Somatodendritic alpha2-adrenoceptors in the locus coeruleus are involved in the in vivo modulation of cortical noradrenaline release by the antidepressant desipramine.
The effect of the antidepressant and selective noradrenaline reuptake blocker desipramine (DMI) on noradrenergic transmission was evaluated in vivo by dual-probe microdialysis. DMI (1, 3, and 10 mg/kg, i.p.) dose-dependently increased extracellular levels of noradrenaline (NA) in the locus coeruleus (LC) area. In the cingulate cortex (Cg), DMI (3 and 10 mg/kg, i.p.) also increased NA dialysate, but at the lowest dose (1 mg/kg, i.p.) it decreased NA levels. When the alpha2-adrenoceptor antagonist RX821002 (1 microM) was perfused in the LC, DMI (1 mg/kg, i.p.) no longer decreased but rather increased NA dialysate in the Cg. In electrophysiological experiments, DMI (1 mg/kg, i.p.) inhibited the firing activity of LC neurons by a mechanism reversed by RX821002. Local DMI (0.01-100 microM) into the LC increased concentration-dependently NA levels in the LC and simultaneously decreased NA levels in the Cg. This decrease was abolished by local RX821002 administration into the LC. The results demonstrate in vivo that DMI inhibits NA reuptake at somatodendritic and nerve terminal levels of noradrenergic cells. The increased NA dialysate in the LC inhibits noradrenergic activity, which in part counteracts the effects of DMI on the Cg. The modulation of cortical NA release by activity of DMI at the somatodendritic level is mediated through alpha2-adrenoceptors located in the LC.
Mateo
Y
Y
Department of Pharmacology, University of the Basque Country, Leioa, Bizkaia, Spain.
Pineda
J
J
Meana
J J
JJ
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D003712:Dendrites / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology*; D004594:Electrophysiology; D006179:Gyrus Cinguli / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D008125:Locus Coeruleus / Q000737:chemistry* / Q000166:cytology / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009474:Neurons / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000032:analysis*
D000317:Adrenergic alpha-Antagonists; D000929:Antidepressive Agents, Tricyclic; D018341:Receptors, Adrenergic, alpha-2; C058525:2-methoxyidazoxan; D003891:Desipramine; D009638:Norepinephrine; D019329:Idazoxan