A comparison of the effects of the 5HT 1A antagonists MM-77 and WAY-100635 on the mouse isolated vasa deferentia M. J. Arkle 1 , S. Arkle 1 & I. S. Ebenezer 1,2 1 Neuropharmacology Research Group, School of Pharmacy and Biomedical Sciences and 2 Insitute of Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth, PO1 2DT, UK Summary 1 Experiments were carried out to characterize the possible adrenergic properties of the 5-HT 1A antagonists WAY 100635 and MM-77 using the mouse isolated vasa deferentia preparation. 2 When vasa deferentia were preincubated for 10 min in the presence of MM-77 (10 )8 – 10 )6 M) or WAY100635 (10 )8 –7 · 10 )7 M), a concentration-dependent inhibition of the contractile response to submaximal electrical field stimulation (10 Hz, 50 V, 50 ms) was observed with pIC 50 values of 7.05 ± 0.01 and 6.85 ± 0.1 respectively. 3 MM-77 (10 )8 –10 )6 M) antagonized the contractile responses of the vasa deferentia to phenylephrine (PE) (10 )6 –10 )3 M) in a concentration-dependent manner. Schild plots of these data were linear and yielded a mean qA 2 value of 6.81 ± 0.084. The mean slope was 1.42 ± 0.22. 4 WAY100635 (10 )8 –10 )6 M) antagonized the contractile responses of the vasa deferentia to PE (10 )6 –10 )3 M) in a concentration-dependent manner. Schild plots of these data were linear and yielded a mean qA 2 value of 7.05 ± 0.08. The mean slope was 0.97 ± 0.1. 5 The results suggest that while WAY100635 acts as a competitive antagonist at a 1 -adrenoceptors, MM-77 displays non-competitive antagonist characteristics at this receptor subtype. 6 These results may have important implications for the use of these compounds as 5-HT 1A receptor antagonists in in vivo studies. Keywords: 5-HT 1A receptors, adrenergic, a-adrenoceptor, vasa deferentia, vas deferens mouse, WAY-100635, MM-77, phenylephrine Introduction Central 5-HT 1A autoreceptors are located on the dendrites and soma of 5-HT neurones that emerge from the raphe nucleus to innervate the brain and spinal cord (Cooper, Bloom & Roth, 1991). Activation of these receptors leads to a decrease in the synthesis and release of 5-HT (Sprouse & Aghajanian, 1987; Hjorth & Magnusson, 1988). There are also postsynaptic 5-HT 1A receptors that are located in brain areas that are innervated by 5-HT neurones (Cooper et al., 1991). Behavioural studies have revealed that 5-HT 1A receptor agon- ists, such as 8-hydroxy-2-(di-N-propylamino)-tetr- alin (8-OH-DPAT), increase feeding in free feeding or non-deprived animals (Dourish, Hutson & Curson, 1985; Ebenezer, 1992a; Ebenezer, Parrot & Vellucci, 1999), but decrease feeding in food- deprived animals (Ebenezer, 1992b; Ebenezer et al., 1999). Studies using the selective 5-HT 1A receptor antagonist, N-(2-(4-2-methoxyphenyl)-1-piperazi- nyl)-N-(2-pyridyl)cyclohexanecarboxamide (WAY 100635) (Fletcher et al., 1994) have revealed that both the hyperphagic and hypophagic actions of 5-HT 1A receptor agonists are mediated by an action at central 5-HT 1A receptors (Fletcher et al., 1996; Arkle & Ebenezer, 2000; Ebenezer, Vellucci & Parrot, 2001). Electrophysiological and neuro- chemical experiments have suggested that the increase in food intake observed following admin- istration of 5-HT 1A receptor agonist is mediated by an action at 5-HT 1A autoreceptors in the raphe nucleus (see Ebenezer, 1992a). However, it is not clear whether the hypophagic effects of these 121 Autonomic & Autacoid Pharmacology, 25, 121–128 Ó 2005 Blackwell Publishing Ltd Correspondence: I. S. Ebenezer