met2, Pro5)-enkephalinamide (EKNH2), an analog with long lasting analgesic activity, were used in freely moving rats bearing a cannula chronically implanted into the jugular vein. Met-enk injected intracerebroventricularly (IVT; 200 and 400 μg/rat) induced a marked and dose-related increase in plasma PRL; EKNH2 (0.2 mg/kg, iv) induced a rise in plasma PRL similar to that evoked by Met-enk (400μg/rat). Metergoline (1 mg/kg, iv), a 5-HT receptor blocker, significantly reduced the PRL-releasing effect of Met-enk (200 μg/rat); these results were duplicated by using another 5-HT receptor blocker, i.e. methysergide (2.5 mg/kg, iv). Metergoline and methysergide also significantly reduced the increase in plasma PRL due to EKNH2. 5,6-Dihydroxytryptamine (50 μg, IVT), a neurotoxic drug which destroys 5-HT nerve terminals, almost completely abolished the rise in plasma PRL induced by EKNH2 (1.0 mg/kg, ip). However, blockade of 5-HT biosynthesis by p-chlorophenylalanine (100 mg/kg, sc, twice) potentiated the rise in plasma PRL induced by EKNH2, an effect possibly resulting from the development of supersensitive 5-HT receptors. Pretreatment with quipazine (15 mg/kg, iv), a direct stimulant of 5-HT receptors, almost completely suppressed the PRL-releasing effect of Met-enk (400 µg/ rat), EKNH2, and IVT injected 5-HT (2 μg/rat). Blockade of catecholamine neurotransmission by a-methyl-p-tyrosine (200 mg/kg, ip) did not modify the PRL-releasing effect of EKNH2. In all, these results suggest that enkephalins exert their PRLreleasing effect via mediation of the brain 5-HT system.