Pergamon Brain Research Bulletin, Vol. 35, Nos. 5/6, pp. 423-432, 1994 Copyright 0 1994 Else&r Science Ltd Printed in the USA. All rights reserved 0361-9230/94 $6.00 + .OO 0361-9230(94)00140-S Cotransmitter-mediated Locus Coeruleus Action on Motoneurons zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQ S. J. FUNG,’ J. Y. H. CHANT D. MANZONI: S. R. WHITE, Y.-Y. LAI,4 H. K. STRAHLENDORF, H. ZHU0,6 R.-H. LIU,7 V. K. REDDY AND C. D. BARNES Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, WA 99x63-6520 FUNG, S. J., J. Y. H. CHAN, D. MANZONI, S. R. WHITE, Y.-Y. LAI, H. K. STRAHLENDORF, H. ZHUO, R.-H. LIU, V. K. REDDY AND C. D. BARNES. Cotransmitter-mediat locus coeruleus action on moroneurons. BRAIN RES BULL 35(5/6) 423-432, 1994.-This article reviews evidence for a direct noradrenergic projection from the dorsolateral pontine tegmentum (DLPT) to spinal motoneurons. The existence of this direct pathway was first inferred by the observation that antidromically evoked responses occur in single cells in the locus coeruleus (LC), a region within the DLPT, following electrical stimulation of the ventral horn of the lumbar spinal cord of the cat. We subsequently confirmed that there is a direct noradrenergic pathway from the LC and adjacent regions of the DLm to the lumbar ventral horn using anatomical studies that combined retrograde tracing with immunohistochemical identification of neurotmnsmitters. These anatomical studies further revealed that many of the norad- renergic neurons in the LC and adjacent regions of the DLPT of the cat that send projections to the spinal cord ventral horn also contain colocalized glutamate (Glu) or enkephalin (ENK). Recent studies from our laboratory suggest that Glu and ENK may function as cotransmitters with norepinephrine (NE) in the descending pathway from the DLPT. Electrical stimulation of the LC evokes a depolarizing response in spinal motoneurons that is only partially blocked by (I, adrenergic antagonists. In addition, NE mimicks only the slowly developing and not the fast component of LC-evoked depolarization. Furthermore, the depolarization evoked by LC stimulation is accompanied by a decrease in membrane resistance, whereas that evoked by NE is accompanied by an increased resistance. That Glu may be a second neurotransmitter involved in LC excitation of motoneurons is supported by our observation that the excitatory response evoked in spinal cord ventral roots by electrical stimulation of the LC is attenuated by a non-N-methyl-o-aspartate glutamatergic antagonist. ENK may participate as a cotransmitter with NE to mediate LC effects on lumbar monosynaptic reflex (MSR) amplitude. Electrical stimulation of the LC has a biphasic effect on MSR amplitude, facilitation followed by inhibition. Adrenergic antagonists block only the facilitatory effect of LC stimulation on MSR amplitude, whereas the ENK antagonist naloxone reverses the inhibition. The chemical heterogeneity of the cat DLPT system and the differential responses of motoneurons to the individual cotransmitters help to explain the diversity of postsynaptic potentials that occur following LC stimuli. Cotransmitter Norepinephrine Enkephalin Glutamate Locus coeruleus Spinal cord Motoneuron Iontophoresis Retrograde labeling Immunohistochemistry THE locus coeruleus (LC) has long been thought to be princi- pally a noradrenergic nucleus. However, recent data from our laboratory and from other investigators indicate that noradren- ergic neurons in the LC and adjacent regions of the dorsolateral pontine tegmentum (DLPT) frequently contain other colocalized neurochemicals that are putative neurotmnsmitters. This review summarizes evidence for neurochemical colocalization in coe- ruleospinal neurons with special emphasis on colocalization in the cat DLPT of norepinephrine (NE), the peptide enkephalin (ENK), and the excitatory amino acid glutamate (Glu). Physio- logical and pharmacological studies that address the question of whether LC effects on spinal motoneurons may be mediated by the release of colocalized Glu or ENK in addition to NE are also summarized. The results of these experiments lead us to postulate that LC effects on target neurons in the spinal cord are mediated by a multiple neurotransmitter system. DESCENDING NORADRENERGIC NEURONS IN THE DORSOLATERAL WNTINE TEGMENTUM (DLF’T) Pioneering histofluorescence studies (13) demonstrated that the ventral gray columns of the spinal cord are enriched with catecholaminergic nerve terminals in several mammalian species including the cat and rat. These catecholaminergic terminals are I To whom requests for reprints should be addressed. * Present address: Veterans General Hosp., VACRS, Taipei, Taiwan 112, Republic of China. ’ Present address: Dept. Fisiol. e B&him.. Univ. di Pisa, Via S Zeno 31. 56100 Pisa. Italv. 4 Present address: Dept. Psychiat., Neurobiol. Res., 15 lA3, VA Med. Ctr., Sepulveda, CA91343. ’ Present address: Dept. Neurosci., Texas Tech. Univ. Hltb. Sci. Ctr., Lubbock, TX 79430. 6 Present address: Dept. Phannacol., Uniformed Services Univ. Hlth. Sci., Bethesda, MD 20814. ’ Present address: Dept. Physiol., UCLA, Los Angeles, CA 90024. 423