GABAERGIC INHIBITION OF THE PITUITARY RELEASE OF ADRENOCORTICOTROPIN AND ALPHA-MELANOTROPIN IS IMPAIRED IN DOGS WITH HEPATIC-ENCEPHALOPATHY

gamma-Aminobutyric acid (GABA) is the principal depressant neurotransm itter system, but its possible role in the regulation of the hypothala mic-pituitary-adrenocortical (HPA) axis has not yet been investigated in the dog. Moreover, GABA is one of the factors underlying the syndro me 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 d ogs and 10 dogs with HE due to congenital portosystemic shunts. The ef fect of an intravenous injection of the GABA antagonist bicuculline on the release of adrenocorticotropin (ACTH), alpha-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 re lease of MSH after bicuculline administration indicated that the effec t of GABA was predominantly in the neurointermediate lobe of the pitui tary. In order to investigate whether the effect of GABA was exerted i n the pituitary or at a suprapituitary level, the effect of incubation with GABA on basal and corticotropin-releasing hormone-induced ACTH r elease was measured in primary cultures of anterior and neurointermedi ate lobe cells from healthy dogs, and no response was observed. We con clude that in healthy dogs, GABA inhibits the release of ACTH and MSH from the neurointermediate lobe of the pituitary at a suprapituitary l evel. In dogs with HE, 1.0 mg/kg of bicuculline caused virtually no st imulation of the secretion of ACTH, MSH, or cortisol, indicating deran ged GABAergic neurotransmission in HE. This may be explained by an inc reased GABA tone that prevents the effect of the antagonist. Such a hi gh GABA tone associated with HE has been documented in several other s pecies. 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 hea lthy dogs (9 +/- 2 . 10(-6)). An increased basal HPA activity in dogs with HE is not in agreement with augmented GABAergic inhibition, but t his contradiction may be explained by the predominance of effects of d opaminergic disinhibition that has been reported in such dogs.