Effects of chronic administration of neuroleptic and anticholinergic agents on densities of D2 dopamine and muscarinic cholinergic receptors in rat striatum.

It has been suggested that the development of tardive dyskinesia (TD), a serious and sometimes permanent movement disorder that may follow the use of neuroleptic drugs, is due to an increase in the density of or to a functional supersensitivity of D2 dopamine receptors in the striatum. The atypical neuroleptic clozapine (CLZ) is thought not to cause either acute extrapyramidal syndromes or TD because of its intrinsic anticholinergic activity. This hypothesis was examined using an increase in the density of striatal D2 dopamine receptors after chronic neuroleptic treatment in rats as a model of the changes underlying TD. Rats were treated for 14 days with saline; the neuroleptics CLZ, thioridazine or fluphenazine decanoate (FD); the anticholinergic drugs atropine or trihexyphenidyl or with FD together with atropine or trihexyphenidyl. Specific binding of [3H]spiroperidol to striatal D2 receptors was increased by 26 to 31% (P less than .05) in the groups treated with FD alone or in conjunction with any of the anticholinergic agents. There was no significant increase in the density of D2 receptors after administration of CLZ or thioridazine. The results are consistent with the hypothesis that an increase in the density of D2 receptors is associated with the development of TD. Because coadministration of anticholinergic drugs with FD does not attenuate the effects of the latter drug on striatal D2 receptors, it is likely that other properties of CLZ are responsible for its reduced propensity to produce alterations in D2 receptors and/or TD.