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 journalArticlepeer-review

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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