Introduction The high incidence of motor side effects associated with neuroleptic drug administration poses a signif- icant problem for the treatment of schizophrenia. These motor problems complicate treatment and are often unresponsive to therapy. 1 There is still consid- erable uncertainty about the mechanisms by which neuroleptics produce these untoward side effects. It has long been hypothesized that stimulation of super- sensitive D2 receptors produces motor side effects associated with neuroleptic use. 1 However, this and other hypotheses invoking deficits in GABA, sero- tonin, norepinephrine and acetylcholine transmission as playing primary roles in this movement disorder have provided inconclusive data regarding the mech- anism(s) underlying the development of neuroleptic- induced motor side effects. 1 One interesting idea that has emerged recently is that effects of neuroleptics on the glutamate system may underlie the development of motor side effects. Chronic administration of typical neuroleptics has effects on glutamate receptors that are not observed with clozapine treatment. 2 Chronic administration of haloperidol, but not clozapine, augments striatal glutamate release. 3–5 It is thus possible that neuro- leptic-induced enhancement of glutamate activity contributes significantly to development of motor side effects by causing prolonged low-level neuro- toxicity at cortico-striatal synapses. This may occur directly via neuroleptic-induced inhibition of gluta- mate transport or indirectly via neuroleptic effects on the dopamine system. Conventional neuroleptics block D2 autoreceptors causing increased release of dopamine. 6 Dopamine can, in turn, block glutamate uptake, 7 thereby increasing synaptic concentrations of glutamate and promoting excitotoxicity. Enhance- ment of glutamatergic transmission could, with either prolonged exposure or in individuals at risk (i.e. with declining mitochondrial function due to age) ultimately result in excitotoxicity. Enhancement of glutamate activity in the presence of elevated catecholamine metabolism could result in poten- tiation of neurotoxicity. 8 Glutamate reuptake is the primary mechanism for reducing synaptic concen- trations of glutamate and preventing excitotoxicity. 9 Accordingly, the present study investigated anti- psychotic drug effects on the gene expression of the glutamate transporter GLT-1 in the striatum. Materials and Methods Adult male Sprague–Dawley rats (Taconic Farms) weighing 300–350 g at the start of the study were assigned to one of three treatment groups: halo- peridol (0.5 mg/kg, i.p.) daily for 30 days, clozapine (10.0 mg/kg, i.p.) daily for 30 days or saline (sterile, i.p., in a volume similar to that used for drug admin- Molecular Neuroscience 111 0111 0111 0111 0111 0111 111p © Rapid Science Publishers Vol 9 No 1 5 January 1998 133 RECENT reports have shown that typical neuroleptics may enhance glutamatergic neurotransmission and that these effects might in part underlie motor side effects of chronic neuroleptic treatment. Since glutamate reuptake is the primary mechanism for controlling extracellular glutamate levels, the present study was conducted to examine whether chronic neuroleptic exposure alters gene expression for the glutamate transporter GLT-1 in the striatum. Although both haloperidol and clozapine treatment for 30 days significantly decreased GLT-1 expression from normal, the effects of haloperidol treat- ment were consistently, and in the dorsal striatum, significantly greater than those of clozapine. These find- ings suggest that a deficiency in glutamate transport may underlie the pathogenesis of neuroleptic-induced movement disorders. Key words: Clozapine; Glutamate; Haloperidol; Neuro- leptics; Reuptake; Striatum Chronic neuroleptic treatment alters expression of glial glutamate transporter GLT-1 mRNA in the striatum J. S. Schneider, CA Timothy Wade and T. I. Lidsky 1 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Rm 521 JAH, Philadelphia, PA 19107; 1 Department of Psychobiology, Institute for Basic Research, Staten Island, NY 10314, USA CA Corresponding Author Website publication 20 December 1997 NeuroReport 9, 133–136 (1998)