We have previously reported that repetitive iv injections of NMA [N-methyl-D, L-aspartate, the mixed analog acting on the iV-methyl-D-aspartate (NMDA) receptor] can induce a consistent increase in LH and PRL secretion in cycling rats, but not in lactating rats. To further explore the use of excitatory amino acids (EAAs) as tools for understanding the regulation of the neuroendocrine reproductive axis, we have examined the effects of multiple injections of kainate, an agonist to another subclass of EAA receptor, on LH and PRL secretion in cycling rats. Recent studies suggest that kainate receptors may be more abundant than NMDA receptors in the hypothalamus. Five iv injections of kainate were administered at 50-min intervals to diestrous or estrous rats. Blood samples were collected every 10 min and assayed for LH and PRL. LH, but not PRL secretion, was stimulated by this regimen of kainate treatment. Surprisingly, the LH response to kainate, unlike NMA, decreased with repetitive injections of the drug. The response to the last pulse of kainate was approximately 30-40% of the first pulse. This decline in LH responsiveness to kainate was not due to desensitization at the level of the pituitary or to refractoriness of GnRH neurons, since further stimulation of LH release could be obtained by the administration of GnRH or NMA. The mechanisms responsible for the diminishing GnRH response to kainate remain unclear. However, we speculate that it might be due to the delayed activation of inhibitory inputs to GnRH neurons or to the desensitization of kainate receptors. On the other hand, the absence of a PRL response to kainate, in contrast to the stimulatory effect of NMA, most likely reflects differences in the distribution of kainate and NMDA receptors on dopamine neurons and neurons containing PRL-releasing factors, or on extrahypothalamic afferent neuronal populations projecting to the hypothalamus. In conclusion, the effects of systemic injections of kainate on LH and PRL secretion differed from NMA in that the LH response could not be sustained with multiple injections and PRL was unresponsive to kainate stimulation.
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