Chronic treatment with desipramine facilitates its effect on extracellular noradrenaline in the rat hippocampus: Studies on the role of presynaptic α2-adrenoceptors

G. Sacchetti, M. Bernini, M. Gobbi, S. Parini, L. Pirona, T. Mennini, R. Samanin

Research output: Contribution to journalArticle

Abstract

Adaptive phenomena such as desensitization of autoreceptors are considered an important factor in the achievement of therapeutic efficacy of antidepressant drugs after chronic treatment. We have studied whether a chronic treatment with desipramine had a greater effect than a single dose on the extracellular concentrations of noradrenaline in the dorsal hippocampus. Administration of 10 mg/kg i.p. desipramine once daily for 14 days significantly raised the basal extracellular noradrenaline in the dorsal hippocampus 24 h but not 48 h after the last drug injection. A challenge dose of desipramine increased extracellular noradrenaline in rats treated chronically with vehicle and desipramine. The effect was significantly higher in rats treated chronically with desipramine 48 h but not 24 h after the last injection. An intraperitoneal administration of the α2-adrenoceptor agonist clonidine at the dose of 10 μg/kg significantly reduced extracellular noradrenaline in the control group but not in animals chronically treated with desipramine whereas 30 μg/kg clonidine produced a similar decrease in both groups. Three concentrations of clonidine (0.05, 0.5 and 1 μM) infused into the hippocampus significantly reduced extracellular noradrenaline to a similar extent in rats chronically treated with saline or desipramine. Fourty-eight hours after the last injection of the chronic treatment, [3H]RX-821002 binding to α2-adrenoceptors in the rat locus coeruleus measured by autoradiography was not significantly modified. A slight (17%) but significant decrease of neuronal uptake of [3H]noradrenaline was found in synaptosome preparations from dorsal hippocampus of rats chronically treated with desipramine, but this was likely due to a decrease in affinity. The results suggest that a repeated treatment with desipramine (10 mg/kg i.p. once daily for 14 days) facilitates its effect on extracellular noradrenaline in the dorsal hippocampus and induces adaptive changes probably involving desensitization of α2-adrenoceptors, with no changes in their density, on noradrenergic neurons in the locus coeruleus.

Original languageEnglish
Pages (from-to)66-72
Number of pages7
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume363
Issue number1
DOIs
Publication statusPublished - 2001

Keywords

  • α-Adrenoc eptor desensitization
  • [H]Noradrenaline uptake
  • Clonidine
  • Desipramine
  • Dorsal hippocampus
  • Locus coeruleus
  • Microdialysis
  • Noradrenaline

ASJC Scopus subject areas

  • Pharmacology

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