ACH, SUBSTANCE-P AND MET-ENKEPHALIN IN THE LOCUS COERULEUS - PHARMACOLOGICAL EVIDENCE FOR INDEPENDENT SITES OF ACTION

The purpose of the present study was to further characterize the nature of cholinergic, opioid and substance P receptors in the rat locus coeruleus (LC) and to determine the degree of specifity of their antagonists using microiontophoretic techniques. This pharmacological approach enabled us to also investigate whether the mode of action of substance P and enkephalin involved a specific modulation of cholinergic transmission in the CNS and whether substance P had any opioid agonist activity. Evidence that cholinergic transmission in the locus coeruleus is purely muscarinic was obtained by studying the potency of a series of cholinergic agonists and antagonists. Their selectivity was tested using glutamate as a control excitatory agent. The muscarinic antagonist scopolamine was found to block the response to ACh without modifying the excitation caused by glutamate or the inhibition due to GABA. Scopolamine did not modify either the excitation of locus coeruleus neurons by substance P or their inhibition by met-enkephalin thus demonstrating that these two neuractive peptides do not act in the locus coeruleus by modulating the release of ACh or by inteerfering with its postsynaptic activity. Naloxone, administered by iontophoresis, in very small amounts was found to be highly selective in antagonizing the action of met-enkephalin but neither altered the inhibition induced by GABA nor the excitation caused by substance P. These results taken together with the fact that substance P and met-enkephalin affect the firing of LC neurons in opposite directions indicate that SP has no opioid agonist or antagonist potency. Parachlorophenyl GABA (baclofen) antagonized the responses of LC neurons to all excitatory neurotransmitters (ACh, Glu, and SP) and thus can not be considered as a specific SP antagonist. In conclusion, these experiments demonstrate that ACh, met-enkephalin, and SP act upon pharmacologically distinct receptors within the LC. © 1979.