Clozapine is an antipsychotic medication with superior efficacy in treatment refractory schizophrenia. The molecular basis of clozapine’s therapeutic profile is not well understood. We studied behavioral effects of clozapine in Caenorhabditis elegans to identify novel pathways that modulate clozapine’s biological effects. Clozapine stimulated egg laying in C. elegans in a dose-dependent manner. This effect was clozapine-specific, as it was not observed with exposure to a typical antipsychotic, haloperidol or an atypical antipsychotic, olanzapine. A candidate gene screen of biogenic amine neurotransmitter systems identified signaling pathways that mediate this clozapine-specific effect on egg laying. Specifically, we found that clozapine-induced increase in egg laying requires tyramine biosynthesis. To test the implications of this finding across species, we explored whether trace amine systems modulate clozapine’s behavioral effects in mammals by studying trace amine-associated receptor 1 (TAAR1) knockout mice. Clozapine increased prepulse inhibition (PPI) in wild-type mice. This increase in PPI was abrogated in TAAR1 knockout mice, implicating TAAR1 in clozapine-induced PPI enhancement. In transfected mammalian cell lines, we found no TAAR activation by antipsychotics, suggesting that modulation of trace amine signaling in mice does not occur directly at the receptor itself. In summary, we report a heretofore- unknown role for trace amine systems in clozapine-mediated effects across two species: C. elegans and mice.
Karmacharya, R.*, S.K. Lynn*, S. Demarco, A. Ortiz, X. Wang, M.Y. Lundy, Z. Xie, B.M. Cohen, G.M. Miller, and E.A. Buttner. 2011. Behavioral effects of clozapine: Involvement of trace amine pathways in C. elegans and M. musculus. Brain Research 1393:91-99.
* These authors contributed equally to the study.
In psychiatrically-well subjects the modulation of event related potentials (ERPs) by emotional facial expressions is found in several ERPs from ~100 ms and later. A face-related EPR, the N170, is abnormally reduced in schizophrenia to faces relative to other complex objects and research suggests emotional modulation of N170 may be reduced as well. To further examine facial emotion modulation of N170, subjects detected neutral facial expressions from among five emotional expressions (happy, sad, fearful, angry, and disgusted). Over occipitotemporal sites, psychiatrically-well subjects showed bilateral differences in N170 amplitude among expressions (P=0.014). Schizophrenia subjects failed to show this modulation (P=0.551). Accuracy on the task did not differ between groups, nor did the pattern of errors. However, in patients, greater positive and negative symptom ratings were associated with increased failure to button press to neutral faces, suggesting misattribution of emotion to neutral expressions in the more ill patients. Because the N170 is largely specific to faces, these results suggest that an impairment specific to the visual processing of facial expressions contributes to the well-known behavioral abnormalities in facial emotion tasks in schizophrenia.
Lynn, S.K., and D.F. Salisbury. 2008. Attenuated modulation of the N170 ERP by facial expressions in schizophrenia. Journal of Clinical EEG & Neuroscience 39(2):108-111.
Principal Investigator: Spencer Lynn
Source: Harvard Medical School, Department of Psychiatry
Award: Livingston Award
The objective of this study was to investigate the causes of emotional impairments and their specificity to schizophrenia by examining event related brain potentials elicited by an important social stimulus–emotional facial expressions–in the context of emotional and non-emotional impairments.
Role: Post-doctoral Fellow
Source: Clinical Research Training Program in Biological and Social/Developmental Psychiatry, Judge Baker Children’s Center, Department of Psychiatry, Harvard Medical School (T32 MH016259).
Preceptor: Dean Salisbury, PhD, Cognitive Neuroscience Laboratory, McLean Hospital, Belmont, Massachusetts