Electrophysiologic studies support the hypothesis that corticotropin-releasing factor, the neurohormone that initiates adrenocorticotropin release during stress, also serves as a neurotransmitter in the pontine noradrenergic nucleus, the locus coeruleus. To elucidate the circuitry underlying proposed corticotropin-releasing factor neurotransmission in the locus coeruleus, the present study utilized immunohistochemical techniques to characterize corticotropin-releasing factor innervation of rat locus coeruleus and pericoerulear regions. Corticotropin-releasing factor-like immunoreactive fibers were identified in the locus coeruleus of colchicine- and non-colchicine-treated rats. However, corticotropin-releasing factor innervation of pericoerulear regions rostral and lateral to the locus coeruleus was more dense than that of the locus coeruleus proper. Double-labeling studies utilizing antisera directed against corticotropin-releasing factor and tyrosine hydroxylase indicated that corticotropin-releasing factor-like immunoreactive fibers overlap with tyrosine hydroxylase-like immunoreactive processes of locus coeruleus neurons, particularly in rostral medial and lateral regions. A group of corticotropin-releasing factor-like immunoreactive neurons was localized just lateral to the locus coeruleus and numerous corticotropin-releasing factor-like immunoreactive neurons were visualized just ventral to the rostral pole of the locus coeruleus in a region corresponding to Barrington's nucleus. None of these corticotropin-releasing factor-like immunoreactive neurons were tyrosine hydroxylase-positive. To determine the source of corticotropin-releasing factor-like immunoreactive fibers in the locus coeruleus, injections of the retrograde tracer [wheat germ agglutinin conjugated to inactivated (apo) horseradish peroxidase coupled to gold particles] were made into the locus coeruleus and sections were processed for corticotropin-releasing factor-like immunoreactivity. Locus coeruleus injections of the retrograde tracer labeled numerous neurons in the medullary nuclei, prepositus hypoglossi and paragigantocellularis, consistent with previous results. In prepositus hypoglossi, retrogradely labeled neurons were a distinct population from a prominent group of more laterally situated corticotropin-releasing factor-like immunoreactive neurons. In contrast to prepositus hypoglossi, approx. 8% of retrogradely labeled neurons in the paragigantocellularis were corticotropin-releasing factor-like immunoreactive, implicating the paragigantocellularis as a source of corticotropin-releasing factor-like immunoreactive fibers in locus coeruleus. In addition, occasional corticotropin-releasing factor-like immunoreactive neurons were visualized in the area of the dorsal cap of the paraventricular nucleus of the hypothalamus that were retrogradely labeled. The present study confirms findings of others describing corticotropin-releasing factor-like immunoreactive cells and fibers in brainstem and extends previous findings by demonstrating an overlap of corticotropin-releasing factor-like immunoreactive fibers with tyrosine hydroxylase-like immunoreactive processes in pericoerulear regions. Additionally, these findings implicate the paragigantocellularis as a potential source of corticotropin-releasing factor-like immunoreactivity in the locus coeruleus. The present study also provides anatomic support for electrophysiologic evidence of a neurotransmitter role for corticotropin-releasing factor in the rat locus coeruleus.
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