Quinolinic acid stimulates luteinizing hormone secretion through a serotonin-dependent mechanism

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Abstract
Previous results from this laboratory suggest that the tryptophan metabolite, quinolinic acid (QUIN), stimulates luteinizing hormone (LH) secretion in female rats, most likely through actions on NMDA-preferring excitatory amino acid receptors. The present experiments examined whether QUIN alters LH secretion through actions requiring intact catecholaminergic or serotonergic mechanisms. Each study examined the effects of intracisternal (i.c.) injections of 25 μl acidic saline or saline containing QUIN (500 nmol) or the synthetic analogue, N-methyl-DL-aspartate (NMA, 500 nmol), into ovariectomized, estradiol benzoate-primed rats after pharmacologic disruption of monoaminergic neurotransmission. In each experiment, animals were decapitated 5 min after QUIN or NMA administration. Experiment 1 examined whether reduction in brain serotonin (5-HT) or of norepinephrine (NE) and epinephrine (E) alters the QUIN- or NMA-induced stimulation of LH secretion. Rats were pretreated with the dopamine-β-hydroxylase inhibitor, FLA-63 (40 mg/kg 2 h prior). A second experiment examined the effects of the 5-HT antagonist, methysergide, on QUIN or NMA stimulation of LH secretion. Methysergide (15 mg/kg) was administered 30 min prior to experimentation. Experiment 3 examined whether selective destruction of raphe serotonergic neurons with the indoleamine neurotoxin, 5,7 dihydroxytryptamine (5,7 DHT), alters QUIN's stimulatory effects. In each study, serum LH concentrations were determined by radioimmunoassay. Hypothalamic catecholamine and 5-HT concentrations were measured by radioenzymatic assay and liquid chromatography with electrochemical detection, respectively. Depletion of brain 5-HT with PCPA significantly reduced the stimulation of LH secretion by QUIN, but not by NMA. Similarly, the administration of the serotonin antagonist, methysergide, and reduction of brain 5-HT induced by injections of 5,7 DHT in the vicinity of raphe nuclei also attentuated QUIN's stimulatory effect on LH. In contrast, depletion of brain NE and E did not significantly affect the release of LH in response to either QUIN or NMA. These findings suggest that QUIN stimulates LH secretion through mechanisms dependent on the activation of serotonergic neurons projecting from the raphe nuclei. The release of LH induced by the synthetic agonist, NMA, appears to be independent of brain monoamines.