The thermogenic actions of α 2 ‐adrenoceptor agonists in reserpinized mice are mediated via a central postsynaptic α 2 ‐adrenoceptor mechanism

1 The dose‐related effects of the selective α 2 ‐adrenoceptor agonists clonidine, UK‐14,304 and B‐HT 933 on the body temperature of untreated and reserpine‐treated mice were investigated. 2 In untreated mice all three agonists induced a dose‐related hypothermia. The highest doses of UK‐14,304 and B‐HT 933, 3 and 100 mg kg −1 respectively, elicited a marked (10°C) hypothermia, whereas the maximal hypothermic effect of clonidine (5.5°C) was less pronounced and reached a plateau at a dose of 0.5 mg kg −1 i.p. 3 Reserpine (2.5 mg kg −1 , s.c.) induced a marked hypothermia in the mouse; 18 h after injection body temperature had decreased to only slightly (0.5–1.5°C) above ambient (19°C). 4 All three α 2 ‐agonists produced a partial dose‐related reversal of reserpine‐induced hypothermia; maximal thermogenic responses (9–10°C increases in body temperature) were elicited by doses of 0.2, 0.5 and 16 mg kg −1 i.p. of clonidine, UK‐14,304 and B‐HT 933 respectively, and the log dose‐response curves for all 3 agonists were bell‐shaped. 5 Following intracerebroventricular administration to reserpine‐treated mice, the thermogenic response to clonidine was more rapid in onset, and the agonist was 20 fold more potent than when injected i.p. 6 The selective α 2 ‐adrenoceptor antagonists, idazoxan (0.05–0.5 mg kg −1 ), Wy 26392 (0.3–5.0 mg kg −1 ) and yohimbine (0.1–1.6 mg kg −1 ) given orally attenuated the thermogenic responses to all 3 agonists in reserpinized mice in a dose‐related manner. Pretreatment with a single dose of idazoxan (0.3 mg kg −1 , orally) elicited a 6 fold parallel shift to the right in the dose‐response curve to clonidine. 7 The selective α 1 ‐adrenoceptor antagonists, prazosin (10 mg kg −1 ) and indoramin (3–10 mg kg −1 ), and the β‐adrenoceptor antagonist, propranolol (10 mg kg −1 ), only partially attenuated the thermogenic responses to the α 2 ‐agonists in reserpinized mice. These effects were variable and not clearly dose‐related. 8 Pretreatment of reserpinized mice with the catecholamine synthesis inhibitor, α‐methyl‐ p ‐tyrosine, markedly attenuated (60–95%) the thermogenic response to the noradrenaline uptake inhibitor, desipramine (0.13–12.5 mg kg −1 , i.p.), but only slightly reduced (10–35%) that to clonidine (0.032–0.5 mg kg −1 , i.p.). 9 These results suggest that α 2 ‐adrenoceptor agonists reverse reserpine‐induced hypothermia via a central mechanism involving activation of postsynaptic α 2 ‐adrenoceptors.