These studies examined the hypothalamic site and receptor subtype mediating the serotonergic (5-HT) control of PRL secretion in conscious male rats. Initially, we characterized the pharmacology of the 5-HT releaser and 5-HT agonists that increase PRL release. Subsequently, we performed lesion experiments to locate the 5-HT receptors involved in PRL secretion. p-Chloroamphetamine, a 5-HT releaser, is postulated to enter serotonergic nerve terminals through the 5-HT uptake mechanism, which can be inhibited by fluoxetine. p-Chloroamphetamine (8 mg/kg, ip) increased the plasma PRL concentration approximately 6-fold. The 5-HT uptake inhibitor fluoxetine almost completely prevented this increase, demonstrating that p-chloroamphetamine increases PRL release via a serotonergic mechanism. The 5-HT1C/5-HT2 agonist ±-l-(2, 5-dimethoxy-4-iodophenyl)2-aminopropane HC1 (ip) produced a strong (30-fold) dose-dependent elevation of plasma PRL, which was virtually eliminated by 0.1 mg/kg (sc) ritan-serin, a 5-HT1C/5-HT2 antagonist. ±-l-(2, 5-Dimethoxy-4-iodophenyl)2-aminopropane HCl injected intracerebroventricularly (icv) in doses below those that were peripherally effective also produced a significant (8-fold) increase in PRL secretion that was again attenuated by icv pretreatment with ritanserin (2 μg/kg). RU 24969 (5-methoxy-3-[l, 2, 3, 4-tetrahydro-4-pyridinyl]lH-indole) was reported to act as both a 5-HT releaser and a direct postsynaptic 5-HT agonist. To test whether 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 secretion was not inhibited by pretreatment with p-chlorophen-ylalanine, suggesting that RU 24969 stimulates PRL secretion only through activation of postsynaptic 5-HT receptors. To test whether RU 24969 acts centrally, it was injected either icv, through chronic icv cannulae, or peripherally (ip). RU 24969 injected icv significantly stimulated PRL secretion (11-fold) at doses 500-fold lower than the peripherally effective doses (10 μg/kg vs. 5 mg/kg), suggesting a role for central 5-HT receptors in the regulation of PRL secretion. In addition, rats pretreated with the 5-HT1C/5-HT2 antagonist LY53857 (icv) significantly inhibited the PRL response if RU 24969 was injected ip, but not icv. The results of these experiments suggest that 5-HT1C or 5-HT2 receptors in the brain participate in the serotonergic stimulation of PRL secretion. To determine the location of the 5-HT receptors that increase PRL secretion, a series of lesion experiments was performed using the cell-selective neurotoxin ibotenic acid. Ibotenic acid was injected (3 μg/0.3 μl) bilaterally into the hypothalamic paraventricular (PVN), dorso-medial, ventromedial, or supraoptic nuclei. The PRL response to p-chloroamphetamine (8 mg/kg, ip) was unaltered in rats with dorsomedial, ventromedial, or supraoptic nucleus lesions. In contrast, rats with histologically confirmed lesions in the PVN had a significantly lower PRL response to both RU 24969 (48% reduction) and p-chloroamphetamine (73% reduction). These data suggest that cell bodies in the hypothalamic PVN are necessary for serotonergic stimulation of PRL secretion.
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