A role of gamma-amino butyric acid (GABA) and glutamate in control of puberty in female rhesus monkeys: Effect of an antisense oligodeoxynucleotide for GAD67 messenger ribonucleic acid and MK801 on luteinizing hormone-releasing hormone release

Previously we have shown that gamma-aminobutyric acid (GABA) is an inhibito ry neurotransmitter restricting the pubertal increase in LHRH release in ju venile monkeys, and that interfering with GABA synthesis with an antisense oligodeoxynucleotide (AS) for glutamic acid decarboxylase (GAD67) mRNA resu lts in an increase in LHRH release in prepubertal monkeys. GAD67 is a catal ytic enzyme that synthesizes GABA from glutamate. To further clarify the ro le of GABA in puberty, we examined whether the inhibition of LHRH release b y GABA continues after the onset of puberty and whether input from glutamat ergic neurons plays any role in the onset of puberty when GABA inhibition d eclines, using a push-pull perfusion method. In Study I, the effects of the AS GAD67 mRNA on LHRH release in pubertal monkeys (34.3 +/- 1.5 months of age, n = 8) were examined, and the results were compared with those in prep ubertal monkeys (18.5 +/- 0.4 months, n = 12). Direct infusion of AS GAD67 (1 mu M) into the stalk-median eminence (S-ME) for 5 h stimulated LHRH rele ase in both prepubertal and pubertal monkeys. However, the increase in LHRH release in pubertal monkeys was significantly (P < 0.01) smaller than that in prepubertal monkeys. Infusion of a scrambled oligo as a control was wit hout effect in either group. In Study II, to examine the possibility that a n increase in glutamate tone after the reduction of an inhibitory GABA tone contributes to the AS GADG7-induced LHRH increase, the effects of the NMDA receptor blocker MK801 (5 mu M) on LHRH release were tested in monkeys tre ated with AS GAD67. MK801 infusion into the S-ME during the treatment of AS GAD67 (1 mu M) suppressed the AS GAD67-induced LHRH release in both age gr oups. MK801 alone did not cause any significant effect in either group. The data are interpreted to mean that GABA continues to suppress LHRH release after the onset of puberty, although the degree of suppression is weakened considerably after the onset of puberty, and that the increased LHRH releas e after AS GAD67 treatment may be partly due to an increase in glutamate to ne mediated by NMDA receptors, as well as due to the decrease in GABA relea se following the decrease in GAD synthesis. Taken together, the present res ults suggest that GAD may play an important role in the onset and progress of puberty in nonhuman primates.