Effects of Antecedent GABA A Receptor Activation on Counterregulatory Responses to Exercise in Healthy Man

Abstract

The aim of this study was to determine whether antecedent stimulation of γ-aminobutyric acid (GABA) A receptors with the benzodiazepine alprazolam can blunt physiologic responses during next-day moderate (90 min) exercise in healthy man. Thirty-one healthy individuals (16 male/15 female aged 28 ± 1 year, BMI 23 ± 3 kg/m(2)) were studied during separate, 2-day protocols. Day 1 consisted of morning and afternoon 2-h hyperinsulinemic-euglycemic or hypoglycemic clamps with or without 1 mg alprazolam given 30 min before a clamp. Day 2 consisted of 90-min euglycemic cycling exercise at 50% VO2max. Despite similar euglycemia (5.3 ± 0.1 mmol/L) and insulinemia (46 ± 6 pmol/L) during day 2 exercise studies, GABA A activation with alprazolam during day 1 euglycemia resulted in significant blunting of plasma epinephrine, norepinephrine, glucagon, cortisol, and growth hormone responses. Lipolysis (glycerol, nonesterified fatty acids) and endogenous glucose production during exercise were also reduced, and glucose infusion rates were increased following prior euglycemia with alprazolam. Prior hypoglycemia with alprazolam resulted in further reduction of glucagon and cortisol responses during exercise. We conclude that prior activation of GABA A pathways can play a significant role in blunting key autonomous nervous system, neuroendocrine, and metabolic physiologic responses during next-day exercise in healthy man.

Trial registration: ClinicalTrials.gov NCT00574639.

Figure 1

Diagram of study procedures.

Figure 2

Plasma glucose (mean ± SE) levels during day 1 and day 2 studies and plasma insulin levels (mean ± SE) during day 2 studies. *P < 0.001 compared with prior eugly/eugly alprazolam, prior hypo/hypo control, and prior hypo/hypo alprazolam. eugly, euglycemia; hypo, hypoglycemia.

Figure 3

Day 2 epinephrine, norepinephrine, glucagon, and pancreatic polypeptide (PP) (change from baseline to final 15 min of day 2 clamps) in overnight-fasted healthy individuals following either day 1 euglycemia, day 1 euglycemia and alprazolam, day 1 hypoglycemia, or day 1 hypoglycemia and alprazolam. *P < 0.006–0.0001 compared with eugly/eugly control (no alprazolam); #P < 0.04 compared with eugly/eugly alprazolam; &P < 0.02 compared with hypo/hypo control (no alprazolam). eugly, euglycemia; hypo, hypoglycemia.

Figure 4

Day 2 growth hormone (GH), cortisol, lactate, NEFA, and glycerol levels (change from baseline to final 15 min of day 2 clamps) in overnight-fasted healthy individuals following either day 1 euglycemia, day 1 euglycemia and alprazolam, day 1 hypoglycemia, or day 1 hypoglycemia and alprazolam. *P < 0.02–0.0009 compared with prior eugly/eugly control (no alprazolam); #P < 0.05–0.006 compared with prior hypo/hypo control (no alprazolam). eugly, euglycemia; hypo, hypoglycemia.

Figure 5

Day 2 EGP, glucose infusion rate (GIR), and rate of glucose disposal (Rd) (final 15 min of day 2 clamps) in overnight-fasted healthy individuals following either day 1 euglycemia (eugly), day 1 eugly and alprazolam, day 1 hypoglycemia (hypo), or day 1 hypo and alprazolam. *P < 0.04–0.0001 compared with eugly/eugly control (no alprazolam).