Brain Research, 296 (1984) 4%65 49 Elsevier Brain Epinephrine Systems: Detailed Comparison of Adrenergic and Noradrenergic Metabolism, Receptor Number and in vitro Regulation, in Two Inbred Rat Strains GUIDO VANTINI, BRUCE D. PERRY, RAS B. GUCHHAIT, DAVID C. U'PRICHARD* and JON M. STOLK Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 2122& and Departments of Pharmacology, Neurobiology and Physiology, Northwestern University, Chicago, IL 60611 and Evanston, IL 60201 (U.S.A.) (Accepted July 26th, 1983) Key words: epinephrine - - norepinephrine - - phenylethanolamine N-methyltransferase - - tyrosine hydroxylase - - catecholamine turnover - - a-adrenergic receptors - - receptor regulation - - inbred rat strains Epinephrine content and PNMT activity in medulla pons and hypothalamus of F344 inbred rats is from 3- to 8-fold higher than that of Bur inbred rats. These strain-dependent differences in brain adrenergic neurons are reciprocally related to altered a 1- and a2-adren- ergic receptor density in PNMT-containing brain regions. Radioligand binding indices related to a2-receptor function reveal that re- ceptors may be 'desensitized' as well as 'down-regulated' in the strain with high PNMT activity (F344), and may be 'supersensitive' as well as 'up-regulated' in the strain with low PNMT activity (Buf). The association between epinephrine-containing neurons and a-adrenergic receptor regulation appears specific, since a-adrenergic receptor density and regulation in brain regions devoid of PNMT and epinephrine is similar in F344 and Buf rats. While noradrenergic metabolism in F344 rats is greater than that in Buf rats, this difference is generalized throughout the brain and, thus, bears no apparent relationship to the localized alterations in a-adrenergic receptor density. Moreover, fl-adrenergic receptor density in the 2 strains is similar in all brain regions. These data suggest that a sig- nificant proportion of a-adrenergic receptors in medulla-pons and hypothalamus are intimately related to and regulated by epineph- rine-containing nerve endings. INTRODUCTION The potential functional role of brain adrenergic neurons, suggested by some of the earliest research on brain catecholamines18,53, has derived recent im- petus from the development of specific and sensitive procedures for their neuroanatomical localiza- tion z122, and measurement of brain epinephrine con- tent 2s and phenylethanolamine N-methyltransferase activity (PNMT)29,32. 41. Neurons containing PNMT immunoreactivity arise in the C1 and C z areas of the medulla obiongata and distribute to specific local brainstem nuclei (e.g. nucleus tractus solitarius, mo- tor nucleus of the vagus nerve, locus coeruleus), in addition to caudal spinal cord and rostral mesence- phalic and diencephalic projections22. Both gross and fine distribution of PNMT activity and epinephrine parallel the distribution of PNMT-immunoreactive neurons 29,41, providing clear evidence for the exist- ence of discrete epinephrine-containing pathways in rat brain. We recently reported initial evidence supporting prominent differences in brainstem PNMT activity and epinephrine content between two inbred rat strains; one strain, F344, had over 3-fold higher PNMT activity than the Buf strain 33. Differences in epinephrine content between the two strains were as- sociated with reciprocal alterations in a-adrenergic binding sites, but only in brain regions containing measurable PNMT activity33. Previous reports have employed the same two inbred rat strains for bio- chemical and behavioral studies. In addition to the differences in adrenergic measures, F344 and Bur rats differ with respect to mid-brain and striatal tyro- sine hydr0xylase and spontaneous motor behavior45, alterations in motor activity in response to intracere- broventricular norepinephrine44, norepinephrine- stimulated cyclic AMP accumulation 46, stimulant-in- * Current address: Nova Pharmaceutical Co., Box 21204, Baltimore, MD 21228, U.S.A. Correspondence: Neuroscience Program, Maryland Psychiatric Research Center, Box 3235, Baltimore, MD 21228, U.S.A. 0006-8993/84/$03.00 © 1984 Elsevier Science Publishers B,V.