Cholinergic and GABAergic mediations of the effects of apomorphine on serotonin neurons

Apomorphine (APO) has been shown to elevate tryptophan, serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the dorsal raphe (DR) and its corresponding projection site, the striatum, but not in the median raphe (MR) and its terminal area, the hippocampus. We have previously demonstrated that these effects are indirectly mediated through dopamine (DA) autoreceptors in the substantia nigra and possibly gamma-aminobutyric acid (GABA) neurons in or near the DR. In the present study, we have further found that the effects of APO on 5-HT neurons are also mediated through both nicotinic and M1 muscarinic cholinergic receptors as well as GABAA receptors in the DR. This suggestion is based on the findings that both atropine and mecamylamine antagonized the effects of APO, while carbachol at a high dose exerted an effect opposite to that of APO. Besides, pirenzepine and bicuculline at low doses also antagonized, whereas saclofen did not alter the influence of APO on 5-HT in the striatum. Bicuculline at a higher dose enhanced tryptophan and 5-HT measures by itself. None of the drugs studied had a significant effect on tryptophan, 5-HT, or 5-HIAA in the hippocampus. These results together suggest that DA, ACh, and GABA neurons are all involved in the actions of APO on 5-HT, while the direct synaptic relationships among these neurotransmitters and the precise anatomical locus for these interactions to occur are still unknown. It is possible that APO, by inhibiting DA neuron firing in the substantia nigra and through the GABA disinhibition mechanism, therefore indirectly activates 5-HT neurons in the DR and the striatum. While the above neuronal firing model well explains the elevation of 5-HIAA, the simultaneous increases of tryptophan and 5-HT, especially tryptophan, may be more readily explained by a mechanism of tryptophan uptake upon APO administration. Further anatomical, biochemical, and electrophysiological studies are ongoing to test this hypothesis and to clarify the circuit and the anatomical locus (loci) for these interactions to occur.