The effects of acute and chronic desipramine on the thermogenic and hypoactivity responses to α₂‐agonists in reserpinized and normal mice

Abstract

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 a2-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 20mg kg-1 orally. 3 Chronic (every 12h for 14 days), but not acute treatment with DMI (15mgkg-1, orally), attenuated the thermogenic responses to low doses (0.02-0.225mg 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.Omgkg-', i.p.) when injected 2h, but not when injected 18-21h before the agonist. In contrast, 18-21 h 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 postsynaptic a2-adrenoceptors, these results suggest that prolonged inhibition of NA uptake decreases the sensitivity of postsynaptic CX2-adrenoceptors. The results of the studies using UK-14,304 indicate that central aC2-adrenoceptors involved in mediating other behavioural and pharmacological responses to a2-agonists are also down-regulated by chronic inhibition of NA uptake.

Acute and chronic effects of desipramine and clorgyline on α2‐adrenoceptors regulating noradrenergic transmission in the rat brain: a dual‐probe microdialysis study

“…Overall, the results suggest that chronic desipramine (14 days) or clorgyline (21 days) treatments lead to an increased availability of NA at cortical level in the synaptic cleft which in turn induces desensitization of presynaptic α 2 ‐adrenoceptors regulating NA release by nerve terminals. This finding extends and, in general, agrees well with previously reported data about antidepressant and electroconvulsive shock effects on α 2 ‐adrenoceptor functional activity at presynaptic ( Heal et al ., 1991b ; Thomas et al ., 1992 ; Mongeau et al ., 1994 ; Yoshioka et al ., 1995 ; Esteban et al ., 1999 ; Invernizzi et al ., 2001 ; Sacchetti et al ., 2001 ) and postsynaptic ( Bill et al ., 1989 ; Menargues et al ., 1990 ; Heal et al ., 1991a , 1991b ) levels in the CNS. On the other hand, long‐term treatment with NA reuptake or MAO inhibitors has been shown to reduce the density of brain α 2 ‐adrenoceptors ( Smith et al ., 1981 ; Cohen et al ., 1982 ; Giralt & García‐Sevilla, 1989 ; Barturen & García‐Sevilla, 1992 ; Ribas et al ., 1993 ).…”

Behavioural and physiological effects induced by an infusion of antisense to α2D‐adrenoceptors in the rat

“…Furthermore, this effect was fully reversed 4 days after the end of the infusion suggesting a specific role for the α 2D ‐adrenoceptor subtype in mediating the hypothermic effect of an α 2 ‐adrenoceptor agonist. In agreement with the present study, the specific α 2 ‐adrenoceptor antagonist, RX821002, did not affect rectal temperature following acute administration (unpublished observation), suggesting α 2D ‐adrenoceptors are not involved in tonic control of temperature but do mediate the hypothermic effects observed with α 2 ‐adrenoceptor agonists ( Bill et al ., 1989a , 1989b ).…”

“…Postsynaptically located α 2 ‐adrenoceptors have been shown to play an important role in a number of physiological functions. For example, α 2 ‐adrenoceptor agonists have been shown to increase pupil diameter (mydriasis) and induce hypothermia in rodents ( Heal et al ., 1995a , 1995b ; Lin et al ., 1981 ; Unnerstall et al ., 1984 ; Bill et al ., 1989a , 1989b ).…”