Effects of acute and chronic clozapine on dopamine release and metabolism in the striatum and nucleus accumbens of conscious rats.
1. The effect of single and repeated (once daily for 23 days) oral doses of 20 and 60 mg kg-1 clozapine on dopamine release and metabolism were studied by intracerebral dialysis in the striatum and nucleus accumbens of conscious rats. 2. The basal output of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum and nucleus accumbens of rats given clozapine 20 or 60 mg kg-1 chronically, measured one day after the last drug dose, was not significantly different from that of vehicle-treated animals. 3. Challenge doses of 20 or 60 mg kg-1 clozapine produced similar increases in dopamine levels in the striatum and nucleus accumbens of animals which had received vehicle or clozapine 20 or 60 mg kg-1 once daily for 23 days, except that 1 h after administration 60 mg kg-1 clozapine had a greater effect in the nucleus accumbens. 4. In animals treated chronically with clozapine 20 and 60 mg kg-1 or vehicle, DOPAC levels in the striatum and nucleus accumbens were increased to the same extent by challenge doses of clozapine (20 or 60 mg kg-1). In animals treated chronically with clozapine, a challenge dose of 60 mg kg-1 had significantly greater effect on HVA only in the nucleus accumbens. 5. When DOPAC and HVA were measured post mortem in the striatum and nucleus accumbens 2 h after various oral doses of clozapine, it was found that 10 mg kg-1 significantly increased dopamine metabolites only in the nucleus accumbens whereas 100 mg kg-1 had this effect in both regions. Clozapine, 30mgkg-' significantly raised DOPAC levels in both regions but HVA was elevated only in the nucleus accumbens. 6. There appeared to be no appreciable changes in dopamine release and metabolism nor any reduction in the effect of clozapine in the nucleus accumbens after chronic drug treatment. In fact the effect was greater in chronically treated rats, particularly in the nucleus accumbens of animals given 60mgkg' clozapine. 7. It was confirmed that measurement of dopamine metabolites in post mortem tissue provides no valuable information on changes in the availability of synaptic dopamine.
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
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Invernizzi
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Morali
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Pozzi
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Samanin
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000758:Anesthesia; D000818:Animals; D003024:Clozapine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003956:Dialysis; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
D015102:3,4-Dihydroxyphenylacetic Acid; D003024:Clozapine; D004298:Dopamine; D006719:Homovanillic Acid