Serotonin 1A receptor ligands act on norepinephrine neuron firing through excitatory amino acid and GABAA receptors: A microiontophoretic study in the rat locus coeruleus

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Abstract
It was previously shown that the excitatory effect of the 5-HT1A agonist 8-OH-DPAT on firing activity of locus coeruleus (LC) norepinephrine (NE) neurons and the inhibitory action of the 5-HT1A antagonist WAY 100,635 are dependent on the presence of 5-HT neurons, whereas the inhibitory action of the 5-HT2 agonist DOI is not. Using in vivo extracellular unitary recordings performed in anesthetized rats, iontophoretic applications of the excitatory amino acid antagonist kynurenate attenuated the enhancement in firing produced by glutamate and kainate. In contrast, GABA applications decreased the firing activity of NE neurons which was attenuated by the enhancement produced by glutamate and kainate. In contrast, GABA applications decreased the firing activity of NE neurons which was attenuated by the GABAA receptor antagonist bicuculline. 8-OH-DPAT (10–60 μg kg−1, i.v.) produced a dose-dependent enhancement in the firing activity of NE neurons that was abolished in the presence of kynurenate application. The selective 5-HT1A receptor antagonist WAY 100,635 (100 μg kg−1, i.v.) suppressed NE firing which was reversed by the selective 5-HT2A antagonist MDL 100,907 (200 μg kg−1, i.v.). In the presence of bicuculline, the inhibitory effect of WAY 100,635 was blunted. These results suggest that WAY 100,635 mainly attenuates NE neuron firing by blocking inhibitory 5-HT1A receptors on glutamatergic neurons, thereby enhancing glutamate release and activating excitatory amino acid receptors, possibly of the kainate subtype, on 5-HT terminals. The ensuing increased 5-HT release would then act on excitatory 5-HT2A receptors on GABA neurons that would ultimately mediate the inhibition of NE neurons. The prevention of the excitatory action of 8-OH-DPAT on NE neuron firing by kynurenate is also consistent with this neurocircuitry. Synapse 42:203–212, 2001.

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