Hatzipetros T et al. (2007) Haloperidol treatment after high-dose methamphetamine administration is excitotoxic to GABA cells in the substantia nigra pars reticulata. J Neurosci 27: 5895–5902

The antipsychotic drug haloperidol is often used in emergency care to treat psychoses induced by methamphetamine, but a recently published animal study by Hatzipetros et al. warns that this therapy might cause neuronal death in the substantia nigra (SN) and could predispose individuals to hyperkinetic movement disorders and seizures.

A novel toxicity to γ-aminobutyric acid (GABA) -releasing cells was observed in the SN pars reticulata (SNr) of adult rats treated with subchronic haloperidol after administration of high doses of methamphetamine. The loss of GABA neurons in this treatment group was demonstrated by significant decreases in the expression of neuronal-specific nuclear protein (P <0.05) and glutamate decarboxylase 67 (P <0.05) compared with controls; death of GABAergic cells in the SNr of treated rats was confirmed by the presence of increased DNA fragmentation. Dopaminergic neurons in the SN were unaffected. Further experiments demonstrated that neither methamphetamine nor haloperidol administration alone caused loss of GABAergic neurons, but that loss of these cells did result from exposure to both drugs combined. The investigations showed that D2 receptor antagonism (with haloperidol) during or after methamphetamine administration causes a persistent release of glutamate in the SNr, activation of glutamate receptors, and subsequent excitotoxicity.

Hatzipetros et al. conclude that the death of GABAergic cells in the SN contraindicates the treatment of methamphetamine-induced psychoses with haloperidol and that current clinical practices may need to be reconsidered.