ejp ELSEVIER European Journal of Pharmacology 316 (1996) 43-47 Short communication Raphe5-HT1A autoreceptors, but not postsynaptic 5-HT1A receptors or [3-adrenoceptors, restrain the citalopram-induced increase in extracellular 5-hydroxytryptamine in vivo Stephan Hjorth *, H. Jfirgen Bengtsson, St6phane Milano Department of Pharmacology, University of G6teborg, G6teborg, Sweden Received 9 September1996; accepted24 September1996 Abstract In vivo microdialysis in rat ventral hippocampus was used (i) to verify the importance of 5-HT1A autoreceptors in the raphe as targets for drugs that enhance the citalopram-induced elevation of forebrain 5-hydroxytryptamine (5-HT), and (ii) to further examine the specificity of (-)-penbutolol in this regard. The selective 5-HTIA receptor antagonist WAY100635 (s.c., or intra-raphe) or the mixed 5-HT~A/~B/13-adrenoceptor antagonist (-)-penbutolol (s.c.), potentiated the citalopram-induced 5-HT rise, whereas local 'reverse' dialysis of WAY100635 into the ventral hippocampus did not. Furthermore, the (-)-penbutolol-induced augmentation proved stereose- lective and not mediated by 13-adrenoceptors (no effect of s.c. (+)-penbutolol, or 13 l- and 132-adrenoceptor blockers (betaxoloi, ICI118.551)). These data provide direct evidence that increased stimulation of 5-HT1A autoreceptors in the midbrain raphe impedes the effect of citalopram on forebrain extracellular 5-HT, whereas neither postsynaptic 5-HT1A receptors nor ~-adrenoceptors appear to be involved. Keywords: Microdialysis, in vivo; Citalopram; WAY-100635; Penbutolol enantiomer; 5-HTIA autoreceptor, raphe; 5-HTIA receptor, postsynaptic; [3-Adrenoceptor;Antidepressantaugmentation 1. Introduction Previous in vivo microdialysis studies have indicated that systemic administration of 5-hydroxytryptamine (5- HT) reuptake blockers may elevate extracellular levels of 5-HT more in the midbrain raphe than in corresponding forebrain projections, tentatively due to a concomitant increase in autoreceptor tone (Adell et al., 1991; Bel and Artigas, 1992). Subsequent work suggested that the 5-HTIA autoreceptors, in particular, may be responsible for re- straining the elevation of extracellular 5-HT induced by selective serotonin reuptake inhibitors (SSRIs) like citalo- pram. However, the results of these latter studies are incomplete, since they involve the use of imperfect phar- * Corresponding author. Institute of Physiology and Pharmacology, Department of Pharmacology, University of G~Steborg,Medicinareg. 7, S-413 90 G/Steborg, Sweden. TeL/fax (direct): +46 (0)31-773 34 28; fax (general): +46 (0)31-82 17 95; e-mail: Stephan.Hjorth@pharm.gu.se macological tools (Invernizzi et al., 1992) and/or systemic (Hjorth, 1993) rather than direct intra-raphe drug adminis- tration. Moreover, the potential contributions from post- synaptic 5-HT1A receptors and [3-adrenoceptors in the SSRI-potentiating effects of selective 5-HTIA and mixed 5-HTlg/13-adrenoceptor agents have not been addressed previously. The purpose of the present experiments was two-fold, (i) to complement and verify, by means of subcutaneous (s.c.), intra-raphe or hippocampal 'reverse'- dialysis administration of the new potent and selective 5-HT1A receptor antagonist, WAY100635 (Forster et al., 1995), the importance of 5-HT1A autoreceptors in the raphe (vs. postsynaptic 5-HTIA receptors), as targets for drugs that potentiate the citalopram-induced elevation of extracellular 5-HT, and (ii) to further examine the speci- ficity of the mixed 5-HTIA/1B and [3-adrenoceptor blocker (-)-penbutolol - in particular, with respect to stereoselec- tivity and involvement of [3-adrenoceptors - in this regard. Preliminary accounts of some of these findings have been given at the 25th Annual Meeting of the American Society 0014-2999/96/$15.00 Copyright © 1996 Elsevier Science B.V. All rights reserved. P// S0014-2999(96)00779-0