Clozapine-induced dopamine levels in the rat striatum and nucleus accumbens are not affected by muscarinic antagonism.
The effect of the muscarinic antagonist, scopolamine, was examined for a change in the increase in extracellular dopamine, dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA), induced by haloperidol or clozapine in the striatum and nucleus accumbens of anaesthetised and awake rats, monitored using in vivo cerebral microdialysis. Rats received scopolamine (1 mg kg(-1); s.c.) or vehicle followed by haloperidol (1 mg kg(-1); s.c.) or clozapine (20 mg kg(-1); s.c.). Dopamine, DOPAC, HVA and 5-HIAA overflow into striatal or accumbens perfusates was determined using high performance liquid chromatography with electrochemical detection (HPLC-ECD). Scopolamine failed to modify the clozapine- or haloperidol-induced efflux of dopamine or its metabolites in either the striatum or nucleus accumbens following systemic administration in anaesthetised or awake rats. Although pretreatment with scopolamine tended to produce a smaller increase in the clozapine-induced efflux of DOPAC in striatal perfusates than following clozapine treatment alone, this was not statistically significant. Furthermore, local infusion of scopolamine (100 microM) with clozapine (1 mM) via the microdialysis probe did not attenuate the elevated efflux of dopamine observed following clozapine alone, in either the striatum or nucleus accumbens, in anaesthetised rats. This treatment did prevent the clozapine-induced increase in DOPAC and HVA in the striatum but not the nucleus accumbens. Carbachol (50 microM) infused into the dorsolateral striatum or nucleus accumbens raised extracellular dopamine levels 200% and 150%, respectively above baseline. Our data suggest that the increased efflux of dopamine and its metabolites in the rat basal ganglia following clozapine administration is not significantly dependent upon the interaction of clozapine with muscarinic receptors.
Gray
A M
AM
Department of Pharmacology, Scientific Development Group, Organon Laboratories, Lanarkshire, Scotland, UK. alex.gray@rtp.ppdi.com
Connick
J H
JH
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004347:Drug Interactions; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000494:pharmacology*
D014150:Antipsychotic Agents; D002316:Cardiotonic Agents; D018727:Muscarinic Antagonists; D015102:3,4-Dihydroxyphenylacetic Acid; D002217:Carbachol; D012601:Scopolamine; D003024:Clozapine; D006220:Haloperidol; D004298:Dopamine