Acute administration of noradrenaline transporter blockers increases dopamine and noradrenaline extracellular levels in the prefrontal cortex (PfCX). On the other hand, reboxetine and desipramine, at doses fully effective in the PfCX, fail to modify extracellular DA in other cortical areas, such as occipital cortex (OCCX). This difference in the responsiveness of OCCX DA as compared to PfCX DA to NET blockade has been ascribed to a stronger inhibitory control exerted by NA on DA release via local α2 receptor. Electrophysiological and neurochemical evidences have been provided that prolonged exposure to antidepressants induces desensitization of autoreceptors . This change, in turn, has been attributed an important role in the mechanism of action of antidepressants. However, the evidence provided thus far has been obtained after interruption of antidepressant exposure, a condition not corresponded to the clinical situation. In the present study we monitored the effect of chronic NET blockade by desipramine on dialysate DA and NA in the PfCX and OCCX of rats challenged with DMI under blockade of α2 receptors by reverse dialysis with idazoxan 24 hours after the last DMI administration, when drug levels are at steady-state. Male Sprague Dawley rats (Harlan Italy) were chronically treated with desipramine (10 mg/kg, i.p. every 24 hours for 14 days) or saline (0.9% 3 ml/kg, same conditions). On the 14th day, the probe was implanted vertically in the PfCX, and in the OCCX; according to the atlas of Paxinos and Watson. On the 15th day, microdialysis experiments were carried out on freely moving rats. In following results were obtained: 1) chronic DMI increases extracellular DA and NA in PfCX and OCCX to levels superimposable to those reached after acute administration of the same dose to naive rats. 2) acute challenge with DMI 24 hours after the last dose of antidepressant, failed to further increase DA and NA in both areas. 3) α2 receptor blockade by idazoxan potentiated the effect of acute DMI to a larger extent in chronic DMI rats than in saline control. These observations challenge the hypothesis that desensitization of α2 receptors occurs during chronic antidepressant treatment.
Presynaptic alpha2-adrenoceptor activity in the prefrontal and occipital cortex after chronic desipramine
VALENTINI, VALENTINA;
2006-01-01
Abstract
Acute administration of noradrenaline transporter blockers increases dopamine and noradrenaline extracellular levels in the prefrontal cortex (PfCX). On the other hand, reboxetine and desipramine, at doses fully effective in the PfCX, fail to modify extracellular DA in other cortical areas, such as occipital cortex (OCCX). This difference in the responsiveness of OCCX DA as compared to PfCX DA to NET blockade has been ascribed to a stronger inhibitory control exerted by NA on DA release via local α2 receptor. Electrophysiological and neurochemical evidences have been provided that prolonged exposure to antidepressants induces desensitization of autoreceptors . This change, in turn, has been attributed an important role in the mechanism of action of antidepressants. However, the evidence provided thus far has been obtained after interruption of antidepressant exposure, a condition not corresponded to the clinical situation. In the present study we monitored the effect of chronic NET blockade by desipramine on dialysate DA and NA in the PfCX and OCCX of rats challenged with DMI under blockade of α2 receptors by reverse dialysis with idazoxan 24 hours after the last DMI administration, when drug levels are at steady-state. Male Sprague Dawley rats (Harlan Italy) were chronically treated with desipramine (10 mg/kg, i.p. every 24 hours for 14 days) or saline (0.9% 3 ml/kg, same conditions). On the 14th day, the probe was implanted vertically in the PfCX, and in the OCCX; according to the atlas of Paxinos and Watson. On the 15th day, microdialysis experiments were carried out on freely moving rats. In following results were obtained: 1) chronic DMI increases extracellular DA and NA in PfCX and OCCX to levels superimposable to those reached after acute administration of the same dose to naive rats. 2) acute challenge with DMI 24 hours after the last dose of antidepressant, failed to further increase DA and NA in both areas. 3) α2 receptor blockade by idazoxan potentiated the effect of acute DMI to a larger extent in chronic DMI rats than in saline control. These observations challenge the hypothesis that desensitization of α2 receptors occurs during chronic antidepressant treatment.
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