Determination of the role of noradrenergic and 5‐hydroxytryptaminergic neurones in postsynaptic α₂‐adrenoceptor desensitization by desipramine and ECS

Abstract

1Experiments were conducted to determine the respective roles which noradrenergic and 5-hydroxytryptaminergic neurones'play in the down-regulation of postsynaptic a2-adrenoceptors by desipramine and electroconvulsive shock (ECS). The functional status of these receptors was monitored by use of clonidine-induced mydriasis in conscious mice. 2 Mydriasis to clonidine (0.1 mgkg 1, i.p.) was markedly attenuated by administration of either desipramine (lOmgkg-1, i.p.) for 14 days or ECS (200V, 2s) given five times over ten days confirming our previous observations. 3 The neurotoxin, DSP4 (lOOmgkg 1, i.p. x 2), reduced brain noradrenaline levels by 64% and abolished the mydriasis induced by the noradrenaline releasing agent and reuptake inhibitor, methamphetamine, without significantly altering the response to clonidine, confirming our earlier results. This lesion prevented the attenuation of clonidine mydriasis by repeated administration of desipramine, but not ECS.4 Lesioning of central 5-hydroxytryptaminergic neurones with 5,7-dihydroxytryptamine (75lig, i.c.v.) had no influence on the reduction in clonidine mydriasis produced by repeated administration of either desipramine or ECS. 5Since noradrenergic neurones are essential for the desensitization of postsynaptic a2-adrenoceptors by desipramine, it indicates that this effect is probably the result of increased synaptic noradrenaline levels. This mechanism is not responsible for the change induced by ECS because this adaptation is independent of an intact noradrenergic input. 5-HT-containing neurones do not play a permissive role in the downregulation of postsynaptic a2-adrenoceptors by either antidepressant treatment.

Comparison of the effects of acute and subchronic administration of atipamezole on reaction to novelty and active avoidance learning in rats

“…Interestingly, it has been reported that chronic treatment with clinically effective antidepressants (both NA and 5-HT uptake inhibitors) as well as with electroconvulsive shocks (ECS) leads to desensitization of postsynaptic α 2 -adrenoceptors in brain. This was noted as an attenuation in the mydriasis response towards an α 2 -adrenoceptor agonist in mice and rat (Menargues et al 1990;Heal et al 1991). The noradrenergic neurotoxin, DSP-4, abolished the effect of NA uptake inhibitor, but the adaption induced by ECS and 5-HT uptake inhibitor was independent of an intact noradrenergic input (Heal et al 1991).…”

“…This was noted as an attenuation in the mydriasis response towards an α 2 -adrenoceptor agonist in mice and rat (Menargues et al 1990;Heal et al 1991). The noradrenergic neurotoxin, DSP-4, abolished the effect of NA uptake inhibitor, but the adaption induced by ECS and 5-HT uptake inhibitor was independent of an intact noradrenergic input (Heal et al 1991). Stress-induced learned helplessness is widely used in animal models of depression (Musty et al 1990;Petty et al 1993).…”

Evidence that RU 24969‐induced locomotor activity in C57/B1/6 mice is specifically mediated by the 5‐HT1B receptor

“…Monoamines and metabolites were detected with a BAS LC-4A detector ( + 0.75 V versus an Ag/AgCl reference electrode). Full details are given in Heal et al (1991). 3-Methoxy-4-hydroxyphenylglycol (MHPG) was measured in whole brain minus cerebellum. Tissue was homogenized in 5 volumes (w/v) of 0.1 M perchloric acid containing 0.1 tLM iso-MHPG (internal standard) and 0.4 mM sodium metabisulphite (antioxidant).…”

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

“…Several studies have demonstrated that α 2 ‐adrenoceptor density is enhanced in post mortem brains of depressed suicide victims ( Meana & García‐Sevilla, 1987 ; Meana et al ., 1992 ; González et al ., 1994 ; Ordway et al ., 1994 ; de paermentier et al ., 1997 ; Callado et al ., 1998 ; García‐Sevilla et al ., 1999 ). Down‐regulation of α 2 ‐adrenoceptor density and desensitization of α 2 ‐adrenoceptor‐mediated responses in the CNS are common responses to the chronic treatment with antidepressant drugs that increase synaptic NA concentration ( Giralt & García‐Sevilla, 1989 ; Menargues et al ., 1990 ; Heal et al ., 1991a , 1991b ; Barturen & García‐Sevilla, 1992 ; Mongeau et al ., 1994 ; Esteban et al ., 1999 ).…”