Serotonin denervation enhances responsiveness of presynaptic dopamine efflux to acute clozapine in nucleus accumbens but not in caudate-putamen.
Clozapine alters mesolimbic dopamine (DA) function but spares nigrostriatal DA function in laboratory animals, but the underlying mechanism is unknown. In the present study, acute intraperitoneal injection of clozapine (5-40 mg/kg) increased extracellular DA levels in nucleus accumbens (Acb) and caudate-putamen (CPu) of awake, freely moving rats as measured by in vivo brain microdialysis, without anatomic selectivity. However, in serotonin (5HT)-denervated rats acute clozapine preferentially enhanced DA levels in Acb as compared to CPu. Since (i) up-regulation of 5HT receptors on DA neurons may result from 5HT denervation, (ii) clozapine has potent anti-5HT action, and (iii) 5HT receptors are more dense in Acb than CPu, these data appear to add additional weight to previous suggestions that a serotonergic mechanism may partly underlie clozapine's mesolimbic selectivity.
Chen
J
J
Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461.
Paredes
W
W
van Praag
H M
HM
Gardner
E L
EL
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects / Q000502:physiology*; D003024:Clozapine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D011699:Putamen / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D012702:Serotonin Antagonists; D015102:3,4-Dihydroxyphenylacetic Acid; D006897:Hydroxyindoleacetic Acid; D003024:Clozapine; D004298:Dopamine; D006719:Homovanillic Acid