Effects of the 5-HT 1B receptor antagonist NAS-181 on extracellular levels of acetylcholine, glutamate and GABA in the frontal cortex and ventral hippocampus of awake rats: A microdialysis study Xiao Jing Hu a , Fu-Hua Wang a , Carina Stenfors c , Sven Ove Ögren a , Jan Kehr a,b, ⁎ a Department of Neuroscience, Retzius väg 8, Karolinska Institutet, SE-171 77, Stockholm, Sweden b Department of Physiology and Pharmacology, Nanna Svartz väg 2, Karolinska Institutet, SE-171 77 Stockholm, Sweden c AstraZeneca R&D Södertälje, Discovery RA CNS and Pain Control, Södertälje, Sweden Received 3 May 2006; received in revised form 20 October 2006; accepted 6 December 2006 Abstract The purpose of this study was to investigate the effects of the 5-HT 1B receptor antagonist NAS-181 ((R)-(+)-2-(3-morpholinomethyl-2H-chromen-8-yl) oxymethyl-morpholine methanesulfonate) on cholinergic, glutamatergic and GABA-ergic neurotransmission in the rat brain in vivo. Extracellular levels of acetylcholine, glutamate and GABA were monitored by microdialysis in the frontal cortex (FC) and ventral hippocampus (VHipp) in separate groups of freely moving rats. NAS-181 (1, 5 or 10 mg/kg, s.c.) caused a dose-dependent increase in ACh levels, reaching the maximal values of 500% (FC) and 230% (VHipp) of controls at 80 min post- injection. On the contrary, NAS-181 injected at doses of 10 or 20 mg/kg s.c. had no effect on basal extracellular levels of Glu and GABA in these areas. The present data suggest that ACh neurotransmission in the FC and VHipp, the brain structures strongly implicated in cognitive function, is under tonic inhibitory control of 5-HT 1B heteroreceptors localized at the cholinergic terminals in these areas. © 2006 Elsevier B.V. and ECNP. All rights reserved. KEYWORDS Acetylcholine; Frontal cortex; Hippocampus; 5-HT 1B receptor; Microdialysis; NAS-181 1. Introduction Several lines of evidence suggest a role of serotonin (5- hydroxytryptamine; 5-HT) and its respective receptors in ⁎ Corresponding author. Department of Neuroscience, Retzius väg 8, Karolinska Institutet, SE-171 77, Stockholm, Sweden. Tel.: +46 8 5248 7084; fax: +46 8 5248 7234. E-mail address: Jan.Kehr@ki.se (J. Kehr). cognitive function (Ahlander-Luttgen et al., 2003; Buhot et al., 2000; Meneses, 1998; Ögren, 1985) and in particular, the modulatory effects mediated via the 5-HT receptors on the cholinergic system in the basal forebrain (for review, see Steckler and Sahgal, 1995). The involvement of numerous subgroups of 5-HT receptors in mediating cognitive behaviour and the release of acetylcholine (ACh) is yet not fully understood. Generally, it is believed that 5-HT exerts inhibitory effects on the cholinergic system (Buhot et al., 0924-977X/$ - see front matter © 2006 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2006.12.002 www.elsevier.com/locate/euroneuro European Neuropsychopharmacology (2007) 17, 580–586