Noradrenergic postganglionic sympathetic innervation of the spleen in 8-month-old (adult) and 27-monthold (aged) Fischer 344 (F344) rats was examined using fluorescence histochemistry for catecholamines coupled with stereologic point-counting analysis for quantitation of noradrenergic varicosities. Noradrenergic varicosities in the spleen were evaluated in four compartments: (1) vascular-, (2) trabecular-, (3) capsular-, and (4) parenchymal-associated fibers. The 27month-old rats were subdivided further into two groups based upon behavioral testing for gustatory neophobia, a condition reported to be associated with acute locus coeruleus lesions in young rats and with diminished norepinephrine (NE) levels in central noradrenergic neurons in aged rats. In the 8-month-old rats, spleens displayed abundant innervation. Noradrenergic plexuses entered the spleen with the splenic artery and its branches, distributed into capsular and trabecular compartments, and followed the vasculature and trabeculae into splenic white pulp. Noradrenergic fibers entered the white pulp mainly in association with the central artery and its branches; liner and punctate varicosities branched mainly from vascular plexuses into the large, well-defined parenchyma of the white pulp, ending primarily among fields of T lymphocytes. Some fibers extended along the inner edge of the marginal zone and the parafollicular zone. Few noradrenergic varicosities were found in the red pulp. In both groups of aged rats, sympathetic noradrenergic innervation was diminished markedly. Noradrenergic varicosities associated with all compartments of the spleen were reduced in density and in overall intensity of fluorescence in 27month-old rats. The white pulp in 27-month-old rat spleen was diminished in size; its altered architecture made the boundaries of the white pulp difficult to delineate from red pulp, particularly with the absence of a robust periarteriolar lymphatic sheath (PALS) and markedly diminished innervation of the PALS. Morphometric analysis of 16-pm-thick sections of spleen provided quantitative evidence of this age-re-@ 1987 Alan R. Liss, Inc. lated decrease in noradrenergic innervation in all splenic compartments: vascular noradrenergic varicosities were diminished by 79.3%, trabecular noradrenergic varicosities were diminished by 68.5%, parenchymal noradrenergic varicosities were diminished by 64.9%, and capsular noradrenergic varicosities were diminished by 56.3%. No differences were observed in the severity of depletion of noradrenergic varicosities in the neophobic aged rats vs. the nonneophobic aged rats, suggesting that the age-related decline in noradrenergic innervation of the spleen is a generalized phenomenon that is not correlated with the state of central noradrenergic neurons. In view of the correlation between age-related decline in splenic noradrenergic innervation and age-related decline in immune functions related to T lymphocytes, and evidence from our laboratories in young adult rats that chemical sympathectomy of the spleen is followed by an 80% reduction in primary antibody responses to a T-dependent antigen challenge, we propose that a causal relationship may exist between diminished innervation and diminished immune function in aged rats.