Behavioral effects of a single neuroleptic treatment grow with the passage of time

The principal finding of this manuscript is that the incidence of catalepsy observed in the rat after a single administration of low, clinically relevant doses of the dopamine receptor antagonists and antipsychotic agents, haloperidol and fluphenazine hydrochloride, grows over time such that one re-exposure to the same compound up to 8 weeks later results in a marked enhancement (i.e. sensitization) of this response. This phenomenon appears to be independent of pharmacokinetic or conditioning factors as well as alterations in dopamine or dihydroxyphenylacetic acid. It suggests that the antidopaminergic influence of acute exposure to a neuroleptic not only persists but continues to sensitize for extraordinary periods of time even after the drug is no longer detectable in the system. Our findings may hold the key to understanding the apparent paradox that although neuroleptics presumably induce their therapeutic actions in disorders such as Tourette syndrome and schizophrenia as well as their parkinsonian effects by blocking dopamine receptors, this antagonism occurs immediately while behavioral changes often require weeks for maximal development.