1. ¹Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2. ²Schizophrenia Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
3. ³Department of Psychiatry, Columbia University, New York, NY, USA

Correspondence: Dr LF Jarskog, Department of Psychiatry, University of North Carolina at Chapel Hill, 7025B Neuroscience Hospital, CB# 7160, Chapel Hill, NC 27599-7160, USA. Tel: +1 919 966 8035; Fax: +1 919 966 8994; E-mail: jarskog@med.unc.edu

Received 17 August 2005; Revised 17 February 2006; Accepted 21 February 2006; Published online 12 April 2006.

Abstract

In schizophrenia, studies indicate that apoptotic susceptibility in cortex may be increased. A role for apoptosis in schizophrenia could potentially contribute to post-mortem evidence of reduced cortical neuropil and neuroimaging studies showing progressive cortical gray matter loss. Interestingly, antipsychotic treatment has been associated with higher cortical levels of anti-apoptotic Bcl-2 protein in rat cortex and preliminary data has suggested a similar association in schizophrenia and bipolar disorder. To better understand the effects of antipsychotics on apoptotic regulation, rats were administered haloperidol, clozapine, quetiapine, or saline daily for 4 weeks. Multiple apoptotic markers, including Bcl-2, pro-apoptotic Bax, anti-apoptotic XIAP, and the downstream protease caspase-3 were measured in frontal cortex using Western blot. Caspase-3 activity, activated caspase-3-positive cell number, and DNA/histone fragmentation levels were also determined. Western blot showed that immunoreactivity of Bax and Bcl-2 bands were unchanged with treatment. However, mean density of the 19 kD activated caspase-3 band was 55% higher with haloperidol (p<0.001), 40% higher with clozapine (p<0.05), and 48% higher with quetiapine (p<0.01) compared to saline control. Specific activity of caspase-3 was also increased across all treatments (p<0.0001), while DNA fragmentation rates remained unchanged. These data suggest that sub-chronic antipsychotic treatment is associated with non-lethal caspase-3 activity. The findings do not support a prominent Bcl-2-mediated neuroprotective role for antipsychotics. Although the association between antipsychotic treatment and increased pro-apoptotic caspase-3 is intriguing, further study is needed to understand its potential effects.