Hypoglycemia-lnduced Inhibition of LH and Stimulation of ACTH Secretion in the Rhesus Monkey is Blocked by Alprazolam

Abstract

Insulin-induced hypoglycemia inhibits luteinizing hormone (LH) secretion and has been used as a model to study stress-induced inhibition of reproductive function. Endogenous opioid peptides have been implicated in mediating the inhibitory effect of hypoglycemia on LH secretion in sheep and rat. The objective of the present study was to determine if corticotropin-releasing hormone (CRH) and endogenous opiates are involved in the LH response to hypoglycemia in the nonhuman primate. Blood samples were collected at 15-min intervals for 6 h from ovariectomized rhesus monkeys (n = 6). Hypoglycemia was induced by injecting insulin 1 h after initiating blood collection. Animals were pretreated 15 min prior to insulin with either saline (n = 6), naloxone, a nonselective opiate receptor antagonist (n = 4), or alprazolam (n = 6), a potent benzodiazepine which has been shown to inhibit CRH. The LH, glucose, adrenocorticotropin (ACTH), and cortisol responses to insulin were determined. Insulin-induced hypoglycemia significantly inhibited LH secretion and increased ACTH and cortisol concentrations. Alprazolam prevented hypoglycemia-induced inhibition of LH independent of an effect on glucose concentrations. The mean (±SEM) LH pulse interval in response to hypoglycemia was decreased in the alprazolam pretreated group compared to the saline pretreated group (77.4 ± 6.0 vs. 130.0 ± 18.4 min), while LH pulse amplitude and mean LH levels were significantly increased (56.2 ± 7.1 vs. 28.3 ± 5.5 ng/ml, and 105.6 ± 14.4 vs. 60.9 ± 12.1 ng/ml respectively). In contrast, naloxone did not prevent hypoglycemia-induced LH inhibition. The mean LH pulse interval, LH pulse amplitude, and LH concentration in the naloxone pretreated monkeys were 152.1 ± 33.4 min, 37.1 ± 8.9 ng/ml, and 63.7 ± 9.1 ng/ml respectively. Alprazolam pretreatment also markedly attenuated the ACTH response to hypoglycemia whereas the cortisol response was only moderately affected. We conclude that insulin-induced hypoglycemia in the monkey inhibits LH secretion through a mechanism involving CRH but not endogenous opiates.

Blockade of GABAA Receptors in the Ventromedial Hypothalamus Further Stimulates Glucagon and Sympathoadrenal but Not the Hypothalamo-Pituitary-Adrenal Response to Hypoglycemia

“…Taken systemically, the benzodiazepine can potentially activate GABAergic receptors in other sites within the central nervous system. More specifically, if activated, GABA receptors in the hypothalamic paraventricular nucleus, which is believed to be the locus for initiation of the stress response, can suppress hypothalmo-pituitary-adrenal (HPA) activity (35). Our findings suggest that GABAergic tone within the VMH may not play a crucial role in regulating the HPA response to hypoglycemia.…”

“…One stimulus in particular, glucoprivation, has been shown to alter GABA levels within the brain (31-33), but the evidence for its role in glucose counterregulation remains somewhat controversial. Alprazolam, a benzodiazepine analog, has been shown to reduce neuroendocrine and adrenomedullary responses to hypoglycemia in humans and primates (34,35). On the other hand, Modafinil, which is thought to lower brain GABA concentrations, has no significant effect on counterregulatory hormone release but does improve adrenergic sensitivity and some aspects of cognitive function during hypoglycemia (36).…”

Glucoreceptors Located Inside the Blood-Brain Barrier Mediate Hypoglycemia-Induced LH Inhibition in Man

“…Insulin-induced hypoglycemia is known to inhibit luteinizing hormone (LH) secretion in various animal species and in humans [1, 2, 3, 4, 5, 6, 7, 8]. Even though it has been hypothesized that during hypoglycemia insulin itself may have a neuromodulatory effect on LH secretion, recent experiments in men suggest that hypoglycemia, rather than insulin, is responsible for the inhibition of LH secretion by acting on hypothalamic glucoreceptors [8].…”

Increased GABAergic Tone in the Ventromedial Hypothalamus Contributes to Suppression of Counterregulatory Reponses After Antecedent Hypoglycemia

“…The evidence for the role of GABA in glucose counterregulation, however, remains somewhat controversial. Benzodiazepine analogs, which activate GABA receptors, have been shown to reduce neuroendocrine and adrenomedullary responses to hypoglycemia in humans and primates (29,30). On the other hand, modafinil, a compound that acts to lower brain GABA concentrations, has been ineffective at altering counterregulatory hormone release in healthy men (31).…”