NEUROCHEMICAL, ELECTROPHYSIOLOGICAL AND IMMUNOCYTOCHEMICAL EVIDENCE FOR A NORADRENERGIC LINK BETWEEN THE SYMPATHETIC NERVOUS-SYSTEM AND THYMOCYTES

The object of these experiments was to investigate whether noradrenali ne is the signal neurotransmitter between the sympathetic nervous syst em and rat thymocytes. Using immunocytochemistry, evidence was obtaine d that the rat thymus (thymic capsule, subcapsular region and connecti ve tissue septa) is innervated by noradrenergic varicose axons termina ls (tyrosine hydroxylase- and dopamine-beta-hydroxylase-immunostained nerve fibres). This innervation is mainly associated with the vasculat ure and separately from vessels along the thymic tissue septa it branc hes into the thymic parenchyma. Using electron microscopy, classical s ynapses between thymocytes and neuronal elements were not observed. Th e neurochemical study revealed that these nerve terminals are able to take up, store and release noradrenaline upon axonal stimulation in a [Ca2+](o)-dependent manner. The release was tetrodotoxin (1 mu M)-sens itive, and reserpine pretreatment prevented axonal stimulation to rele ase noradrenaline, indicating vesicular origin of noradrenaline. In ad dition, it was found that the release of noradrenaline was subjected t o negative feedback modulation via presynaptic alpha(2)-adrenoreceptor s. Using a patch-clamp technique, electrophysiological evidence was ob tained showing that noradrenaline inhibits in a concentration-dependen t manner outward voltage-dependent potassium (K+) currents recorded fr om isolated thymocytes. Since noradrenergic varicose axon terminals en ter the parenchyma among thymocytes and the boutons are not in close a pposition to their target cells, noradrenaline released from these ter minals diffuses away from release site to reach its targets, thymocyte s, and to exert its inhibitory effect on voltage-dependent K+-current. Since K+ channels are believed to be involved in T cell proliferation and differentiation, the modulation of K+ channel gating by noradrena line released in response to axonal activity suggests that noradrenali ne may play an important role in the fine tuning of thymocyte responsi veness to regulatory signals from blood-born or locally released hormo nes and cytokines. In this respect, noradrenaline released from non-sy naptic neuronal varicosities and exerting its effect within the radius of diffusion may serve as a chemical link between the sympathetic ner vous system and thymocytes and may have physiological and pathological importance in the thymus during stress and inflammatory/immune respon ses.