Effects of Gamma-Aminobutyric Acid-A Receptor Antagonist Bicuculline, on the Electrical Activity of Luteinizing Hormone-Releasing Hormone Pulse Generator in the Ovariectomized Rat

Abstract

The role of GABA neurons in the control of pulsatile release of LHRH was investigated by checking the effect of the GABAa receptor agonist, muscimol, and antagonist, bicuculline, on the electrical activity of the luteinizing hormone-releasing hormone (LHRH) pulse generator in the ovariectomized rat fitted with chronically implanted electrode arrays in the medial basal hypothalamus. In untreated control animals, the hypothalamic multiunit activity (MUA) exhibited, at an average of 20.5-min intervals, characteristic increases (volleys), each of which was associated with the initiation of an LH pulse. A bolus i.v. injection of muscimol (2 mg/kg) significantly increased the interval between MUA volleys and LH pulses without affecting the pulse amplitude. Continuous i.v. infusion of saline increased the interval between MUA volleys to an average of 24.1 min without affecting the LH pulse amplitudes. Bicuculline infusion (10 mg/kg/h) altered neither the interval between MUA volleys nor the pulsatile release of LH. This was further checked in the condition where presynaptic inhibition by opioid peptides on the noradrenergic system was presumably decreased by naloxone. Naloxone infusion (0.5 or 0.7 mg/ kg/h) caused the MUA volleys to occur markedly frequently, an average of 13.8-min intervals. The interval during combined infusion of bicuculline with naloxone was an average of 16.2 min, suggesting that bicuculline could not decrease the interval that was set by naloxone. The results show that, although exogenous GABAa receptor agonist is capable of inhibiting the activity of LHRH pulse generator, the reduction in the endogenous GABAa receptor activity does not cause a significant effect, suggesting a minor role of inhibitory GABA neurons in the control of pulsatile release of LHRH. Further, together with the well-known fact that activation of GABAa receptor hyperpolarizes neurons postsynaptically, it is assumed that the GABAergic system, unlike the opioidergic one, is not involved in the presynaptic inhibition of the adrenergic receptor system which is probably implicated in the frequency control of LHRH pulse generator.

Role of Gamma-Aminobutyric Acid Neurons in the Release of Gonadotropin-Releasing Hormone in Cultured Rat Embryonic Olfactory Placodes

“…Infusion of 20 µ M GABA prolonged the interval and decreased the amplitude of GnRH pulses, resulting in a decrease in mean GnRH release. These GABA effects on pulsatile GnRH release are in good accordance with previous reports; a GABA or GABA A receptor system exerted an inhibitory influence on LH release in gonadectomized rats [35, 36, 37, 38, 39, 40, 41]and on GnRH release in rat hypothalamic fragments [42, 43, 44, 45], although some groups have reported a stimulatory influence instead [46, 47, 48, 49, 50, 51]. Together with morphological observations, the present results provide evidence that the inhibition of pulsatile LH release by GABA is caused by the direct action of GABA on GnRH neurons.…”

“…As noted above, it has been suggested that GABA inhibits GnRH release through the GABA A receptor system [42, 43, 44, 45]. But bicuculline did not affect the electrical activity of the GnRH pulse generator or the pulsatile LH release [40]. Therefore, we concluded that, although the GnRH pulse generator has a GABA A receptor system, this does not play a role in the generation of GnRH pulses.…”

“…This feature of a GnRH pulse generator located in the culture seems quite similar to that of the GnRH pulse generator in vivo [40]. As noted above, it has been suggested that GABA inhibits GnRH release through the GABA A receptor system [42, 43, 44, 45].…”

“…The latter GnRH neurons would not release GnRH in a pulsatile fashion because of the strong tonic inhibition by GABAergic inputs and, if deinhibited by bicuculline, could release a certain amount of GnRH into the medium. The GnRH pulses seen over the amount of GnRH released by bicuculline, therefore, reflect those produced by GnRH neurons involved in the pulse generator, because, as in the in vivo study [40], the frequency was not changed by bicuculline. An experiment to provoke more pronounced GnRH release than the present study is now in progress by priming the culture with estrogen.…”

Electrical Activity of the Pulse Generator of Gonadotropin-Releasing Hormone in 26-Month-Old Female Rats

“…We also tried to measure the response of the pulse generator to the opiate receptor antagonist naloxone, which is very effective in altering the activity in young rats [2, 20, 21, 22, 23]. …”