To test the hypothesis that the pubertal increase in luteinizing hormone-releasing hormone (LHRH) re-lease is withheld by a dominant inhibitory neuronal system, the role of -aminobutyric acid (GABA), a known inhibitory neurotransmitter, in the control of LHRH release was examined in conscious female monkeys at the prepubertal and pubertal stages using a push-pull perfusion method. GABA, bicuculline (a GABAA receptor blocker), and 2-hydroxysaclofen (a GABAB receptor blocker) were directly infused into the stalk-median eminence while perfusates were collected for LHRH determination. Bicuculline, but not saclofen, induced a large and prompt increase in LHRH release in prepubertal monkeys, whereas it stimulated LHRH release slightly in pubertal monkeys. In contrast, GABA suppressed LHRH release in pubertal, but not prepubertal, monkeys. These differential effects of GABA and the GABA antagonist on LHRH release in the two developmental stages were due to an age factor rather than to the steroid hormonal background. Moreover, GABA release in the stalk-median eminence of prepubertal monkeys was much higher than that in pubertal monkeys. Thus, the results suggest that in the prepubertal period there is a powerful GABA inhibition of the LHRH neurosecretory system: infusions of GABAA, but not GABAB, antagonists stimulate LHRH release by removal of the endogenous GABA inhibition, whereas exogenous GABA is ineffective because of high endogenous GABA levels. The decrease of this tonic inhibition may be a key factor for the onset of puberty in non-human primates.Two lines of evidence support the hypothesis that an increase in pulsatile luteinizing hormone-releasing hormone (LHRH) release is the critical factor for the onset of puberty in primates: An increase in pulsatile LHRH release occurs at the onset of puberty in female rhesus monkeys (1-3), and pulsatile infusion of LHRH into sexually immature monkeys with a pump induces precocious puberty (4). However, the mechanism by which LHRH release increases at puberty in primates is still unknown. The pubertal increase in LHRH release is probably not due to the developmental changes in properties of LHRH neurons themselves, since (i) the expression of LHRH mRNA is similar in monkeys during the prepubertal period and in adulthood (5) and (ii) prior to puberty, LHRH release can be induced by electrical stimulation of the medial basal hypothalamus (MBH) (2) or by neurochemical stimulation with N-methyl-D-aspartate (6). In fact, these studies further indicate that releasable LHRH is present in the hypothalamus of prepubertal monkeys but that the control mechanisms for pulsatile LHRH release are immature before the onset of puberty.The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.