l-760735 and 7-7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one

These experiments examined the role of substance P-selective neurokinin 1 receptors in the restraint-induced activation of the rat locus coeruleus. Immunohistochemistry revealed high levels of neurokinin 1 receptor expression in the plasma membrane of tyrosine hydroxylase-positive locus coeruleus neurons. The selective neurokinin 1 receptor antagonists, RP 67580 (5 nmol) and L-760,735 (3.4 nmol), were administered intracerebroventricularly prior to restraint stress, and c-fos protein was measured as an index of locus coeruleus activation. Both antagonists attenuated the restraint-induced increase in locus coeruleus c-fos expression, whereas their inactive enantiomers were ineffective. These results suggest that neurokinin 1 receptors may mediate activation of locus coeruleus neurons during stress. Neurokinin 1 receptor antagonists may prove to be novel therapeutic compounds in the treatment of anxiety and depression.

Topics: Animals; Cell Membrane; Immunohistochemistry; Indoles; Injections, Intraventricular; Isoindoles; Locus Coeruleus; Male; Morpholines; Neurokinin-1 Receptor Antagonists; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Restraint, Physical; Stress, Physiological; Tyrosine 3-Monooxygenase