Elsevier

Biological Psychiatry

Volume 64, Issue 5, 1 September 2008, Pages 392-400
Biological Psychiatry

Archival Report
The Hallucinogen DOI Reduces Low-Frequency Oscillations in Rat Prefrontal Cortex: Reversal by Antipsychotic Drugs

https://doi.org/10.1016/j.biopsych.2008.03.013Get rights and content

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 μV2 in basal conditions and after 50–300 μg/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 (1 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.

Section snippets

Animals

Male albino Wistar rats (250–320 g, Iffa Credo, Lyon, France) were kept in a controlled environment (12-hour light-dark cycle, 22 ± 2°C) with food and water provided ad libitum. Animal care followed the European Union regulations (O.J. of E.C. L358/1 18/12/1986).

Drugs and Reagents

Clozapine and DOI were obtained from Sigma/RBI (Natick, Massachusetts); M100907 [R-(+)-alpha-(2,3-dimethoxyphenil)-1-[4-fluorophenylethyl]-4-piperidinemethanol] (Lilly code LY 368675) was from Eli Lilly (Indianapolis, Indiana), and

Effects of DOI on Pyramidal Neuron Activity in mPFC

The effects of intravenous (IV) administration of DOI on the discharge rate of pyramidal neurons in the rat mPFC have been previously described (23). Here we extend our analysis of these data by showing the effect of DOI on burst firing and LFP. In the subgroup of units in which firing rate was increased by DOI (.05–0.3 mg/kg IV; n = 18), a parallel increase in the number of spikes fired in bursts, the total number of bursts and the duration of burst episodes was observed (Table 1). Conversely,

Discussion

This study sheds new light on the neurobiological basis of the psychotomimetic effect of the 5-HT2A/2C receptor agonist DOI. Previous in vitro studies showed that DOI increased spontaneous and evoked EPSCs in layer V pyramidal neurons of the rat mPFC (24, 25). Subsequent in vivo studies indicated that systemic DOI administration markedly altered the firing rate of pyramidal neurons with an overall increase in discharge (23). Likewise, DOI increased high-frequency network activity in rat mPFC

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