Neuropharmacology 43 (2002) 959–965 www.elsevier.com/locate/neuropharm 5-HT 1A receptor-mediated autoinhibition does not function at physiological firing rates: evidence from in vitro electrophysiological studies in the rat dorsal raphe nucleus D.A. Johnson * , S.E. Gartside, C.D. Ingram Psychobiology Research Group, University of Newcastle upon Tyne, School of Neurosciences and Psychiatry, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK Received 7 March 2002; received in revised form 6 June 2002; accepted 26 June 2002 Abstract 5-HT 1A -mediated autoinhibition of neurones in the dorsal raphe nucleus (DRN) is considered to be the principal inhibitory regulator of 5-HT neuronal activity. The activation of this receptor by endogenous 5-HT was investigated using electrophysiological recordings from the rat DRN in vitro. At a concentration which blocked the inhibitory effect of exogenous 5-HT, the 5-HT 1A antagonist WAY 100635 did not alter basal firing rate or modulate the excitatory response to the a 1 -agonist phenylephrine. Blockade of 5-HT reuptake by a concentration of fluoxetine, which enhanced the inhibitory effect of exogenous 5-HT, lowered phenylephrine- induced basal firing presumably due to potentiation of the effect of endogenous 5-HT. However, this effect was not firing rate dependent and neither the proportional increase nor the time-course of the response to a higher concentration of phenylephrine were altered in the presence of fluoxetine. These data suggest that the inhibitory 5-HT 1A receptor on raphe neurones is neither tonically activated nor plays any role in modulating the response to excitatory transmitters. Thus, at physiological firing rates this receptor does not appear to function as an autoreceptor of serotonergic neurones of the DRN.  2002 Elsevier Science Ltd. All rights reserved. Keywords: Serotonin (5-HT); Dorsal raphe nucleus (DRN); Fluoxetine; Autoinhibition; 5-HT reuptake; 5-HT 1A receptor 1. Introduction The somatodendritic 5-HT 1A receptor of the midbrain raphe nuclei is implicated in the pathophysiology of depression and has become the focus for the develop- ment of therapeutic treatments for affective disorders. Within the dorsal raphe nucleus (DRN), the 5-HT 1A receptor is thought to function as an autoreceptor and is considered to be the principal inhibitory regulator of 5- HT neuronal activity (Barnes and Sharp, 1999; Pineyro and Blier, 1999). Administration of selective 5-HT 1A receptor agonists either in vivo or in vitro results in the inhibition of neuronal firing (Blier and de Montigny, 1987; Lanfumey et al., 1993; Arborelius et al., 1994) and in vivo causes a decrease in 5-HT release in DRN * Corresponding author. Tel.: +44 191 222 5529; fax: +44 191 222 5227. E-mail address: d.a.johnson@ncl.ac.uk (D.A. Johnson). 0028-3908/02/$ - see front matter.  2002 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(02)00116-8 projection areas (Sharp et al., 1989, 1996, 1997). Evi- dence supports that endogenous 5-HT can also activate 5-HT 1A receptors since 5-HT reuptake inhibitors decrease serotonergic firing via the activation of 5-HT 1A receptors (Gartside et al., 1995). Whilst the inhibitory effects which result from 5-HT 1A receptor activation are unquestionable, it is unclear under what conditions these receptors are normally activated. It is uncertain whether there is a tonic level of autoinhi- bition at normal firing rates, or whether receptor acti- vation occurs only under pathological conditions or in response to pharmacological intervention. 5-HT 1A recep- tors have been shown to be present on the cell bodies and dendrites of 5-HT neurones in the DRN (Verge et al., 1985) and, taken together with evidence of somatod- endritic release of 5-HT (Adell et al., 1993; Bosker et al., 1994; Davidson and Stamford, 1995), this might sug- gest that activation of 5-HT 1A receptors by local 5-HT can occur. Such activation might be expected to provide a tonic inhibitory influence on 5-HT neuronal firing.