Neurochemical Regulation of LC Neuron Firing

Immunohistochemical methods have shown that many neurotransmitters may contribute to the regulation of LC-NE neuron activity. Most of them are found in neurons of the two major LC afferents, the PGi and the PrH. These include epinephrine, excitatory amino acids, enkephalin, corticotropin releasing factor (CRF), substance P, serotonin (5-HT), and g-aminobutyric acid (GABA). Adrenergic innervation of the LC derives from the PGi and may mediate part of the postactivation inhibition in LC responses to footshocks. GABA innervation arises from the PrH, the PGi, and other nuclei. The LC receives a rich enkephalinergic innervation, a large percentage of which arises from the PGi and PrH, and LC neurons are particularly invested with m-opiate receptors. CRF innervation of the LC is noteworthy because the LC-NE system is sensitive to most stressors (see Section IV.C). CRF is presumed to play a crucial role in eliciting the coordinated set of endocrine, autonomic, and behavioral events that constitute the stress response. This peptide was initially characterized as the hypothalamic hormone inducing adrenocorticotropin release, but CRF is now considered as a neurotrans-mitter that, among others, stimulates the LC in response to hypotensive stress. CRF seems to originate from the PGi and the hypothalamus.

LC neurons also carry a2-adrenergic autoreceptors, allowing inhibitory feedback via recurrent collaterals. Intracellular studies have demonstrated that the stimulation of a2-adrenergic receptors inhibits firing by opening an inwardly rectifying potassium channel via a G-protein. The injection of clonidine, an a2-adrenergic agonist that suppresses LC neuron activity, is often used as a tool to characterize NE-LC neurons. These cells also contain many m-opiate receptors, whose similarly activation results in an inhibition of the firing by a mechanism identical to that of a2-adrenergic receptors. In particular, m-opiate and a2-adrenergic receptors share the same potassium channels.

Several inputs to the pericerulear region exert an excitatory influence on LC discharge, suggesting that these projections may be glutamatergic. Other transmitter receptors were identified on these distal den-drites, including CRF receptor, met-enkephalin, and m-opiate receptors.

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