Assessment of the functional role of brain adrenergic neurons: chronic effects of phenylethanolamine N-methyltransferase inhibitors and alpha adrenergic receptor antagonists on brain norepinephrine metabolism.

The potential role of brain adrenergic neurons in regulating noradrenergic neuronal metabolism was assessed using inhibitors of phenylethanolamine N-methyltransferase (PNMT), the enzyme responsible for epinephrine production. Two centrally active PNMT inhibitors (SK&F 64139 and LY134046) were administered over a 6-day treatment period to cause prolonged reductions in epinephrine formation. In brain regions containing endogenous epinephrine (medulla-pons and hypothalamus), chronic treatment with PNMT inhibitors produced: 1) reductions of epinephrine content, 2) elevation of tyrosine hydroxylase activity and 3) elevation of alpha-1 and particularly alpha-2 adrenergic receptor radioligand binding sites; neither norepinephrine turnover nor beta adrenergic receptor binding was affected. In brain regions devoid of endogenous epinephrine (cerebellum, frontal cortex and hippocampus), chronic treatment with PNMT inhibitors produced 1) a variable increase in tyrosine hydroxylase activity (cerebellum only) and 2) a reduction in norepinephrine turnover; neither alpha or beta adrenergic receptor binding was altered. A PNMT inhibitor failing to cross the blood-brain barrier, SK&F 29661, and an alpha-1 adrenoceptor antagonist, prazosin, had no effect on brain catecholamine metabolism. High doses of an alpha-2 adrenoceptor antagonist, yohimbine, increased medulla-pons tyrosine hydroxylase activity but also resulted in prominent reductions in norepinephrine content in all brain regions. The results suggest that prolonged reductions in endogenous brain epinephrine formation produce unique effects on brain norepinephrine function; these effects are regionally distinctive and are qualitatively different from the effects seen with chronic alpha-1 or alpha-2 adrenergic receptor blockade. These data are consistent with regulation of brainstem norepinephrine-containing cell bodies by endogenous adrenergic systems, probably via medullary-pontine alpha-2 adrenergic receptors.