Morphological substrates underlying opioid, epinephrine and gamma-aminobutyric acid inhibitory actions in the rat locus coeruleus

Abstract

The locus coeruleus (LC) has been implicated in attentional processes related to orienting behaviors, learning and memory, anxiety, stress, the sleep-wake cycle, and autonomic control, as well as to contributing to the affective state. Direct activation of LC neurons causes desynchronization of the electroencephalogram, suggesting that the LC is an important modulator of the behavioral state. The LC has been an intensely studied neuronal system, as the physiology and pharmacology of this nucleus is well understood. This is mainly because of the similarity in neurochemical composition of LC cells which all contain norepinephrine in the rat. However, the homogeneity in neurotransmitter content in LC neurons is sharply contrasted by the heterogeneity of neurochemicals found in its afferent processes. Among these are axon terminals that contain inhibitory and excitatory amino acids, monoamines, and neuropeptides, many of which have been shown to exert differential physiological effects on LC discharge activity. Although much attention has focused on physiological activation of LC neurons, substantial evidence indicates that diverse afferents prominently inhibit noradrenergic cellular activity. Such inhibitory neurochemicals, which arise from local and extrinsic sources, include gamma-aminobutyric acid (GABA) and epinephrine as well as the neuropeptides methionine5-enkephalin and leucine5-enkephalin. Inhibitory transmission in the LC has widespread implications for norepinephrine release at diverse postsynaptic targets, and clinically useful pharmacological agents such as clonidine, an alpha2 adrenergic receptor agonist that potently inhibits the firing of LC neurons, alleviate some negative physical symptoms observed following withdrawal from opiates. In the present review, the synaptic and functional organization of selected inhibitory-type neurotransmitters in the LC obtained from immunoelectron microscopic data will be discussed.