Acute and chronic effects of desipramine and clorgyline on alpha(2)-adrenoceptors regulating noradrenergic transmission in the rat brain: a dual-probe microdialysis study.
1. The effects of desipramine (3 mg kg(-1) i.p.) and clorgyline (1 mg kg(-1) i.p.) on extracellular noradrenaline (NA) in the locus coeruleus (LC) and cingulate cortex were assessed in freely-moving rats by dual-probe microdialysis. Functional activities of alpha(2)-adrenoceptors regulating NA release in the LC and cingulate cortex were determined by systemic (0.3 mg kg(-1) i.p.) or local (0.1 - 100 microM) clonidine administration. 2. Extracellular NA was increased in the LC and cingulate cortex following acute desipramine but not clorgyline treatment. Systemic clonidine decreased NA similarly in desipramine-, clorgyline-, and saline-treated animals, in both brain areas. 3. Long-term (twice daily, 14 days) but not short-term (twice daily, 7 days) desipramine, and long-term clorgyline (once daily, 21 days) treatments increased NA (3 fold) in cingulate cortex but not in the LC. Following long-term treatments, responses of NA to systemic clonidine were attenuated in the LC and cingulate cortex. 4. Clonidine perfusion by reverse dialysis into the cingulate cortex decreased local NA (-55 +/- 9%). The effect was attenuated by long-term desipramine (-31 +/- 9%) and clorgyline (-10 +/- 2%) treatments. 5. Clonidine perfusion by reverse dialysis into the LC decreased NA in the LC (-89 +/- 2%) and in cingulate cortex (-52 +/- 12%). This effect was attenuated in the LC following long-term desipramine (-72 +/- 4%) and clorgyline (-62 +/- 12%) treatments but it was not modified in the cingulate cortex (-57 +/- 10% and -68 +/- 6%, respectively). 6. These findings demonstrate that chronic desipramine or clorgyline treatments increase NA in noradrenergic terminal areas and desensitize alpha(2)-adrenoceptors modulating local NA release at somatodendritic and terminal levels. However, somatodendritic alpha(2)-adrenoceptors that control LC firing activity are not desensitized.
Mateo
Y
Y
Department of Pharmacology, University of the Basque Country, E-48940 Leioa, Bizkaia, Spain.
Fernández-Pastor
B
B
Meana
J J
JJ
D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D003000:Clonidine / Q000494:pharmacology; D003010:Clorgyline / Q000008:administration & dosage / Q000494:pharmacology*; D003891:Desipramine / Q000008:administration & dosage / Q000494:pharmacology*; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013997:Time Factors
D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D018341:Receptors, Adrenergic, alpha-2; D003010:Clorgyline; D003000:Clonidine; D003891:Desipramine; D009638:Norepinephrine