Elevation of extracellular cortical noradrenaline may contribute to the antidepressant activity of zotepine: an in vivo microdialysis study in freely moving rats.
The antipsychotic, zotepine, as well as possessing affinity for dopamine D1- and D2-1ike receptors, has high affinity for the noradrenaline (NA) transporter and inhibits [3H]NA uptake by rat frontal cortex synaptosomes, in vitro. The present studies investigated the effects of zotepine on extracellular NA in the frontal cortex of freely moving rats using in vivo microdialysis. Removal of calcium from the perfusate reduced extracellular NA by 70.5% and prevented the 50 mM KCl-stimulated increase in NA levels. Zotepine (0.5-1.5 mg kg(-1) i.p.), evoked biphasic, dose-dependent rises in extracellular NA with maximal increases observed at 60 min (+ 171.0%) and 240 min (+ 211.5%) post-treatment. The increases in NA levels were sustained for up to 100 min post-dosing. Clozapine (10.0 mg kg(-1) i.p.), resulted in a smaller, transient increase in NA levels (+ 72.0%) which lasted for 20 min post-treatment. Neither ziprasidone (3.0 mg kg(-1) i.p.) nor olanzapine (1.0 mg kg(-1) i.p.) influenced extracellular NA. Systemic treatment with the antidepressant desipramine (0.3 mg kg(-1) i.p.) resulted in a prolonged elevation of NA levels over 240 min (maximal increase of + 354.3%), whilst local infusion of nisoxetine (1-100 microM) through the dialysis probe increased NA levels in a concentration-dependent manner (up to 587.8% of control values). These data suggest that the inhibition of NA uptake by zotepine and its subsequent prolonged elevation of extracellular cortical NA may underlie the reported antidepressant properties of zotepine in schizophrenic patients.
CNS Biology, Knoll Pharmaceuticals Research and Development, Nottingham, UK. Helen.Rowley@knoll.co.uk
H L
HL
Rowley
I C
IC
Kilpatrick
P L
PL
Needham
D J
DJ
Heal
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D003988:Dibenzothiepins / Q000494:pharmacology*; D005110:Extracellular Space / Q000502:physiology; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D003988:Dibenzothiepins; D005473:Fluoxetine; C011386:nisoxetine; D011188:Potassium; D002118:Calcium; D003891:Desipramine; C022172:zotepine; D009638:Norepinephrine