Haloperidol-induced morphological alterations are associated with changes in calcium/calmodulin kinase II activity and glutamate immunoreactivity.

Abstract

Administration of haloperidol for 2 weeks causes an increase within the caudate nucleus of asymmetrical synapses associated with a discontinuous or perforated, postsynaptic density (PSD) [Meshul et al. (1992), Psychopharmacology, 106:45-52; Meshul et al. (1992), Neuropsychopharmacology, 7:285-293]. Coadministration of the N-methyl-D-aspartate noncompetitive antagonist, MK-801, with haloperidol blocked the increase in striatal synapses containing a perforated PSD [Meshul et al. (1994), Brain Res., 648:181-195]. Examination of the caudate using immuno-gold electron microscopy revealed the vast majority (90%) of asymmetrical synapses were labelled with a glutamate antibody [Meshul et al. (1994), Brain Res., 648:181-195]. The purpose of this study was to determine if there were any changes in the density of glutamate immunoreactivity within presynaptic terminals of asymmetric synapses within the striatum following treatment with haloperidol for 1 month that would correlate with the previously observed increase in synapses with perforated PSDs. We also determined the activity of striatal calcium/calmodulin kinase II (CaMK II), an enzyme known to be localized within the synaptic region, after administration of haloperidol. We report here that haloperidol causes an increase in the activity of CaMK II and a decrease in the density of immuno-gold labelling for glutamate within the nerve terminals of asymmetrical synapses containing a perforated or nonperforated PSD. These results are consistent with the hypothesis that the haloperidol-induced increase in activity of CaMK II and the increase in glutamate release, as suggested by the decrease in presynaptic glutamate immunoreactivity, may ultimately lead to an increase in the number of synapses displaying a perforated PSD. These results support the speculation that the haloperidol-induced increase in synapses containing a perforated PSD may be associated with enhanced activity at excitatory synapses.