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Order in the Cortex: Clozapine Curbs Unruly Networks

13 September 2007. Changes in neuronal activity in the prefrontal cortex (PFC) are thought to give rise to some of the cognitive symptoms of schizophrenia. Successful treatment of these symptoms with antipsychotic medicines predicts better disease management and outcome. Of the drugs available, the atypical antipsychotic clozapine is regarded as the most effective against cognitive symptoms, but how it acts on neurons of the PFC is not understood.

To shed some light on that question, two groups took the tack of recording single neuron activity in living animals treated with NMDA receptor antagonists to induce schizophrenia-like symptoms. The studies, one published by a group led by Pau Celada and Francesco Artigas of the Institut d’Investigacions Biomediques de Barcelona in Spain in PNAS on September 4, and another from Houman Homayoun and Bita Moghaddam of the University of Pittsburgh, Pennsylvania, in Biological Psychiatry last year, come up with similar findings: NMDA antagonists disrupt spontaneous rates and patterns of PFC neuronal spiking, which clozapine restores with a surprising and unique deftness. Compared to the first-generation (typical) medicine haloperidol, clozapine has an ability to fine-tune neuronal activity toward a more normal state, which may help explain its improved clinical efficacy.

In their study, published online October 13, 2006, Homayoun and Moghaddam carried out single neuron recording in awake rats after treatment with clozapine or haloperidol, and the NMDA antagonist MK801, which induces some symptoms of schizophrenia in humans. When they gave clozapine alone, the researchers saw the firing rates of some neurons increase, while other decreased or stayed the same. In all, they saw effects on half the neurons they recorded. Interestingly, clozapine tended to activate neurons with low baseline firing rates, and inhibit those with high baseline rate. This effect was not seen with haloperidol, which caused only transient increases in activity in some neurons, but sustained decreases in others.

MK801 by itself increased activity in 80 percent of recorded neurons, while in animals pretreated with clozapine and then MK801, significantly fewer neurons showed increased activity, and the increases were of lower magnitude. Half of the neurons in the clozapine group showed no change in activity. Haloperidol was much less effective at reducing the number of neurons with high activity, and did not reduce average firing rates at all.

Because the experiments involved awake animals, the researchers could look at behavior, and they found that despite the vastly different effects of the drugs on PFC firing, either antipsychotic reversed the appearance of stereotypical repetitive behaviors induced by MK801. They saw a close correlation between behavioral responses and neuronal firing in individual clozapine-treated animals, but not in those treated with haloperidol. From this, the authors conclude that the behavioral effect of haloperidol is “most probably” mediated at the subcortical level.

“The present data suggest that clozapine modulates PFC neuronal firing on the basis of baseline activity level of different ensembles. This modulatory activity might confer clozapine an ability to fine-tune the PFC function through gating unwanted disturbances in neuronal signal to noise ratio,” Homayoun and Moghaddam write.

The new data from the Spanish group support those results, with the psychotomimetic phencyclidine (PCP) used to induce PFC functional abnormalities in anesthetized rats. In single cell recordings of PFC pyramidal neurons, they found that PCP activated some neurons and inhibited others. First author Lucila Kargieman and colleagues also found a disruption in neuronal synchrony. By measuring local field potentials, they discovered that PCP decreased cortical synchrony in the delta frequency range. In addition, they found that PCP caused induction of c-fos expression in PFC pyramidal neurons, an indicator of increased neuronal activity. Either clozapine or haloperidol treatment reduced the excess neuronal firing and re-established synchrony. Clozapine also inhibited fos induction.

Taken together, the results of both papers suggest that antipsychotic drugs may partly exert their therapeutic effect by normalizing PFC activity, which is required for higher order functions that integrate external information with internal representations to determine behavior. This could occur via blocking dopamine D2 receptors. In the case of clozapine, other receptor targets may help produce its constellation of actions distinct from older drugs like haloperidol. Whatever the cause, the ability of clozapine to modulate neuronal activity both up and down could be one key to its therapeutic actions.—Pat McCaffrey.

References:
Kargieman L, Santana N, Mengod G, Celada P, Artigas F. Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine. Proc Natl Acad Sci U S A. 2007 Sep 4; [Epub ahead of print] Abstract Homayoun H, Moghaddam B. Fine-tuning of awake prefrontal cortex neurons by clozapine: comparison with haloperidol and N-desmethylclozapine. Biol Psychiatry. 2007 Mar 1;61(5):679-87. Epub 2006 Oct 13. Abstract

 
Comments on News and Primary Papers
Primary Papers: Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine.

Comment by:  Dan Javitt, SRF Advisor
Submitted 13 September 2007 Posted 13 September 2007

PCP model forges ahead
What is the true cause of schizophrenia? Over the past 50 years, the amphetamine and PCP models have been fighting it out. Amphetamine got out to an early lead, mostly because it was discovered first, and PCP has been playing catch-up ever since. One way to keep score with these models is to track citations in general “high-profile” science journals such as PNAS for (dopamine or D2) vs. (glutamate or NMDA), and schizophrenia.

Since 1967, in MEDLINE, the amphetamine model has a commanding lead, 35 cites to 19. However, since 2004, the two models are exactly equal, with 12 cites each. With this article, glutamate forges out to a commanding lead.

The article by Kargieman and colleagues also points out the importance of delta rhythms as indices of thalamocortical activity. The finding that PCP disrupts delta rhythmicity resonates with the emerging literature on slow-wave sleep reductions in schizophrenia. The finding that clozapine reverses PCP-induced disruption of delta sleep is consistent with improvements in slow-wave sleep that...  Read more


View all comments by Dan Javitt

Comment by:  J David Jentsch
Submitted 16 September 2007 Posted 17 September 2007

The article by Kargieman and colleagues further specifies the cellular mechanisms underlying the actions of clozapine in a model of pharmacologically induced cortical dysfunction. Separately, clozapine has been demonstrated to be capable of reducing or eliminating the complex behavioral and cognitive impairments elicited by acutely administered NMDA antagonists (Geyer et al., 2001; Idris et al., 2005; Lipina et al., 2005), and these cellular mechanisms shown by Kargieman et al. may represent the level of interaction between clozapine and phencyclidine-like drugs.

What is surprising from so many of these studies is the quality of the reversal of effects produced by clozapine, despite the fact that it (like most other antipsychotic drugs) has limited efficacy both at an individual and population level. Furthermore, there remain many reports in the literature demonstrating that while some cognitive and symptomatic domains in schizophrenia...  Read more


View all comments by J David Jentsch

Comment by:  Jeremy Seamans
Submitted 28 September 2007 Posted 28 September 2007

The paper by Kargieman et al. provides an interesting perspective on the effects of PCP on activity in the prefrontal cortex. Dr. Javitt brings up an excellent point in his commentary that the study highlights the importance of PCP in this preparation as a model of slow-wave sleep disturbances in schizophrenia. In anesthetized animals, field potential recordings resemble the up and down states observed in slow-wave sleep. These states are driven by NMDA receptors and, accordingly, NMDA antagonists such as PCP and ketamine should reduce them as reported. The odd thing about NMDA antagonists is that they themselves can be used as anesthetics to produce a state where slow delta oscillations predominate. For instance, robust up and down states or slow oscillations at or below delta are observed when ketamine is used as an anesthetic. Therefore, NMDA antagonists can induce a state where delta activity is prominent, yet if the subject is already in that state, the effect of the drug is to reduce such activity.

So this also may be the case with PCP. There are numerous EEG studies...  Read more


View all comments by Jeremy Seamans
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