Differential sensitivity of two dopaminergic structures in rat brain to haloperidol and to clozapine

The mechanisms underlying the dissociation of the extrapyramidal and antipsychotic properties of haloperidol as compared to clozapine were explored by studying the effects of these drugs on dopamine metabolism in the straitum and tuberculum olfactorium (TO) of the rat. Homovanillic acid and 3,4-dihydroxyphenylacetic acid were simutaneously measured in these regions by a gas chromatographic techinque after treating the rats with different doses of the drugs. Dose-response curves and time-action curves were generated. For both drugs, a higher dose was required to achieve half-maximal metabolite elevation in the TO as compared to the striatum. The apparent differential sensitivity to haloperidol was attributed to differences in time to peak response. The time to peak response to clozapine was similar in both structures. Thus, the striatum appears to be more sensitive to clozapine than the TO with respect to elevation of dopamine metabolites. The effect of haloperidol on dopamine metabolism in the striatum was more persistent than that in the TO. After 4 hours, metabolite levels were still elevated in the striatum, whereas after 2 hours they returned to base line in the TO. The extrapyramidal effects of haloperidol may be due to the persistent action of this drug on dopamine metabolism in the striatum, and the lack of extrapyramidal effects of clozapine may be due to its brief action on dopamine metabolism in the striatum.