A comparative study of the anticholinesterase activity of several antipsychotic agents.

Drug-induced inhibition of plasma and tissue cholinesterase activity was evaluated in rats. The dopamine receptor antagonists haloperidol (HALO), chlorpromazine (CPZ), thioridazine (THIO), fluphenazine (FLU), clozapine (CLO) and sulpiride (SULP), used as neuroleptics, were tested. Two biochemical parameters were measured in vitro: the minimal effective concentration (MEC) for cholinesterase inhibition and the 50% inhibitory concentration (IC50). In addition, animals were tested for rotational activity after a unilateral intrastriatal injection of the drugs. The doses used for each drug were previously determined IC50s. After unilateral striatal drug injection, rats were challenged with intraperitoneal amphetamine injection in order to stimulate rotation. All drugs tested induced decreases in cholinesterase activity. Plasma MEC for THIO, FLU, HALO and CPZ were significantly lower than for CLO and SULP. In striatum, the MEC for TIO, CPZ and FLU was significantly lower than for HAL. According to plasma IC50, THIO, CPZ and CLO are potent cholinesterase inhibitors. CLO showed the lowest potency of cholinesterase inhibition in the striatum and THIO showed the highest potency in plasma and striatum. In conclusion, anticholinesterase activity is not related to D(2) receptor blockade or antipsychotic potency; and therefore the antipsychotic effects are not related to an increase in acetylcholine. All drugs induced similar contralateral rotation, except for CLO that was different from SULP and was not different from its control. Since equivalent cholinesterase inhibitory concentrations were used for all drugs and no differences in nigrostriatal behavioral effects were observed, these data suggest the participation of an important cholinergic component in this behavior. Therapeutically, the stronger the cholinesterase inhibition is, the more potent the cholinergic effects are and, consequently, the induction of extrapyramidal symptoms becomes more feasible.