Effects of increase of brain GABA levels on the hypothalamic-pituitary-luteinizing hormone axis in rats

We recently determined that castration specifically decreased GABA turnover in discrete rostral and mediobasal hypothalamic structures. This study aimed to investigate whether testosterone could stimulate GABAergic neuronal activity in these hypothalamic GABAergic neurons in the castrate rat, and to compare the effects of episodic testosterone replacement with the constant levels provided by subcutaneous testosterone implants. Animals were divided into 4 experimental groups: intact, 48 h castrate, 48 h castrate + testosterone capsules (2 × 30 mm Silastic implants, 1.57 mm ID, 3.18 mm OD) and 48 h castrate + testosterone injections (100 µg/injection s.c, every 8 h). GABA concentrations were measured in 4 microdissected brain regions either before or 60 min after inhibition of the GABA degrading enzyme, GABA transaminase, by injection of aminooxyacetic acid (AOAA, 100 mg/kg i.p.). The rate of GABA accumulation in the tissue following injection of AOAA was used as an index of GABAergic neuronal activity. Castration resulted in a 10-fold increase in serum LH concentrations compared with intact rats. Either mode of testosterone administration completely prevented this castration-induced LH rise. In the diagonal band of Broca at the level of the organum vasculosum of the lamina terminalis, the medial preoptic nucleus and in the median eminence, GABA turnover was significantly reduced by castration to approximately 50% that of intact rats. Either testosterone implants or testosterone injections prevented this castration-induced decrease in GABA turnover, such that the turnover rates were not significantly different from intact rats. There was no effect of castration with or without testosterone replacement in the cingulate cortex. This study demonstrates that castration causes selective decreases in GABAergic neuronal activity in the preoptic area and in the ME, and that the replacement of testosterone after castration prevents the decrease in GABA turnover in these regions. These results suggest that under normal physiological conditions, GABAergic neurons terminating in the DBB(ovlt), MPN and ME are positively regulated by testosterone.

Section: Discussionsupporting

confidence: 71%

Castration-Induced Decrease in the Activity of Medial Preoptic and Tuberoinfundibular GABAergic Neurons Is Prevented by Testosterone

Grattan

Selmanoff²

1994

“…Estrogen has been shown not only to increase the release [26] and turnover [27] of GABA in the rat hypothalamus, but also to increase receptor levels of this .inhibitory neurotransmitter [28]. The finding that GABA inhibits LH secretion [29,30] and GABA tur nover rate is correlated with estradiol levels in the rat led Wuttke and co-workers [27] to hypothesize that GABA mediates the negative feedback action of estradiol on go nadotropin secretion. This functional relationship is in accord with the anatomical data describing both es tradiol-receptive GABAergic neurons in the hypothala mus [31 ] and the comingling of GABAergic neurons with GnRH-containing cells [32].…”

Section: Discussionmentioning

confidence: 99%

Hypoglycemic ‘Stress’ and Gonadotropin-Releasing Hormone Pulse Generator Activity in the Rhesus Monkey: Role of the Ovary

Chen¹,

O’Byrne²,

Chiappini³

et al. 1992

148

101

Observations of long standing have suggested that the ‘stress’ of chair restraint inhibits the GnRH pulse generator in normal female monkeys while this phenomenon is rarely observed in ovariectomized animals. The role of the ovary in the response of the GnRH pulse generator to the stress of insulin hypoglycemia was investigated in both intact and ovariectomized rhesus monkeys. Following an overnight fast the animals, previously habituated to restraint, were placed in primate chairs and GnRH pulse generator activity monitored electrophysiologically. Insulin-induced reductions in mean blood glucose concentrations of 10-40% of control values interrupted pulse generator activity in intact monkeys but were without effect in ovariectomized animals. With larger reductions in blood glucose, pulse generator activity was interrupted in both groups but the inhibition was twice as long in intact than in ovariectomized animals. The reduced responsiveness of ovariectomized animals to insulin hypoglycemia was significantly reversed by estradiol replacement. Naloxone administration did not prevent the hypoglycemia-induced inhibition of pulse generator activity in either intact or ovariectomized rhesus monkeys. It is concluded that hypoglycemic ‘stress’ inhibits the GnRH pulse generator by a nonopioidergic mechanism and that ovarian products, most probably estradiol, exacerbate this effect.

“…This suggests that the GABAergic inhibition of pul satile LH secretion [1,2] is partially mediated by GABAb receptors, in addition to a mediation by classic GABAa receptors [4,5], although the relative contribution of these receptors is unknown at present. The GABAb re ceptor-mediated suppression of the LH pulse frequency may have a causal relationship to the baclofen-induced inhibition of the preovulatory LH surge [8,10], as dis cussed elsewhere [8].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that y-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the central nervous system, is involved in the neuroendocrine control of the episodic LH secretion. The existing pulsatile LH secre tion is inhibited by reducing the degradation of the en dogenous GABA [1] Receptors mediating the GABAergic transmission have been classified into two major subtypes, GABAa and GABAb, according to their pharmacological proper ties. Since muscimol, a selective GABAa receptor ago nist, inhibits the existing pulsatile LH secretion in ovari ectomized rats [4,5], the GABAergic inhibition of LH pulses seems to be mediated in part by GABAa receptors.…”

mentioning

confidence: 99%

Modulation of Pulsatile LH Secretion by Baclofen, a Selective GABA<sub>B</sub> Receptor Agonist, in Ovariectomized Rats

Akema

Kimura

1992

The effect of activation of central γ-aminobutyric acid β (GABAB) receptors on pulsatile luteinizing hormone (LH) secretion was examined in unanesthetized ovariectomized rats. Intraventricular injections of 2 or 10 µg baclofen, a selective GABAB receptor agonist, usually arrested the existing pulsatile LH secretion for a short period, then LH pulses resumed with reduced frequencies and increased amplitudes. The increase in the pulse amplitude was not necessarily accompanied by a reduction in the pulse frequency, but was observed even after nonelongated interpulse intervals in animals receiving the GABA agonist. Mean LH levels showed complex bi- and triphasic fluctuations after the central administration of high and low doses of baclofen, respectively. It was concluded that central GABAB receptors are involved in the modulatory mechanism affecting the LH pulse frequency and amplitude in the ovariectomized rat.