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

In this study, we used a complementary in vivo electrophysiological an d (in individual rats) neurochemical approach to characterize the acti ons of chemically diverse serotonin (5HT)(1A) receptor ligands at cent ral 5-HT1A autoreceptors as compared to dopamine (DA) D-2 autoreceptor s and presynaptic alpha-2 adrenergic receptors (ARs). The novel, high efficacy, 5-HT1A agonists, WY 48,723 (an arylpiperazine), (+)-flesinox an (a benzodioxane) and S 14671 and S 14506 (methoxynaphtylpiperazines ) mimicked the aminotetralin, 8-hydroxy-2-(di-n-propylamino)tetralin h ydrobromide (8-OH-DPAT), in inhibiting the firing of dorsal raphe nucl eus (DRN) neurons. Similarly, the firing rate of DRN neurons was reduc ed by the ''partial'' agonists, MDL 73005EF, BMY 7378, NAN-190, tandos pirone and the novel pyrimidinylpiperazine, zalospirone. Furthermore, S 14489, S 15535 and S 15931, novel benzodioxopiperazines, which behav e as antagonists at postsynaptic 5-HT1A receptors, inhibited completel y DRN firing, whereas the methoxyphenylpiperazine, WAY 100,135, and th e aryloxoarylamine, (-)-tertatolol, were ineffective. Indeed, in analo gy to spiperone, both WAY 100,135 and (-)-tertatolol behaved as appare ntly competitive antagonists in that, in their presence, the dose-resp onse curves for inhibition of DRN firing by S 14671, S 14506 or 8-OH-D PAT were shifted in parallel to the right with no loss of maximal effe ct. In distinction to WAY 100,135 and (-)-tertatolol, a further novel, putative ''antagonist,'' SDZ 216-525 (a benzoisothiazo/piperazine) we akly inhibited the electrical activity of the DRN. With the exception of (-)-tertatolol, which behaved as a weak agonist, a very similar pat tern of inhibition of 5-HT turnover was seen in the striatum (innervat ed by the DRN), the hippocampus and the hypothalamus (DRN and median r aphe nucleus) and the spinal cord (nucleus raphe magnus), with the str iatum displaying the greatest sensitivity. Drug potency for inhibition of firing and turnover was highly correlated (r = 0.80-0.82) and thes e 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 o nly by 8-OH-DPAT, whereas the majority of the other 5-HT1A ligands, in analogy to raclopride, enhanced DA turnover. The facilitation of DA t urnover appeared to reflect direct blockade of DA D-2 autoreceptors be cause 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 no t, however, correlate with their affinity at alpha-2 ARs (r = 0.13), p robably because the alpha-2 AR antagonist actions of several ligands r eflect 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, di splay marked selectivity for 5-HT1A autoreceptors and an evaluation of their potential therapeutic properties should prove of particular int erest.