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Phencyclidine (PCP) induces a psychotomimetic state that closely resembles schizophrenia. Therefore, PCP-treated animals can provide a model for schizophrenia. Using differential display, we identified a gene regulated by the delayed action of PCP in rat nucleus accumbens (NAcs). Sequence analysis showed that the cDNA clone obtained was identical to rat synapse-associated protein 90/ postsynaptic density-95-associated protein 1 (SAPAP1). Quantitative reverse transcriptase (RT)-PCR analysis showed that SAPAP1 mRNA had increased significantly in rat NAc (Po0.0001) and hippocampus (Po0.01) 24 h after a PCP (10 mg/kg) injection as compared to the controls. Immunoquantification using an anti-SAPAP1 antibody indicated that immunoreactivity for SAPAP1 increased significantly (Po0.05) in the NAcs of unmedicated patients with schizophrenia, as compared to the control subjects and medicated patients with schizophrenia. Our findings support the hypothesis that there is abnormal glutamatergic neurotransmission in schizophrenia and show evidence of abnormalities in the intracellular signal transduction via N-methyl-D-aspartate (NMDA) receptors.

We searched for changes in glutamatergic transmission via N-methyl-D-aspartate (NMDA) receptors in the hippocampus and striatum of rats behaviourally sensitized to methamphetamine (Meth). Prior to being given a challenge dose of Meth (2 mg/kg, s.c.), the rats were given Meth (4 mg/kg, s.c.) five times a week for 3 wk. Seven days after the challenge test, we examined glutamate (Glu) release from hippocampal and striatal slices evoked by 30 mm KCl, and NMDA-evoked dopamine (DA) release from striatal slices. We further immunoquantified NMDAR1, R2A and R2B receptors as well as the fodrin alpha-subunit, a 240 kDa cytoskeletal protein that is cleaved to form 150 kDa limited proteolytic fragments by NMDA receptor stimulation. In the study of KCl-evoked Glu release, Glu release from the hippocampus was 31% lower in the Meth-sensitized rats than in the control rats, while Glu release from the striatum was 34% higher in the Meth-sensitized rats. NMDAR1, R2A and R2B immunoreactivities in the striatum were significantly lower in the Meth-sensitized rats (by 12, 13 and 12%, respectively) than those in the control rats. However, no differences in the immunoreactivities were found for the hippocampus. Immunoquantification of the fodrin alpha-subunit in the hippocampus revealed that 150 kDa fragments were significantly lower (by 10%) in the Meth-sensitized rats than in the control rats. In contrast to the control rats, NMDA-evoked DA release from the striatum was diminished in the Meth-sensitized rats. These results indicate that the activity of the Glu system is functionally decreased in the hippocampus of Meth-sensitized rats, whereas the Glu system in the striatum of Meth- sensitized rats shows adaptive and functional changes in the receptors in response to the increased Glu release.

We investigated changes in signal transduction via calcineurin (CaN) in the striatum of rats behaviorally sensitized to methamphetamine (Meth). The rats were injected with Meth (4 mg/kg, s.c.) five times a week for 3 weeks and then were given a challenge dose of Meth (2 mg/kg, s.c.). Seven days after the challenge test, we determined the levels of CaN Aalpha and Abeta by Western blotting. We further immunoquantified DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, mw 32,000) and phosphothreonine-DARPP-32, which can be dephosphorylated at threonine sites by CaN. We found that both CaN Aalpha and Abeta were significantly decreased in the particulate fractions but were not changed in the soluble fractions from the striatum of Meth-sensitized rats as compared with control rats. The same findings were observed in the striatum of rats 6 h after the injection of PCP (10 mg/kg, s.c.). In the striatum of Meth-sensitized rats, phosphothreonine-DARPP-32 immunoreactivities significantly increased, but DARPP-32 immunoreactivities were not significantly different from those of the control rats. These results indicate that the activity of signal transduction via CaN is functionally decreased in the striatum of Meth-sensitized rats.