Schizophrenia Research Forum - A Catalyst for Creative Thinking

Modeling Psychosis in Prefrontal Cortex—The Effects of Amphetamine

29 September 2006. Amphetamine “psychosis,” typically brought on by repeated exposure to the drug, mimics many aspects of the psychosis of untreated schizophrenia. Much of the research into the biological substrates of this psychosis has focused on subcortical nuclei, but there is also evidence for amphetamine-induced changes in cortical areas, particularly prefrontal cortex (PFC).

Two recent papers explore the cortical changes brought on by repeated amphetamine administration in animal models: in a paper published online August 16, 2006, in Neuropsychopharmacology, Lynn Selemon and colleagues at Yale University report that several years after a series of exposures to amphetamine, pyramidal cells in the PFC of monkeys have altered dendritic morphologies, specifically changes that suggest atrophy of the dendritic arbors, indicating that these are permanent brain changes wrought by the drug.

Houman Homayoun and Bita Moghaddam of the University of Pittsburgh, writing in the August 2 issue of the Journal of Neuroscience, report that the electrophysiological characteristics of PFC neurons begin to change after just a few doses of the drug, and that the amphetamine exposure has opposite effects in two subregions of prefrontal cortex—a progressive hyperactivation of orbitofrontal cortex and hypoactivation of medial prefrontal cortex.

Modeling psychosis
Amphetamine psychosis has been proposed as a model for some features of schizophrenia, particularly the positive symptoms such as hallucinations (Snyder, 1973). It has generally been argued that initial physiologic changes in subcortical midbrain dopaminergic neurons and their targets in the striatum sensitize the neural networks involved so that later exposures can induce psychosis. This model of amphetamine sensitization has also been adopted as a paradigm for researchers interested in the addictive powers of drugs of abuse.

The Yale group founded by the late Patricia Goldman-Rakic, whose work has been carried on by Selemon and others, has argued for an important role of prefrontal cortex in mediating the changes in behavior that occur following repeated amphetamine exposure, whether in humans or animals. Working in monkeys, they found that amphetamine generates both psychotic-like behaviors and deficits in working memory, the latter a function in which prefrontal cortex plays a critical role.

In their current paper, Selemon and colleagues revisited brain tissue from monkeys that had been part of the earlier behavioral experiments. The animals had received low doses of the drug for 6 or 12 weeks, followed by challenge doses during experiments. Three years after these exposures, the authors report, Golgi impregnation revealed reductions in overall dendritic branching in PFC, in peak spine density in layers II and superficial III, as well as in the distance from the cell body to the region of peak spine density.

This evidence parallels findings in schizophrenia of reductions in the complexity of dendritic arbors in prefrontal cortex in schizophrenia patients. However, they differ from findings in rodents, in which Terry Robinson and colleagues at the University of Michigan have reported that repeated amphetamine exposure leads to increases in measures of dendritic “health,” such as length, branching, or spine density. In addition to possible methodologic differences, Selemon and colleagues point out that the rat morphologic studies were done several months, rather than years, after the amphetamine exposure. “[I]t is possible that the rodent findings represent the early changes in morphology that occur in response to a sensitizing regimen of AMPH exposure while those reported here represent the long-term consequences to a prolonged and seemingly permanent state of dopamine dysregulation in the prefrontal cortex,” they write.

The chicken or the egg?
Which comes first as a result of amphetamine administration— restructuring in subcortical nuclei or in cortical areas? Does one necessarily precede or influence the other? In their recent paper, Homayoun and Moghaddam report that cortical changes occur very early in a paradigm of amphetamine sensitization, suggesting that these are not necessarily sequelae of subcortical changes. The authors report that the amphetamine model produces hypofunction of the medial prefrontal cortex (mPFC), and hyperfunction of orbitofrontal cortex (OFC), findings which, they point out, parallel imaging data from patients with schizophrenia (Ragland et al., 2004).

The authors recorded single-cell activity from mPFC and OFC in conscious, behaving rats. In the first set of experiments, the animals were moving about their home cages, with no particular tasks to attend to. Using an array of implanted electrodes, the authors recorded from a number of neurons at a time, presumed to be pyramidal cells based on their firing patterns. In both mPFC and OFC, the researchers found neurons that are excited by or inhibited by amphetamine, as indicated by changes in firing rate. Neurons in both areas became more responsive to amphetamine during the course of the 5-day (2 mg/kg i.p.) sensitization protocol, and remained more responsive for at least a month after amphetamine exposure. However, there were region-specific differences. Firing rates and clusters of action potentials, or “bursting,” generally decreased in mPFC, but increased in OFC. “This is significant because both the rate and pattern of single-unit firing in the PFC are critical for the maintenance of cognitive functions and reinforcement assessment that are served by these regions,” the authors write.

Of course, idling in their home cage may not particularly tax the rats’ PFC neurons, so Homayoun and Moghaddam recorded from animals that were engaged in an operant responding task where they had to do some thinking and keep track of which hole to nose poke in order to receive a food reward. With increasing amphetamine exposure, the rats perform more poorly, and the researchers report electrophysiological findings consistent with the first experiment—growing mPFC inhibition mirrored by OFC excitation paralleling the impairment in the learning task.

“Given the evidence establishing that mPFC neurons sustain cognitive functions, such as reasoning and decision making, and OFC neurons encode the salient value of rewards, the present data may suggest that even limited exposure to amphetamine delivers a ‘double whammy’ that may be critical for development of addiction or psychosis: it reduces the influence of mPFC on behavior at the same [time] that it exaggerates the salient value of a rewarding experience,” conclude the authors.—Hakon Heimer.

Homayoun H, Moghaddam B. Progression of cellular adaptations in medial prefrontal and orbitofrontal cortex in response to repeated amphetamine. J Neurosci. 2006 Aug 2;26(31):8025-39. Abstract

Selemon LD, Begovic A, Goldman-Rakic PS, Castner SA. Amphetamine Sensitization Alters Dendritic Morphology in Prefrontal Cortical Pyramidal Neurons in the Non-Human Primate. Neuropsychopharmacology. 2006 Aug 16; [Epub ahead of print] Abstract

Q&A with Bita Moghaddam. SRF questions by Hakon Heimer.

Q: Leaving schizophrenia aside for the moment, what are the most important findings and take-home messages of your paper in terms of the amphetamine sensitization model.
A: It suggests that the influence of medial prefrontal cortex on behavior has diminished at the same time as the influence of the orbitofrontal cortex on behavior has been increased. So what are the implications of that? Well, we know that medial prefrontal cortex controls executive functions like decision-making and planning, so if those functions have been disrupted, then the ability to make decisions, or perform other cognitive functions that are regulated by prefrontal cortex like working memory are compromised. On the other hand, the orbitofrontal cortex is responsible for putting salient values on stimuli, so by becoming overactive, or by possibly having more of a control over behavior, it may be exaggerating the value of what’s immediately apparent.

Q: How do these results bear on the chicken-and-egg question: are amphetamine-induced changes likely to be subcortical or cortical first, or simultaneous? Is that a useful way to think about this question?
A: That is a good question, but I think, frankly, it doesn’t matter in terms of function. What amphetamine is essentially doing is releasing monoamines all over the brain, and although a lot of dopamine is being released in the striatum, serotonin, norepinephrine, as well as dopamine are also being released in the prefrontal cortex. But let’s, for the sake of argument, assume that initially it is the striatum that’s being disrupted. The bottom line is that it’s resulting in cortical dysfunction. So for schizophrenia, you could argue: okay, regardless of whether the cortical dysfunction is primary or secondary to the striatal dysfunction, this is a model that is producing prefrontal cortical hypofunction.

Our data suggest that, actually, prefrontal cortex changes may precede striatal changes, only because we see plasticity after a single injection, whereas most of the published work on subcortical systems report plasticity after several days of treatment.

Q: Getting to schizophrenia, you jokingly said in an e-mail that the repeated amphetamine model had been hijacked by the drug abuse crowd as the model of drug-induced plasticity that leads to addiction. Could you just say a little bit about the value of the amphetamine model for psychosis research?
A: Its relevance to addiction is highly theoretical, whereas its relevance to schizophrenia is backed up by well-documented clinical findings. It is a well-characterized model of psychosis and has excellent predictive validity for antipsychotic drugs. Also, recent work, including our paper, shows that it has construct validity in terms of prefrontal cortical deficits. It is a model that, I would argue, has advantages over the PCP model and other pharmacological models, the first being its predictive validity because the amphetamine psychosis is treated with antipsychotic drugs. A PCP-induced psychosis is not typically treated with antipsychotic drugs. I think the field has been dismissing the amphetamine model because people assume that it’s only a model of psychosis …it’s not really modeling affective and cognitive deficits in schizophrenia. But the work that Pat Goldman-Rakic’s lab and Lynn Selemon did shows that actually, no, there are indeed cognitive deficits. We have also seen sustained working memory deficits in rats after amphetamine, so this model is clearly associated with cognitive deficits. Addiction literature also shows that stimulant abusers have working memory and cognitive deficits. In short, I think the assumption that the amphetamine model does not model cognitive or “cortical” deficits related to schizophrenia is unfounded.

In terms of negative symptoms, our data showing changes in orbitofrontal cortex after amphetamine is interesting. Orbitofrontal cortex has a great deal of influence on emotional processing, suggesting that the circuits that control affective regulation and possibly negative symptoms are also profoundly disrupted by chronic amphetamine.

Q: The operant conditioning paradigm that you use—can you draw any link from that very simple task to schizophrenia, or is that too much of a stretch.
A: It’s too much of a stretch.

Q: So the value of this part of the study is demonstrating changes in different states.
A: Yes. To quote a colleague, “How do you know that it is the drug and not behavior that is affecting cortical neurons?” Amphetamine makes animals hyperactive so the concern was that locomotion or the “behavioral state” may lead to secondary changes in cortical neurons. To address this, we tested animals in two different behavioral states, while they were doing nothing in their home cage and while they were in a Skinner box doing an instrumental responding task.

Q: How do you think this is relevant to schizophrenia?
A: I am excited about the coexistence of prefrontal cortex hypoactivity and orbitotemporal area hyperactivity! It’s consistent with the few imaging studies in patients with schizophrenia that have actually looked at both regions and see a similar diverging pattern of prefrontal cortex hyperactivation and orbitoprefrontal overactivation: an example is an American Journal of Psychiatry paper from Raquel Gur’s group (
Ragland et al., 2004). I also think our findings provide a cellular basis for why there are these sustained cognitive disruptions in the amphetamine models that are, again, relevant to schizophrenia. With something like the PCP or ketamine models, you don’t see a prefrontal cortex hypofunction. You see just an exaggerated discharge of all activity, which is clearly impairing prefrontal function, but you don’t see hypoactivity at the neuronal level. It is important that in animals that were doing a task, the change in the pattern of activation—medial prefrontal neurons becoming less active, orbitofrontal neurons becoming more active—was selective to those neurons that were encoding goal-directed behavior. And again, I think in that sense, this does have relevance to both cognitive and negative symptoms of schizophrenia. You have a model that’s selectively disrupting the pattern of activity of those neurons that may play a role in planning for goal-directed and reward-related behavior.

Q: In what way is the drug abuse research of potential interest to people studying schizophrenia psychosis? How do you see the links between these two literatures?
A: For basic science people, they are highly linked. We read each other’s papers, because we’re very much studying the same pathways. Clinically speaking, comorbidity is a huge issue. Nearly 80 percent of patients with schizophrenia smoke. Incidence of abuse of other drugs is 60-80 percent, depending on whose stats you look at. I know the schizophrenia field is becoming very interested in comorbidity. I think we can learn a lot about addiction and schizophrenia by studying mechanisms that are common in both disorders. It is great that in the past few years the addiction literature has been paying a lot of attention to cognition, mostly because the rates of abstinence, or failure to remain abstinent, are very much dependent on cognitive functioning. Many in the drug abuse field are thinking that addiction is a cortical disease, so they are finding themselves reading the schizophrenia/affective disorder literature. I think the literatures are highly related. I know at the basic level, a lot of us go to each other’s meetings and read each other’s papers.

Comments on News and Primary Papers
Comment by:  Henry Holcomb
Submitted 29 September 2006
Posted 2 October 2006

Chronic phencyclidine administration remains the single best model for human psychosis. The crucial paper by Jentsch and colleagues (Jentsch et al., 1997), identifies every element needed for a satisfactory representation of the schizophrenia syndrome.

Though acute NMDA receptor antagonists induce hypermetabolism, prolonged phencyclidine induces a hypometabolic state (Wu et al., 1991; Tamminga et al., 1995) accompanied by severe dopaminergic disturbances (Aalto et al., 2005; Narendran et al., 2005).

Moghaddam's comments emphasize that there are multiple routes to psychosis, and these may converge on cortical glutamatergic/dopaminergic interactions (Narendran et al., 2005). But the numerous studies by her own group and those of Farber, Krystal, Vollenweider, Newcomer, Rowland, Tamminga, and Lahti suggest that there is much to be learned from additional work on the NMDA receptor antagonist preparation.


Jentsch JD, Redmond DE Jr, Elsworth JD, Taylor JR, Youngren KD, Roth RH. Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. Science. 1997 Aug 15;277(5328):953-5. Abstract

Wu JC, Buchsbaum MS, Bunney WE. Positron emission tomography study of phencyclidine users as a possible drug model of schizophrenia. Yakubutsu Seishin Kodo. 1991 Feb;11(1):47-8. No abstract available. Abstract

Aalto S, Ihalainen J, Hirvonen J, Kajander J, Scheinin H, Tanila H, Nagren K, Vilkman H, Gustafsson LL, Syvalahti E, Hietala J. Cortical glutamate-dopamine interaction and ketamine-induced psychotic symptoms in man. Psychopharmacology (Berl). 2005 Nov;182(3):375-83. Epub 2005 Oct 19. Abstract

Narendran R, Frankle WG, Keefe R, Gil R, Martinez D, Slifstein M, Kegeles LS, Talbot PS, Huang Y, Hwang DR, Khenissi L, Cooper TB, Laruelle M, Abi-Dargham A. Altered prefrontal dopaminergic function in chronic recreational ketamine users. Am J Psychiatry. 2005 Dec;162(12):2352-9. Abstract

Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997 Apr 15;17(8):2921-7. Abstract

Farber NB, Kim SH, Dikranian K, Jiang XP, Heinkel C. Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity. Mol Psychiatry. 2002;7(1):32-43. Abstract

Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994 Mar;51(3):199-214. Abstract

Vollenweider FX, Leenders KL, Scharfetter C, Antonini A, Maguire P, Missimer J, Angst J. Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). Eur Neuropsychopharmacol. 1997 Feb;7(1):9-24. Abstract

Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney JW. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology. 1999 Feb;20(2):106-18. Abstract

Rowland LM, Bustillo JR, Mullins PG, Jung RE, Lenroot R, Landgraf E, Barrow R, Yeo R, Lauriello J, Brooks WM. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. Am J Psychiatry. 2005 Feb;162(2):394-6. Abstract

Tamminga CA, Holcomb HH, Gao XM, Lahti AC. Glutamate pharmacology and the treatment of schizophrenia: current status and future directions. Int Clin Psychopharmacol. 1995 Sep;10 Suppl 3:29-37. Abstract

Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001 Oct;25(4):455-67. Abstract

View all comments by Henry HolcombComment by:  Elizabeth Ryan
Submitted 7 October 2006
Posted 7 October 2006
  I recommend the Primary Papers

Excellent overview. My daughter has been addicted to meth for over twenty years and I AM seeing her inability to make constructive, long-term decisions, even when "clean." Our oldest son has schizophrenia, and although he is highly functioning, shows some of the impairment(s) my daughter exhibits.

View all comments by Elizabeth RyanComment by:  J David Jentsch
Submitted 21 November 2006
Posted 22 November 2006
  I recommend the Primary Papers

Moghaddam is correct in arguing that long-term intake of, or exposure to, amphetamine-like drugs produces a spectrum of changes in cortical and subcortical function that underlie cognitive and affective abnormalities that relate to the abuse potential of the drugs, as well as the associated drug-induced psychotic symptoms. This may be particularly true for methamphetamine (Yui et al., 1999). Indeed, Jane Taylor and I proposed 7 years ago now (Jentsch and Taylor, 1999) that dysregulation of frontal cortical function is a common feature of long-term exposure to drugs of abuse; today, this is a phenomenon that is generally accepted as contributing directly to the addictive process (London et al., 2000; Everitt et al., 2001; Robinson and Berridge, 2003; Goldstein and Volkow, 2002; Lubman et al., 2004). In that sense, the concept that amphetamine alters frontal lobe function in important ways relevant to both addictive and psychotic disorders is hardly new.

A separate question touched upon in the article and subsequent discussion is whether either amphetamine or phencyclidine represents a more informative or valid model for schizophrenia and/or its symptoms than the other.

For nearly 60 years, investigators have used amphetamine-like and phencyclidine-like drugs to simulate psychopathological states in human beings and animals that correspond (to varying degrees) with sequelae of schizophrenia. One clear issue that has emerged from the 6 decades of research is that these two drugs produce some similar and some different effects on behavior, which is not surprising, owing to their distinctive pharmacologic and neurochemical mechanisms of action. What is unfortunate is that the apparent differences have led to a history of conflict over which represents the better model for psychotic disorders. In opposition to the overly dogmatic arguments of those in favor of one approach or the other, I argue that we should focus on the commonalities of the action of these two classes of agents to find the mechanisms that will ultimately have the broadest implications for understanding schizophrenia.

What is clear is that, under the right conditions (dose, route of administration, frequency and duration of exposure, etc.), people who are passively exposed to these drugs or who voluntarily consume them can show psychopathological states that include behavioral dimensions of psychotic disorders; this is markedly different from a drug like nicotine which virtually never does. Although these agents very specifically produce psychopathology of interest to schizophrenia researchers, the “right conditions” required for each to achieve temporary or persistent psychotomimetic effects are not known. For example, it is simply not clear what determines which methamphetamine abusers will develop psychotic symptoms and which will not (is it ethnicity, age of onset, total lifetime dose, underlying genetic risk?).

If we knew what the right conditions were for both drugs and could mimic those in animals, I believe that we would find a common set of neuroadaptations in the prefrontal cortex and its striato-pallido-thalamic targets that represent the final common pathway by which these two otherwise distinct agents dysregulate the normal mental and emotional function of animals and people who are exposed to them. I further propose that, if we knew the right conditions under which cannabis induced psychotic symptoms, it would point to the same pathway. At this nexus, we will additionally discover mechanisms that help to explain the comorbidity between substance abuse and psychotic disorders, as the common features for all of these agents is their abuse liability and psychotomimetic properties.

Without the information about the right conditions, the conflict over the validity of amphetamine versus phencyclidine models is unresolvable. Clearly, there are many studies in which one or the other drug was given to animals with little behavioral, physiological, or anatomical feature of schizophrenia being induced. But this is not because there is no general validity for either model; it is because we haven’t learned quite yet what the conditions are under which these drugs affect people in a manner relevant to the field and should be expected to affect animals.

At the current time, concluding that one or the other model is better (whatever that means, in scientific terms) or is more accurate in its ability to induce a model for the disorder is premature.


Everitt BJ, Dickinson A, Robbins TW. The neuropsychological basis of addictive behaviour. Brain Res Brain Res Rev. 2001 Oct;36(2-3):129-38. Review. Abstract

Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry. 2002 Oct;159(10):1642-52. Review. Abstract

Jentsch JD, Taylor JR. Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology (Berl). 1999 Oct;146(4):373-90. Review. Abstract

London ED, Ernst M, Grant S, Bonson K, Weinstein A. Orbitofrontal cortex and human drug abuse: functional imaging. Cereb Cortex. 2000 Mar 1;10(3):334-42. Abstract

Lubman DI, Yucel M, Pantelis C. Addiction, a condition of compulsive behaviour? Neuroimaging and neuropsychological evidence of inhibitory dysregulation. Addiction. 2004 Dec;99(12):1491-502. Review. Abstract

Robinson TE, Berridge KC. Addiction. Annu Rev Psychol. 2003;54:25-53. Epub 2002 Jun 10. Review. Abstract

Yui K, Goto K, Ikemoto S, Ishiguro T, Angrist B, Duncan GE, Sheitman BB, Lieberman JA, Bracha SH, Ali SF. Neurobiological basis of relapse prediction in stimulant-induced psychosis and schizophrenia: the role of sensitization. Mol Psychiatry. 1999 Nov;4(6):512-23. Review. Abstract

View all comments by J David JentschComment by:  J. Daniel Ragland
Submitted 13 December 2006
Posted 13 December 2006
  I recommend the Primary Papers

The acknowledgment that amphetamine psychosis (like schizophrenia) can have inverse effects (both hypo- and hyperfunction) on different regions of the prefrontal cortex (PFC) is an important one, and worth emphasizing. There is regional specificity of effects within the PFC, not just a global increase or decrease in function. In addition to the distinction between the orbital and medial PFC mentioned in the article, there is converging evidence from the working memory imaging literature that schizophrenia may have inverse effects on ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, with increased VLPFC and decreased DLPFC activation in schizophrenia (Glahn et al., 2005). This has potentially important implications for understanding compensatory performance strategies, and for devising cognitive remediation interventions.


Glahn, D.C., Ragland, J.D., Abramoff, A., Barrett, J., Laird, A.R., Bearden, C.E., Velligan, D.I.: Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Hum Brain Mapp. 2005 May;25(1):60-9. Abstract

View all comments by J. Daniel Ragland

Comments on Related News

Related News: Learning from Drug Candidates—New Kid Targets Same Block

Comment by:  Dan Javitt, SRF Advisor
Submitted 10 November 2008
Posted 10 November 2008

The article by Homayoun and Moghaddam is another in an excellent series of articles investigating effects of metabotropic agents on brain function relevant to schizophrenia. As opposed to previous studies by this group that targeted rodent medial prefrontal cortex, which is used as a model of dorsolateral prefrontal cortex in humans, this study targets orbitofrontal cortex. The main finding of this study, like prior studies by this group, is that effects of the NMDA antagonist MK-801 can be reversed by the LY354740, a selective metabotropic group 2/3 agonist. LY354740 has previously been shown to reverse ketamine effects in humans (Krystal et al., 2005) and to be effective in treatment of generalized anxiety disorder in humans (Dunayevich et al., 2008). It is pharmacologically related to LY2130023 (Rorick-Kehn et al., 2007), a compound that has shown efficacy in treatment of schizophrenia (Patil et al., 2007).

In addition, the study builds upon prior studies of mGluR5 agonists (e.g., Darrah et al., 2008) to show that CDPPB, a novel modulator of mGluR5 receptors, also reverses acute effects of MK-801. mGluR5 receptors interact closely with NMDA receptors. It has been known for a long time that mGluR5 antagonists induce symptoms similar to those of NMDA antagonists, suggesting a potential role for agents that can stimulate mGluR5 activity. However, mGluR5 receptors are prone to downregulation following application of agonists, so the evaluation of mGluR5 receptors as a therapeutic target in schizophrenia has had to await development of high-affinity, CNS penetrant mGluR5 modulators that do not cause desensitization. The similar effects of an mGluR2/3 agonist and an mGluR5 modulator suggest that multiple approaches may be taken to normalize NMDA function in schizophrenia, including modulation of both presynaptic glutamate and postsynaptic NMDA function. mGluR5 receptors are active also in visual cortex (Sarihi et al., 2008), and so would potentially reverse effects of NMDA antagonists on sensory, as well as frontal deficits associated with schizophrenia.

In our own research studies, we have found that structural white matter alterations in orbitofrontal cortex correlate with ability to identify emotion (Leitman et al., 2007), attesting to the importance of this brain region to cognitive dysfunction in schizophrenia. Structural change in this region also correlates with aggression (Hoptman et al., 2005), which is an important issue determining clinical outcome in individuals with schizophrenia. Our findings thus support the concept that glutamatergic neurotransmission within orbitofrontal cortex may play as important a role in schizophrenia as dysfunction within dorsolateral prefrontal cortex, and deserves to be studied with equal fervor.

Despite the tremendous value of the study, every silver lining must have its cloud. In this case, the caveat relates to the finding that effects of MK-801 in this model were also reversed by haloperidol and clozapine. On the one hand, it is good news, as it suggests that metabotropic compounds may be as effective as antipsychotics in treating the well-known dopaminergic dysregulation associated with schizophrenia. In the one published clinical trial of LY2130023 (Patil et al., 2007), the compound proved almost as effective as olanzapine despite use of what may not have been an optimized dose.

On the other hand, however, it suggests that the orbitofrontal model, like the prior dorsolateral model, does not yet capture the aspects of schizophrenia that respond poorly to antipsychotics, such as primary negative symptoms and cognitive dysfunction. It is important to develop compounds that are as good as antipsychotics in treating positive symptoms, but without the well-known side metabolic and motor side effects. However, it is even more important to develop treatments that target aspects of schizophrenia that remain unresponsive to current therapeutic approaches. To date, no clinical data are available regarding effects of either mGlu2/3 agonists or mGlu5 modulators on neurocognition in humans. The ultimate challenge may be to show that metabotropic modulators can reverse effects of NMDA antagonists in models where antipsychotics such as haloperidol or clozapine prove ineffective. Another critical issue is whether these compounds will be effective during longer-term treatment (Imre et al., 2006). To do so, longer-term treatment studies are required. Nevertheless, these data provide further hope to the development of non-dopaminergic treatment approaches in schizophrenia.


Darrah JM, Stefani MR, Moghaddam B. Interaction of N-methyl-D-aspartate and group 5 metabotropic glutamate receptors on behavioral flexibility using a novel operant set-shift paradigm. Behav Pharmacol. 2008 May 1;19(3):225-34. Abstract

Dunayevich E, Erickson J, Levine L, Landbloom R, Schoepp DD, Tollefson GD. Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacology. 2008 Jun 1;33(7):1603-10. Abstract

Hoptman MJ, Volavka J, Weiss EM, Czobor P, Szeszko PR, Gerig G, Chakos M, Blocher J, Citrome LL, Lindenmayer JP, Sheitman B, Lieberman JA, Bilder RM. Quantitative MRI measures of orbitofrontal cortex in patients with chronic schizophrenia or schizoaffective disorder. Psychiatry Res. 2005 Nov 30;140(2):133-45. Abstract

Imre G, Fokkema DS, Ter Horst GJ. Subchronic administration of LY354740 does not modify ketamine-evoked behavior and neuronal activity in rats. Eur J Pharmacol. 2006 Aug 21;544(1-3):77-81. Abstract

Krystal JH, Abi-Saab W, Perry E, D'Souza DC, Liu N, Gueorguieva R, McDougall L, Hunsberger T, Belger A, Levine L, Breier A. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology (Berl). 2005 Apr 1;179(1):303-9. Abstract

Leitman DI, Hoptman MJ, Foxe JJ, Saccente E, Wylie GR, Nierenberg J, Jalbrzikowski M, Lim KO, Javitt DC. The neural substrates of impaired prosodic detection in schizophrenia and its sensorial antecedents. Am J Psychiatry. 2007 Mar 1;164(3):474-82. Abstract

Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med. 2007 Sep 1;13(9):1102-7. Abstract

Rorick-Kehn LM, Johnson BG, Burkey JL, Wright RA, Calligaro DO, Marek GJ, Nisenbaum ES, Catlow JT, Kingston AE, Giera DD, Herin MF, Monn JA, McKinzie DL, Schoepp DD. Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039). J Pharmacol Exp Ther. 2007 Apr 1;321(1):308-17. Abstract

Sarihi A, Jiang B, Komaki A, Sohya K, Yanagawa Y, Tsumoto T. Metabotropic glutamate receptor type 5-dependent long-term potentiation of excitatory synapses on fast-spiking GABAergic neurons in mouse visual cortex. J Neurosci. 2008 Jan 30;28(5):1224-35. Abstract

View all comments by Dan Javitt

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Comment by:  Henry Holcomb
Submitted 15 November 2008
Posted 15 November 2008

Homayoun and Moghaddam (PNAS) present important new data concerning the glutamatergic system and psychosis. They suggest the orbital frontal cortex (OFC) is particularly important in the pathophysiology of schizophrenia. They show that treatment with an NMDA receptor (NMDAR) antagonist induces OFC pyramidal neuron hyperactivity (secondary to GABA interneuron hypoactivity). This was reversed with haloperidol, clozapine, and a selective mGlu2/3 agonist, LY354740. This brief essay emphasizes how their findings support hypotheses of a common pathway in the biology of psychotic disorders. This group’s work (Adams et al., 2001; Moghaddam and Adams, 1998) contributes to an extensive body of research on the biology of psychosis. Human research shows that extensive frontal cortical systems and diverse molecular interactions may converge to form a common pathway to produce psychosis.

In their formulations of schizophrenia, Olney (Olney and Farber, 1995), Farber (Farber et al., 2002), and Tamminga (Tamminga et al., 1987) suggested a prominent role for disturbed glutamatergic neurotransmission. Human neurometabolic imaging studies using the NMDAR antagonist ketamine subsequently demonstrated marked brain metabolic hyperactivity. Using blood flow and glucose utilization as surrogate markers of neural activity investigators characterized the brain response to intravenous ketamine administration (Breier et al., 1997; Holcomb et al., 2005; Lahti et al., 1995; Vollenweider et al., 1997). Frontal and anterior cingulate (rostral component) regions of healthy volunteers and schizophrenic participants became hypermetabolic. But it is important to note that hypermetabolic response patterns are also generated in other human, psychotogenic drug models of psychosis. These include high dose amphetamine (Vollenweider et al., 1998), psilocybin (Gouzoulis-Mayfrank et al., 1999; Vollenweider et al., 1997), and cannabis (Mathew et al., 1989; O'Leary et al., 2007).

There is now compelling evidence to directly link cortical metabolic patterns to cortical glutamate/glutamine dynamics (Rothman et al., 1999). Rowland and colleagues’ magnetic resonance spectroscopy (MRS) study of ketamine given to healthy volunteers demonstrated a significant elevation in rostral anterior cingulate glutamine, a putative marker of increased glutamate release (Rowland et al., 2005). It seems reasonable to interpret Theberge and colleagues’ MRS study of never treated schizophrenia (Theberge et al., 2002) as a chemical confirmation of Soyka’s neurometabolic study, also of unmedicated schizophrenic patients (Soyka et al., 2005). Theberge found elevated glutamine in the anterior cingulate. Soyka found elevated glucose utilization in the frontal cortex. These studies, taken together, implicate increased glutamate release as a common mechanism in the pathology of early schizophrenia. Psychosis may arise from NMDA receptor antagonism (ketamine and PCP), stimulation of the 5-HT 2A-mGluR2 complex (psilocybin), or direct stimulation of the CB1 receptor on GABA interneurons (Katona and Freund, 2008). In each instance the consequence is an acute and robust glutamate release caused by disinhibition of pyramidal neurons.

Though Homayoun and Moghaddam have provided an elegant description of this phenomenon in the OFC, it is likely to be equally important in the medial and dorsolateral prefrontal cortex, as well as the anterior cingulate cortex. But the methodology and theory of this paper should help clinical investigators. The thoughtful study of metabotropic glutamatergic receptors and their clinical application (Patil et al., 2007) will go far to illuminate the subtle pathophysiology of psychosis.


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