The neurochemistry of the GnRH pulse generator

We review the crucial role of the two neurotransmitters norepinephrine (NE) and GABA in eliciting GnRH pulses. NE acts via an α1-receptor mechanism and also GABA acts at the α-subtype of the GABA receptor. The function of NE appears to be induction of phasic activation of GnRH neurons and GABA inhibits GnRH neurons tonically until they are all ready for phasic activation. By an unknown mechanism preoptic GABA release is dramatically reduced which causes simultaneous desinhibition of the GnRH neurons. Hence they release their product into the portal vessels simultaneously which is the appropriate signal for the pituitary gonadotrophs. The action of norepinephrine and GABA is most likely exerted at the perikarya level of the GnRH neurons since the α1-adreno receptor blocker doxazosin and GABA inhibit GnRH secretion only when applied into the medial preoptic/anterior hypothalamic area (where in the rat brain the GnRH perikarya are located). Utilizing a quantitative reverse transcription polymerase chain reaction, we demonstrate furthermore that GnRH receptors are present in the mediobasal hypothalamus as well as in the preoptic area of rats. Their function appears to serve autoinhibitory purposes since Buserelin added to medium significantly decreased GnRH release. Simultaneously, the release of GABA was increased and that of glutamate decreased. We conclude from these experiments that GABAergic and glutamatergic neurons in the hypothalamus may also be GnRH-receptive.