The anterior hypothalamic preoptic area (AH/POA) was examined as a possible site of action of clonidine and other alpha noradrenergic receptor agonists which evoke motor and autonomie changes. Chronically indwelling guide cannulae were implanted stereotaxically in the diencephalon of the cat. Following post-operative recovery, a micro-injection into AH/POA was made in a volume of 1.0 μl of one of the following compounds: 5.0–50.0 μg clonidine, 5.0–50.0 μg norepinephrine, 5.0–50.0 μg phenylephrine and 5.0–50.0 μg methoxamine. The smallest dose of 5.0 μg clonidine produced a brief period of restlessness, licking, retching and emesis but a much longer-lasting mydriasis. When the dose of clonidine was raised to 20 μg, the cat became behaviorally sedated, after a latency of about 15 min, for a period of up to 1.0–2.0 hr. This was accompanied by a prolonged period of mydriais and preceded by a short interval of restlessness, licking, retching and emesis. After the highest dose of 50.0 μg clonidine was micro-injected in AH/POA, a profound impairment of motor activity, adynomia and restlessness developed within 15–20 min, persisted for 30 to 60 min and was accompanied also by mydriasis with maximal pupillary dilation lasting for up to six hr. When 5.0–50.0 μg phenylephrine or 5.0–50.0 μg norepinephrine were micro-injected at clonidine-reactive sites in AH/POA, only rarely were brief instances of restlessness, licking, retching and emesis observed; however, methoxamine at all doses tested failed to produce any visible signs of autonomie or motor disturbance. Pretreatment of clonidine-sensitive sites by micro-injection of yohimbine (5.0–10.0 μg), an alpha-2 noradrenergic antagonist, inhibited the clonidine-induced sedation and impairment of motor activity; conversely, the mixed alpha-receptor blocking drug, phentolamine, did not alter clonidine's locomotor effects. Both antagonists failed to block mydriasis in the cat, and similar pre-treatment with the antimuscarinic drug, atropine (5.0–20.0 μg), 5-hydroxytryptamine antagonist, methysergide (5.0–20.0 μg), the dopamine antagonist, chlorpromazine (5.0–20.0 μg) or the opioid antagonist, naloxone (5.0–20.0 μg), failed to attenuate the clonidine-induced mydriasis. These results suggest that clonidine-induced sedation and motor impairment in the cat are mediated by a localized alpha-2 noradrenergic receptor mechanism in the diencephalon; however, the concomitant mydriasis is apparently not subserved by alpha noradrenergic, muscarinic. serotonergic, dopaminergic and opioid receptor sub-types in this forebrain structure.