Journal
BIOLOGICAL PSYCHIATRY
Volume 64, Issue 5, Pages 392-400Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2008.03.013
Keywords
5-HT2A receptors; EEG; local field potential; psychotomimetic agents; pyramidal neurons; schizophrenia
Categories
Funding
- Spanish Ministry of Health
- [SAF 2007-62378]
- [FIS 060264]
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Background: Perceptual and psychic alterations and thought disorder are fundamental elements of schizophrenia symptoms, a pathology associated with an abnormal macro- and microcircuitry of several brain areas including the prefrontal cortex (PFC). Alterations in information processing in PFC may partly underlie schizophrenia symptoms. Methods: The 5-HT2A/2C agonist DOI and antipsychotic drugs were administered to anesthetized rats. Single unit and local field potential (LFP) extracellular recordings were made in medial PFC (mPFC). Electrolytic lesions were performed in the thalamic nuclei. Results: DOI markedly disrupts cellular and network activity in rat PFC. DOI altered pyramidal discharge in mPFC (39% excited, 27% inhibited, 34% unaffected; n = 51). In all instances,DOI concurrently reduced low-frequency oscillations (.3-4 Hz; power spectrum: .25 +/- .02 and .14 +/- 01 mu V-2 in basal conditions and after 50-300 mu g/kg intravenous (IV) DOI, respectively; n = 51). Moreover, DOI disrupted the temporal association between the active phase of LFP and pyramidal discharge. Both effects were reversed by M100907 (5-HT2A receptor antagonist) and were not attenuated by thalamic lesions, supporting an intracortical origin of the effects of DOI. The reduction in low-frequency oscillations induced by DOI was significantly reversed by the antipsychotic drugs haloperidol (.1-.2 mg/kg IV) and clozapine (I mg/kg IV). Conclusions: DOI disorganizes network activity in PFC, reducing low-frequency oscillations and desynchronizing pyramidal discharge from active phases of LFP. These effects may underlie DOI's psychotomimetic action. The reversal by clozapine and haloperidol indicates that antipsychotic drugs may reduce psychotic symptoms by normalizing an altered PFC function.
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