Noradrenergic median modulation of serotonin release in rat dorsal and raphe nuclei via alpha(1) and alpha(2) adrenoceptors

The rat rostral raphe nuclei receive catecholaminergic innervation from the locus coeruleus and other areas. In the present study, we investigated nor adrenergic modulation of 5-HT release in rat dorsal and median raphe nuclei (DRN and MRN) slices (350 mum thick) superfused with artificial cerebrospi nal fluid (aCSF). The raphe was locally stimulated (0.1 ms pulses, 10 mA) a nd 5-HT release was monitored at carbon fibre microelectrodes using fast cy clic voltammetry. The selective noradrenaline reuptake inhibitor desipramin e (50 nM) did not increase stimulated (20 pulses, 100 Hz) 5-HT release but significantly slowed 5-HT reuptake in both DRN and MRN. On short stimulus t rains (10 pulses, 200 Hz), the alpha (2)-selective agonist dexmedetomidine (10 nM) decreased evoked 5-HT release in DRN and MRN (to 44 +/-3 and 43 +/- 7% of pre-drug values, respectively, at minimum). In both nuclei, this resp onse was antagonised by the selective alpha (2A)-antagonist BRL 44408 (1 mu M: P <0.001 vs. dexmedetomidine) but not by the selective alpha (2B/C)-adre noceptor antagonist ARC 239 (500 nM), the selective 5-HT1A antagonist WAY 1 00635 (100 nM) or the alpha (1)-selective antagonist prazosin (1 muM), sugg esting that the effect of dexmedetomidine is wholly attributable to alpha ( 2A)-receptor activation. The alpha (1)-adrenoceptor agonist phenylephrine ( 5 muM) significantly decreased 5-HT release (to 49 +/-7 and 41 +/-4% of pre -drug values in DRN and MRN, respectively). The response was blocked by pra zosin (P <0.001) and BRL 44408 (P <0.01) in DRN and by prazosin, BRL 44408 and WAY 100635 (all P <0.05) in MRN, suggesting that the effect of phenylep hrine is, under these conditions, only partly mediated via alpha (1)-adreno ceptors. On long stimuli (30 pulses, 10 Hz), BRL 44408 (1 muM) increased ev oked 5-HT efflux to 187 +/- 17 and 178 +/-2% of pre-drug values in DRN and MRN, respectively (both P <0.001 vs. vehicle). Collectively, these data sho w that activation of both alpha (1) and alpha (2A)-adrenoceptors can decrea se stimulated 5-HT release in the rostral raphe nuclei. Since the effect of dexmedetomidine was not antagonised by prazosin, we suggest that its effec t was mediated directly, possibly through alpha (2A) receptors located on 5 -HT cell elements, and not transduced indirectly through alpha (1)-adrenoce ptor activation, as previously suggested by others. (C) 2001 Elsevier Scien ce Ltd. All rights reserved.