α 2 ‐Adrenoceptor agonists induce mydriasis in the rat by an action within the central nervous system

The effects of intravenous administration of the selective α 2 ‐adrenoceptor agonists clonidine, UK 14,304 and guanoxabenz on rat pupil diameter were investigated. In rats anaesthetized with pentobarbitone, each agonist produced a marked dose‐related increase in pupil diameter; the rank order of potency was: clonidine > UK 14,304 > guanoxabenz. Pretreatment with the selective α 2 ‐adrenoceptor antagonist, RX 781094 (0.5 mg/kg, i.v.), produced a parallel 30–40 fold shift to the right of the dose‐pupil dilator response curves for the three agonists. Yohimbine (1.5 mg/kg, i.v.) produced about a 10 fold rightward shift of the dose‐response curve for guanoxabenz. In contrast, the α 1 ‐selective antagonist, prazosin (0.5 mg/kg, i.v.), failed to affect the dose‐response relation for guanoxabenz. Several antagonists of varying selectivities towards α 1 ‐ and α 2 ‐adrenoceptors were tested for their ability to reverse the maximal mydriasis induced by guanoxabenz (0.3 mg/kg, i.v.). The rank order of potency of the antagonists producing a 50% reversal of this effect was: RX 781094 > yohimbine > piperoxan = rauwolscine > mianserin > RS 21361. Neither corynanthine nor prazosin reversed the guanoxabenz‐induced mydriasis. Topical application of RX 781094 (0.1 to 3% w/v solutions) onto one eye produced a slow reversal of guanoxabenz‐induced mydriasis; the time course and degree of reversal were virtually the same in both eyes. Intracerebroventricular administration of RX 781094 (1.25–15 μg total dose) caused a rapid dose‐related reversal of the maximal mydriasis induced by guanoxabenz (0.3 mg/kg, i.v.). Guanoxabenz (0.3 and 1.0 mg/kg, i.v.) did not produce any dilation of the physostigmine‐constricted undamaged pupil of the pithed rat. Intravenous adrenaline was found to produce a small mydriatic effect, while atropine completely antagonized the effects of physostigmine in this preparation. These results indicate that α 2 ‐adrenoceptor agonists induce mydriasis in the rat through a central α 2 ‐adrenoceptor mechanism. However, the site of action within the central nervous system remains to be determined.