Neuropharmacology 45 (2003) 72–81 www.elsevier.com/locate/neuropharm In vivo inhibition of neuronal activity in the rat ventromedial prefrontal cortex by midbrain-raphe nuclei: role of 5-HT 1A receptors Miha ´ly Hajo ´s a,* , Sarah E. Gartside b , Viktor Varga c , Trevor Sharp d a Neurobiology, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, MI 49007, USA b School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle, UK c Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary d University Department of Pharmacology, Mansfield Road, Oxford, UK Received 24 October 2002; received in revised form 14 March 2003; accepted 18 March 2003 Abstract The ventral part of the medial prefrontal cortex (mPFC) plays an important role in mood and cognition. This study examined the effect of the 5-HT in this region by measuring the electrophysiological response of ventral mPFC neurones to electrical stimulation of the dorsal and median raphe nuclei (DRN and MRN), which are the source of the 5-HT input. DRN or MRN stimulation evoked a consistent, short-latency, post-stimulus inhibition in the majority of ventral mPFC neurones tested (DRN: 44/73 neurones; MRN: 24/31 neurones). Some neurones responded to DRN or MRN stimulation with antidromic spikes indicating that they were mPFC-raphe projection neurones. Both DRN- and MRN-evoked inhibitions were attenuated by systemic administration of the 5-HT 1A antagonist WAY 100635 (0.1 mg/kg i.v.). DRN-evoked inhibition was also attenuated by iontophoretic application of WAY 100635 and by systemic administration of the 5-HT 1A antagonist, NAD-299 (4 mg/kg i.v.) but not the 5-HT 2 antagonist ketanserin (4 mg/kg, i.v.). These data suggest that DRN and MRN 5-HT neurones inhibit neurones in the ventral mPFC via activation of 5-HT 1A receptors. Some of these mPFC neurones may be part of a 5-HT 1A receptor-controlled postsynaptic feedback loop to the DRN and MRN.  2003 Elsevier Science Ltd. All rights reserved. Keywords: Medial prefrontal cortex; 5-HT; Dorsal raphe nucleus; Median raphe nucleus; 5-HT 1A receptor; Electrophysiology 1. Introduction A wealth of evidence from neuropsychological, neu- roanatomical and functional imaging studies in animals and humans indicates that the medial prefrontal cortex (mPFC) is a key component of cortico-limbic-striatal cir- cuits that are thought to generate pathological emotional behaviour and the accompanying physiological disturb- ances (Drevets, 2001; Mayberg et al., 1999). The ventral mPFC is of special interest because it is strongly impli- cated in the expression of behavioural, neuroendocrine and autonomic responses to emotionally relevant stimuli, * Corresponding author. Tel.: +1-269-833-7847; fax: +1-269-833- 2525. E-mail address: mihaly.hajos@pharmacia.com (M. Hajo ´s). 0028-3908/03/$ - see front matter  2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0028-3908(03)00139-4 and recent imaging studies indicate abnormalities in structure and function of this region in patients with mood disorder (Drevets et al., 1997; Kennedy et al., 2001). In addition to its putative importance in mood disorders, the ventral mPFC is established to play an important role in cognition, specifically in working memory and memory processing (Fritts et al., 1998; Vertes, 2002; Wall et al., 2001). The brain 5-hydroxytryptamine (5-HT, serotonin) sys- tem has long been implicated in both the cause and treat- ment of mood disorder (for reviews see Blier and Abbott, 2001; Dursun et al., 2001; Middlemiss et al., 2002) as well as in cognitive processes (Lehmann et al., 2002; Murphy et al., 2002; Schechter et al., 2002). Inter- estingly, 5-HT systems have been shown to have ana- tomical connections with the ventral mPFC. Thus, trac- ing studies indicate that ascending 5-HT pathways from