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Excitation of noradrenergic cell firing by 5-hydroxytryptamine1A agonists correlates with dopamine antagonist properties

MF Piercey, MW Smith and JT Lum-Ragan

Upjohn Company, Kalamazoo, Michigan.

The 5-HT1A receptor agonists buspirone, 8-hydroxy-N,N-dipropyl-2- aminotetralin, gepirone and ipsapirone were evaluated for their receptor binding profiles and their effects on firing rates of 5-HT, dopamine (DA) and noradrenaline (NA) neurons in the dorsal raphe, substantia nigra pars compacta and the locus ceruleus, respectively. All agents bound to 5-HT1A receptors with high affinities. All agents also bound to dopamine D2 receptors but, with the exception of buspirone, affinities were usually much lower than for 5-HT1A receptors. All agents depressed 5-HT neurons, with 8-hydroxy-N,N- dipropyl-2-aminotetralin having a potency about 8 to 12 times those for the other three. All agents also antagonized the inhibition of DA neurons by amphetamine, an index of DA antagonist properties. Buspirone reversed amphetamine's effects with doses similar to those for depressing 5-HT neurons, but the remaining three required much higher doses to affect DA neuron function. All four 5-HT1A agonists excited NA neurons. In each case, doses required for excitation of NA cells were similar to those reversing amphetamine's effects on DA cells, but not to those for depressing 5-HT cells. Haloperidol also stimulated NA cells. It is concluded that excitation of NA neurons by 5-HT1A agonists may be due to interactions with dopaminergic, rather than serotonergic, receptors.

Volume 268, Issue 3, pp. 1297-1303, 03/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1994 by the American Society for Pharmacology and Experimental Therapeutics.