EVIDENCE THAT CHANGES IN THE FUNCTION OF THE SUBTYPES OF THE RECEPTORS FOR GAMMA-AMINO BUTYRIC-ACID MAY BE INVOLVED IN THE SEASONAL-CHANGESIN THE NEGATIVE-FEEDBACK EFFECTS OF ESTROGEN ON GONADOTROPIN-RELEASING-HORMONE SECRETION AND PLASMA LUTEINIZING-HORMONE LEVELS IN THE EWE

We have investigated the effects of gamma-amino butyric acid (GABA) ag onists and antagonists to GABA(A) and GABA(B) receptors microinjected (1 mul) into the medial preoptic area (MPOA) on LH secretion in ovarie ctomized (OVX) ewes with or without estrogen (E) treatment, during the nonbreeding season. Guide tubes (19 gauge) were placed into the MPOA of OVX ewes and injections of 1 mug or 10 mug of the GABA(A) agonist m uscimol or the GABA(A) antagonist bicuculline, and 10 mug of the GABA( B) agonist baclofen or the GABA(B) antagonist phaclofen were made into conscious animals. Jugular venous blood was collected at 10-min inter vals for 3 h, the injection of GABA drug or vehicle was given and samp les collected for a further 3 h. The plasma samples were assayed for L H. On completion of the experiments the brains were sectioned to locat e the sites of injection. Thirty-four ewes were used, of which 30 had correct guide tube placement. In OVX sheep, both muscimol and bicucull ine injection caused suppression of plasma LH concentrations, with a c essation of pulsatile release in many instances. Injection with baclof en or phaclofen into these sheep had no effect on LH secretion. When O VX sheep were treated with 0.5-cm Silastic implants (sc) of E for at l east 7 days, there was a variable response to muscimol and bicuculline injection, depending on the degree of suppression of LH secretion by E. When E had little effect on plasma LH levels, muscimol and bicucull ine both suppressed LH secretion in a similar manner to that observed in OVX ewes. When E treatment fully suppressed plasma LH levels, musci mol and bicuculline both stimulated LH secretion. This stimulation oft en took the form of a sustained, nonpulsatile secretion of LH. Baclofe n injection into OVX ewes treated with E increased mean plasma LH leve ls through an increase in pulse amplitude, although there was only an effect on the amplitude of the first pulse after injection. Conversely , phaclofen injection in OVX ewes treated with E resulted in a reducti on in LH pulse amplitude. These results provide evidence for a seasona l shift in the regulation of GnRH secretion by GABAergic neurons in th e MPOA of the ewe. In contrast to the breeding season, where there was no effect of GABA(B) ligands, these appear to function in non-breedin g season, this may be part of the mechanism for the seasonal shift in the negative-feedback effect of E on LH secretion. GABA(A) receptors a ppear to have a role similar to that observed during the breeding seas on with regard to the regulated timing of pulsatile GnRH secretion and may have an additional role in the mediation of E-negative feedback.