Effect of ritanserin on the interaction of amfonelic acid and neuroleptic-induced striatal dopamine metabolism.
In the present study we evaluated the interaction of amfonelic acid (AFA) with the typical neuroleptic haloperidol and the atypical antipsychotic clozapine on rat striatal dopamine metabolism in the absence or presence of the 5HT2 receptor antagonist ritanserin. In the absence of ritanserin, AFA significantly enhanced haloperidol stimulated 3,4- dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) accumulation by 36% and 37% respectively above that produced by haloperidol alone. This effect is believed to be due to AFA's ability to facilitate dopamine release produced by the potent haloperidol-induced increase in nigrostriatal impulse flow. In contrast, AFA did not potentiate the ability of clozapine to stimulate DOPAC or HVA. This lack of potentiation could be explained by clozapine's known potent 5HT2 receptor blocking activity attenuating its stimulatory effects on impulse flow. To test this, we combined ritanserin with haloperidol and again studied the interaction with AFA on dopamine metabolism. In the presence of ritanserin, AFA failed to potentiate the effects of haloperidol on DOPAC or HVA accumulation; an effect similar to that seen with clozapine. This result extends the idea that 5HT2 receptor blockade modulates nigrostriatal dopaminergic neurotransmission.
Department of Biological Research, Hoechst-Roussel Pharmaceuticals Inc., Somerville, NJ 08876.
L R
LR
Brougham
P G
PG
Conway
D B
DB
Ellis
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009268:Nalidixic Acid / Q000031:analogs & derivatives; D009287:Naphthyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D016713:Ritanserin / Q000494:pharmacology*; D012702:Serotonin Antagonists; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D014150:Antipsychotic Agents; D009287:Naphthyridines; D012702:Serotonin Antagonists; D016713:Ritanserin; D009268:Nalidixic Acid; D003024:Clozapine; D006220:Haloperidol; C006486:amfonelic acid; D004298:Dopamine