MODULATION OF THE ACTIVITY OF CENTRAL SEROTONINERGIC NEURONS BY NOVEL SEROTONIN(1A) RECEPTOR AGONISTS AND ANTAGONISTS - A COMPARISON TO ADRENERGIC AND DOPAMINERGIC-NEURONS IN RATS

In this study, we used a complementary in vivo electrophysiological and (in individual rats) neurochemical approach to characterize the actions of chemically diverse serotonin (5HT)(1A) receptor ligands at central 5-HT1A autoreceptors as compared to dopamine (DA) D-2 autoreceptors and presynaptic alpha-2 adrenergic receptors (ARs). The novel, high efficacy, 5-HT1A agonists, WY 48,723 (an arylpiperazine), (+)-flesinoxan (a benzodioxane) and S 14671 and S 14506 (methoxynaphtylpiperazines) mimicked the aminotetralin, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), in inhibiting the firing of dorsal raphe nucleus (DRN) neurons. Similarly, the firing rate of DRN neurons was reduced by the ''partial'' agonists, MDL 73005EF, BMY 7378, NAN-190, tandospirone and the novel pyrimidinylpiperazine, zalospirone. Furthermore, S 14489, S 15535 and S 15931, novel benzodioxopiperazines, which behave as antagonists at postsynaptic 5-HT1A receptors, inhibited completely DRN firing, whereas the methoxyphenylpiperazine, WAY 100,135, and the aryloxoarylamine, (-)-tertatolol, were ineffective. Indeed, in analogy to spiperone, both WAY 100,135 and (-)-tertatolol behaved as apparently competitive antagonists in that, in their presence, the dose-response curves for inhibition of DRN firing by S 14671, S 14506 or 8-OH-DPAT were shifted in parallel to the right with no loss of maximal effect. In distinction to WAY 100,135 and (-)-tertatolol, a further novel, putative ''antagonist,'' SDZ 216-525 (a benzoisothiazo/piperazine) weakly inhibited the electrical activity of the DRN. With the exception of (-)-tertatolol, which behaved as a weak agonist, a very similar pattern of inhibition of 5-HT turnover was seen in the striatum (innervated by the DRN), the hippocampus and the hypothalamus (DRN and median raphe nucleus) and the spinal cord (nucleus raphe magnus), with the striatum displaying the greatest sensitivity. Drug potency for inhibition of firing and turnover was highly correlated (r = 0.80-0.82) and these actions were significantly correlated to affinity at (hippocampal) 5-HT1A receptors (r = 0.62-0.73). As concerns DA D-2 autoreceptors, the agonist action of apomorphine in reducing DA turnover were mimicked only by 8-OH-DPAT, whereas the majority of the other 5-HT1A ligands, in analogy to raclopride, enhanced DA turnover. The facilitation of DA turnover appeared to reflect direct blockade of DA D-2 autoreceptors because potency was correlated powerfully to affinity at these D-2 sites (r = 0.89). None of the 5-HT1A ligands mimicked the agonist action of clonidine at alpha-2 AR autoreceptors, whereas the turnover-enhancing actions of the alpha-2 AR antagonists, idazoxan and 1-(2-pyrimidinyl)piperazine, were mimicked by many 5-HT1A ligands. Their potency did not, however, correlate with their affinity at alpha-2 ARs (r = 0.13), probably because the alpha-2 AR antagonist actions of several ligands reflect their metabolism to 1-(2-pyrimidinyl)piperazine. In conclusion, in addition to their agonist or antagonist actions at central 5-HT1A autoreceptors, many 5-HT1A ligands display pronounced in vivo actions at presynaptic DA D-2 receptors and alpha-2 ARs. Nevertheless, several ligands, such as S 14671, (+)-flesinoxan, S 15535 and WAY 100,135, display marked selectivity for 5-HT1A autoreceptors and an evaluation of their potential therapeutic properties should prove of particular interest.