Gabaergic inhibition of the pituitary release of adrenocorticotropin and α-melanotropin is impaired in dogs with hepatic encephalopathy

Abstract

γ-Aminobutyric acid (GABA) is the principal depressant neurotransmitter system, but its possible role in the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis has not yet been investigated in the dog. Moreover, GABA is one of the factors underlying the syndrome of hepatic encephalopathy (HE), and in dogs with HE, the regulation of the HPA axis is deranged. We have therefore investigated the role of the GABA system in the regulation of the HPC system in 10 healthy dogs and 10 dogs with HE due to congenital portosystemic shunts. The effect of an intravenous injection of the GABA antagonist bicuculline on the release of adrenocorticotropin (ACTH), α-melanotropin (MSH), and cortisol was measured in plasma. In healthy dogs, a dose of 1.0 mg/kg caused a marked release of ACTH, MSH, and cortisol, but doses of 0.001 to 0.5 mg/kg produced an inconsistent or no response. The high release of MSH after bicuculline administration indicated that the effect of GABA was predominantly in the neurointermediate lobe of the pituitary. In order to investigate whether the effect of GABA was exerted in the pituitary or at a suprapituitary level, the effect of incubation with GABA on basal and corticotropin-releasing hormone-induced ACTH release was measured in primary cultures of anterior and neurointermediate lobe cells from healthy dogs, and no response was observed. We conclude that in healthy dogs, GABA inhibits the release of ACTH and MSH from the neurointermediate lobe of the pituitary at a suprapituitary level. In dogs with HE, 1.0 mg/kg of bicuculline caused virtually no stimulation of the secretion of ACTH, MSH, or cortisol, indicating deranged GABAergic neurotransmission in HE. This may be explained by an increased GABA tone that prevents the effect of the antagonist. Such a high GABA tone associated with HE has been documented in several other species. Dogs with HE had significantly increased basal levels of ACTH, MSH, and cortisol in plasma, and their cortisol:creatinine ratios in 24-hr urine samples (63 ± 14 · 10 −6 were higher than those of healthy dogs (9 ± 2 · 10 −6). An increased basal HPA activity in dogs with HE is not in agreement with augmented GABAergic inhibition, but this contradiction may be explained by the predominance of effects of dopaminergic disinhibition that has been reported in such dogs.