This thesis explored the mechanism of action of MPTP and its toxic metabolite, MPP⁺, and compared it to the mechanism of action of haloperidol metabolites, some of which are found in schizophrenic patients. Experiments assessed the effects of these compounds on several aspects of amine uptake in mouse brain synaptosomes. Both MPTP and MPP⁺ were inhibitors of labeled neurotransmitter (serotonin and dopamine) uptake consistent with previous studies. MPP⁺ had a higher inhibitory potency in the dopaminergic system, while MPTP had a higher inhibitory potency in the serotonergic system. Haloperidol metabolites (HPP⁺, R-HPP⁺, and HPTP) also inhibited both amine transport systems with a greater affinity for the serotonergic system. Additional studies demonstrated that all of the above compounds showed reversible inhibition of serotonin uptake following drug removal by centrifugation and resuspension. In the dopaminergic system, both MPTP and MPP⁺ were reversible; however, HPP⁺ was not. This finding suggests that HPP⁺ treatment may result in irreversible poisoning of the nerve terminal or it may demonstrate a slow off-rate for its interaction with the dopamine transporter. Furthermore, HPP+ showed non-competitive inhibition of both serotonin and dopamine uptake. Amine uptake in the presence and absence of HPP* had a decreased maximal inhibitory effect and no potency change. The reversible inhibition of serotonin uptake by HPP⁺ might suggest competitive inhibition, but apparently, the comparative rates of binding and unbinding of HPP⁺ and serotonin resulted in a non-competitive interaction.

These experiments support the use of MPTP as a model system for analyzing the neurotoxic potential of toxins, drug metabolites, and pesticides. The similar in vitro potencies suggest that the haloperidol derivatives could have effects similar to those of MPP⁺ in vivo.