1. The effects of acute and chronic (14 day) administration of the noradrenaline uptake inhibitor, desipramine (DMI), on the thermogenic responses to clonidine in reserpine-treated mice, and on the hypothermic and hypoactivity responses to the alpha 2-agonist, UK-14,304, in untreated mice were examined. 2. Taking the capacity of DMI to delay the onset of reserpine-induced hypothermia as an indicator of noradrenaline (NA) uptake inhibition, the lowest dose of DMI to inhibit uptake significantly for 12 h in the mouse was shown to be between 10 and 20 mg kg-1 orally. 3. Chronic (every 12 h for 14 days), but not acute treatment with DMI (15 mg kg-1, orally), attenuated the thermogenic responses to low doses (0.02-0.225 mg kg-1, i.p.) of clonidine (injected 20 h after the last dose of DMI) in reserpinized mice. 4. Acute DMI administration slightly attenuated the hypothermia and hypoactivity induced by UK-14,304 (0.25-1.0 mg kg-1, i.p.) when injected 2h, but not when injected 18-21h before the agonist. In contrast, 18-21h after withdrawal from chronic DMI both of these responses to UK-14, 304 were markedly attenuated. 5. As the thermogenic response to clonidine in reserpinized mice appears to involve central post-synaptic alpha 2-adrenoceptors, these results suggest that prolonged inhibition of NA uptake decreases the sensitivity of postsynaptic alpha 2-adrenoceptors. The results of the studies using UK-14,304 indicate that central alpha 2-adrenoceptors involved in mediating other behavioural and pharmacological responses to alpha 2-agonists are also down-regulated by chronic inhibition of NA uptake.