Chronic clozapine selectively decreases prefrontal cortex dopamine as shown by simultaneous cortical, accumbens, and striatal microdialysis in freely moving rats.
We used microdialysis to study the acute and chronic effects of clozapine on the metabolism of dopamine (DA) in terminal areas of the mesocortical, mesolimbic, and nigrostriatal systems simultaneously. In the acute experiment, groups of four rats received the following doses: 0 (vehicle), 10, 20, and 40 mg/kg of clozapine subcutaneously, which resulted in a dose-related increase in extracellular DA, 3,4-dihydroxyphenalacetic acid (DOPAC), and homovanillic acid (HVA) in the prefrontal cortex (PFC). In the nucleus accumbens (NAC) and striatum (STR), no significant changes were observed at any dose. In the chronic experiment, six rats received 20 mg/kg of clozapine and a control group received vehicle daily for 30 days. After 30 days of treatment, DA, DOPAC, and HVA were significantly lower in the PFC, and unchanged in the NAC or STR. The 30th clozapine injection failed to increase DA, DOPAC, or HVA in any of the three regions. We conclude that clozapine acted selectively on the mesocortical system, and that this may underlie clozapine's therapeutic, antipsychotic effect.
Department of Psychology, Princeton University, NJ 08544-1010, USA.
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Hoebel
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D003024:Clozapine; D004298:Dopamine; D006719:Homovanillic Acid