8-OH-DPAT-INDUCED MYDRIASIS IN MICE - A PHARMACOLOGICAL CHARACTERIZATION

8-Hydroxy(di-n-propylamino)tetralin (8-OH-DPAT; 0.1-50 mg/kg i.p.) evo ked a dose-dependent mydriatic response in conscious mice (ED(50) = 5. 8 mg/kg i.p.) which was maximal after 10 min. 8-OH-DPAT (2 mg/kg i.p.) -induced mydriasis was attenuated by the alpha(2)-adrenoceptor antagon ists, idazoxan (1 and 3 mg/kg i.p.) and yohimbine (1 and 3 mg/kg i.p.) , by the 5-HT1 receptor antagonists, pindolol (10 mg/kg i.p.) and quip azine (2 mg/kg i.p.), and by the selective 5-HT1A receptor antagonist, methoxyphenyl)piperazin-1-yl]-2-phenylpropionamide ((-)-WAY 100135; 1 -10 mg/kg s.c.). These data argue that both central alpha(2)-adrenocep tors and 5-HT1A receptors are involved in the mediation of mydriasis i nduced by 8-OH-DPAT. The synaptic location of these receptors was dete rmined using either N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP- 4; 100 mg/kg i.p.) or 5,7-dihydroxytryptamine (5,7-DHT; 75 mu g i.c.v. ) + p-chlorophenylalanine (PCPA; 200 mg/kg i.p.); these lesioning proc edures respectively produced highly significant losses of whole brain noradrenaline (72% depletion) and 5-HT (78% depletion). The former abo lished 8-OH-DPAT (5 mg/kg i.p. (ED(50))) mydriasis, whereas the latter was without effect. s-OH-DPAT (0.5 - 5 mg/kg i.p.) also dose-dependen tly increased the noradrenaline metabolite, 3-mtrhoxy-4-hydroxy-phenyl glycol (MHPG), in mouse whole brain minus cerebellum. Taken together t hese results show that 8-OH-DPAT initially stimulates 5-HT1A receptors , and it is likely that this is followed by release of noradrenaline o nto postsynaptic alpha(2) adrenoceptors, the latter effect being respo nsible for the mydriatic response.