Evidence for GABAergic inhibition of a hypothalamic sympathoexcitatory mechanism in anesthetized rats.

The hypothesis that endogenous gamma-aminobutyric acid (GABA) suppresses the activity of a latent hypothalamic sympathoexcitatory mechanism was tested by examining the effects of stereotaxic intrahypothalamic microinjection of drugs influencing GABAergic inhibition in anesthetized rats. Bicuculline methiodide (BMI) 1-25 ng, a competitive antagonist at post-synaptic GABA receptors, as well as isoniazid (INH) 35 and 70 micrograms and 3-mercaptopropionic acid (3MP) 0.02 microliter, inhibitors of GABA synthesis, all evoked marked increases in heart rate and modest pressor responses. However, while the effects of BMI appeared almost immediately and peaked within 10 min of injection, changes caused by INH or 3MP developed much more slowly, attaining a maximum 35-40 and 19 min after injection, respectively. The effects of BMI on heart rate were blocked by pretreatment with propranolol 2 mg/kg i.v. or hexamethonium 20 mg/kg i.v. plus atropine 2 mg/kg i.v. and were shown to be highly localized to the posterior hypothalamic nucleus and the adjacent lateral hypothalamus. In addition to the cardiovascular effects, BMI also elicited dose-related increases in respiratory rate which were independent of the heart rate changes although they followed a similar time course. The results support the notion that hypothalamic GABA inhibits a local mechanism capable of generating cardiorespiratory arousal.