Chronic treatment with desipramine facilitates its effect on extracellular noradrenaline in the rat hippocampus: studies on the role of presynaptic alpha2-adrenoceptors.
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 alpha2-adrenoceptor agonist clonidine at the dose of 10 microg/kg significantly reduced extracellular noradrenaline in the control group but not in animals chronically treated with desipramine whereas 30 microg/kg clonidine produced a similar decrease in both groups. Three concentrations of clonidine (0.05, 0.5 and 1 microM) 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 alpha2-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 alpha2-adrenoceptors, with no changes in their density, on noradrenergic neurons in the locus coeruleus.
Sacchetti
G
G
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Bernini
M
M
Gobbi
M
M
Parini
S
S
Pirona
L
L
Mennini
T
T
Samanin
R
R
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D019329:Idazoxan / Q000031:analogs & derivatives* / Q000378:metabolism; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism / Q000502:physiology; D017661:Receptors, Presynaptic / Q000378:metabolism / Q000502:physiology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014316:Tritium
D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D018341:Receptors, Adrenergic, alpha-2; D017661:Receptors, Presynaptic; D014316:Tritium; C058525:2-methoxyidazoxan; D003000:Clonidine; D003891:Desipramine; D009638:Norepinephrine; D019329:Idazoxan