NEURONS IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS MEDIATE THE SEROTONERGIC STIMULATION OF PROLACTIN SECRETION VIA 5-HT1C 2 RECEPTORS/

These studies examined the hypothalamic site and receptor subtype medi ating the serotonergic (5-HT) control of PRL secretion in conscious ma le rats. Initially, we characterized the pharmacology of the 5-HT rele aser and 5-HT agonists that increase PRL release. Subsequently, we per formed lesion experiments to locate the 5-HT receptors involved in PRL secretion. p-Chloroamphetamine, a 5-HT releaser, is postulated to ent er serotonergic nerve terminals through the 5-HT uptake mechanism, whi ch can be inhibited by fluoxetine. p-Chloroamphetamine (8 mg/kg, ip) i ncreased the plasma PRL concentration approximately 6-fold. The 5-HT u ptake inhibitor fluoxetine almost completely prevented this increase, demonstrating that p-chloroamphetamine increases PRL release via a ser otonergic mechanism. The 5-HT1C/5-HT2 agonist +/--1-(2,5-dimethoxy-4-i odophenyl)2-aminopropane HCI (ip) produced a strong (30-fold) dose-dep endent elevation of plasma PRL, which was virtually eliminated by 0.1 mg/kg (sc) ritanserin, a 5-HT1C/5-HT2 antagonist. +/--1-(2,5-Dimethoxy -4-iodophenyl) 2-aminopropane HCI injected intracerebroventricularly ( icv) in doses below those that were peripherally effective also produc ed a significant (8-fold) increase in PRL secretion that was again att enuated by icv pretreatment with ritanserin (2 mug/kg). RU 24969 thoxy -3-[1,2,3,4-tetrahydro-4-pyridinyl]1H-indole) was reported to act as b oth a 5-HT releaser and a direct postsynaptic 5-HT agonist. To test wh ether RU 24969 releases 5-HT to increase PRL secretion, we depleted 5- HT stores with the 5-HT synthesis inhibitor p-chlorophenylalanine. The ability of RU 24969 (0.5, 1, 5, and 10 mg/kg, ip) to elevate PRL secr etion was not inhibited by pretreatment with p-chlorophenylalanine, su ggesting that RU 24969 stimulates PRL secretion only through activatio n of postsynaptic 5-HT receptors. To test whether RU 24969 acts centra lly, it was injected either icv, through chronic icv cannulae, or peri pherally (ip). RU 24969 injected icv significantly stimulated PRL secr etion (11-fold) at doses 500-fold lower than the peripherally effectiv e doses (10 mug/kg vs. 5 mg/kg), suggesting a role for central 5-HT re ceptors in the regulation of PRL secretion. In addition, rats pretreat ed with the 5-HT1C/5-HT2 antagonist LY53857 (icv) significantly inhibi ted the PRL response if RU 24969 was injected ip, but not icv. The res ults of these experiments suggest that 5-HT1C or 5-HT2 receptors in th e brain participate in the serotonergic stimulation of PRL secretion. To determine the location of the 5-HT receptors that increase PRL secr etion, a series of lesion experiments was performed using the cell-sel ective neurotoxin ibotenic acid. Ibotenic acid was injected (3 mug/0.3 mul) bilaterally into the hypothalamic paraventricular (PVN), dorsome dial, ventromedial, or supraoptic nuclei. The PRL response to p-chloro amphetamine (8 mg/kg, ip) was unaltered in rats with dorsomedial, vent romedial, or supraoptic nucleus lesions. In contrast, rats with histol ogically confirmed lesions in the PVN had a significantly lower PRL re sponse to both RU 24969 (48% reduction) and p-chloroamphetamine (73% r eduction). These data suggest that cell bodies in the hypothalamic PVN are necessary for serotonergic stimulation of PRL secretion.