STRAIN ENCODED (SENC) IMAGING FOR DETECTION OF REGIONAL DYSFUNCTION IN PATIENTS WITH MYOCARDIAL INFARCTION AT 3T Li Pan, MS,1 Ahmed S. Fahmy, MS,2 Amy Spooner, MD,1 Robert G. Weiss, MD,1 Matthias Stuber, PhD,1 Nael F. Osman, PhD.1 1 Johns Hopkins School of Medicine, Bal- timore, MD, USA, 2 Johns Hopkins University, Baltimore, MD, USA. (a) Longitudinal strain measurments by segment
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Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Eur Neuropsychopharmacol. 2008 November ; 18(11): 773–786. doi:10.1016/j.euroneuro.2008.06.005.
Glutamatergic Dysfunction in Schizophrenia: from basic
neuroscience to clinical psychopharmacology
Rodrigo D. Paz1,2, Sonia Tardito2, Marco Atzori3, and Kuei Y. Tseng4
1Departamento de Psiquiatría y Neurociencias, Universidad Diego Portales, Santiago, Chile
2Instituto Psiquiátrico José Horwitz Barak, Santiago, Chile 3University of Texas at Dallas, School for Behavioral and Brain Sciences, Richardson, Texas, USA 4Department of Cellular & Molecular Pharmacology, RFUMS/The Chicago Medical School, NorthChicago, Illinois, USA Abstract
The underlying cellular mechanisms leading to frontal cortical hypofunction (i.e., hypofrontality) inschizophrenia remain unclear. Both hypoactive and hyperreactive prefrontal cortical (PFC) stateshave been reported in schizophrenia patients. Recent proton magnetic resonance spectroscopy studiesrevealed that antipsychotic-naïve patients with first-psychotic episode exhibit a hyperactive PFC.
Conversely, PFC activity seems to be diminished in patients chronically exposed to conventionalantipsychotic treatments, an effect that could reflect the therapeutic action as well as some of theimpairing side effects induced by long-term blockade of dopamine transmission. In this review, wewill provide an evolving picture of the pathophysiology of schizophrenia moving from dopamine toa more glutamatergic-centered hypothesis. We will discuss how alternative antipsychotic strategiesmay emerge by using drugs that reduce excessive glutamatergic response without altering the balanceof synaptic and extrasynaptic normal glutamatergic neurotransmission. Preclinical studies indicatethat acamprosate, a FDA approved drug for relapse prevention in detoxified alcoholic patients,reduces the glutamatergic hyperactivity triggered by ethanol withdrawal without depressing normalglutamatergic transmission. Whether this effect is mediated by a direct modulation of NMDAreceptors or by antagonism of metabotropic glutamate receptor remains to be determined. Wehypothesize that drugs with similar pharmacological actions to acamprosate may provide a betterand safer approach to reverse psychotic symptoms and cognitive deficits without altering the balance of excitation and inhibition of the corticolimbic dopamine-PFC system. It is predicted thatschizophrenia patients treated with acamprosate-like compounds will not exhibit progressive corticalatrophy associated with the anti-dopaminergic effect of classical antipsychotic exposure.
schizophrenia; antipsychotic drugs; adolescence; NMDA; prefrontal cortex; dopamine; GABA;psychosis Corresponding Author: Kuei Y. Tseng, MD & PhD, Department of Cellular and Molecular Pharmacology, RFUMS/The Chicago MedicalSchool, North Chicago, Illinois 60064, USA, Phone: (1) 847-578-8655; Fax: (1) 847-578-3268, firstname.lastname@example.org.
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New and Old Problems in the Treatment of Schizophrenia Symptoms
Since the serendipitous discovery of drugs with antipsychotic properties in the '50s prolonged hospitalizations were no longer necessary for most patients with schizophrenia (Beasley et al.,2006, Freedman, 2005, Meltzer et al., 1990, Wiersma et al., 2000). During the '60s, thediscovery of clozapine, an antipsychotic drug exempt from extra-pyramidal side effects,introduced significant improvements in the treatment of this disorder (Hippius, 1989). Later,the demonstration of the unique effectiveness of this drug in refractory psychotic symptomsrepresented another advance (Kane et al., 1988). However, the emergence of fatalagranulocytosis during the '70s, and the more recent awareness of metabolic side effects(Bustillo et al., 1996, Cohen et al., 1990, Henderson et al., 2000, Lamberti et al., 2006) as wellas potentially lethal cases of pancreatitis, myocarditis and polyserositis (Killian et al., 1999,La Grenade et al., 2001, Merrill et al., 2006, Schonfeldt-Lecuona and Connemann, 2002,Wehmeier et al., 2003) associated with chronic exposure to clozapine, fueled the search forclozapine-like drugs not associated with life-threatening side effects. Pursuing this goal, severalnew antipsychotic drugs have been developed during the last decades. A reduced incidence ofextra-pyramidal side effects without inducing agranulocytosis has been demonstrated inpatients treated with second-generation drugs (Freedman, 2005, Gardner et al., 2005).
However, none of these so-called second-generation antipsychotics have achieved similarefficacy to clozapine (Azorin et al., 2001, Breier et al., 1999, Chakos et al., 2001, Conley et al., 1999, Davis et al., 2003, McEvoy et al., 2006, Shaw et al., 2006). More importantly,increased weight gain, hypercholesterolemia, diabetes and hyperprolactinemia still representserious side effects associated with chronic exposure to some of these compounds (Kapur etal., 2002, Volavka et al., 2004).
Besides the side effects, current available antipsychotic drugs have shown very limited impacton another core feature of schizophrenia, that is, cognitive and emotional impairments(Carpenter and Gold, 2002, Gardner et al., 2005, Keefe et al., 2006a, Keefe et al., 2006b,Mishara and Goldberg, 2004, Rosenheck et al., 2006). In fact, cognitive deficits are betterpredictor of the degree of social disability in patients with schizophrenia than the residualpsychotic symptoms (Gold et al., 2002, Green et al., 2000, Green et al., 2002, Hyman andFenton, 2003, Milev et al., 2005, Rosenheck et al., 2006). Likewise, emotional deficits haveemerged as another important predictor of disability in these patients (Milev et al., 2005). Thus,the lack of effectiveness of first and second generation antipsychotic drugs on cognitive andemotional deficits in schizophrenia may explain why the long-term prognosis in this psychiatricdisorder remains unsatisfactory (Hegarty et al., 1994, Malla and Payne, 2005, Wiersma et al.,2000).
Here, we will review recent evidence supporting an evolving picture of the pathophysiologyof schizophrenia moving from dopamine (DA) to a more glutamatergic-centered hypothesis.
We will first summarize the limitations of currently available antipsychotic drugs and presentevidence indicative of a hyperglutamatergic prefrontal cortex (PFC) underlying psychoticsymptoms in schizophrenia. Alternative notions from simple hypofrontality to a more complexdevelopmental dysregulation of prefrontal functioning will be introduced, in particular whetherthe glutamatergic hypothesis may be best framed as hypo- vs. hyperglutamatergic state. Next,we will discuss how partial NMDA receptor agonists and metabotropic glutamate receptor 5(mGluR5) antagonists (e.g. acamprosate) may be more effective in treating cognitive deficitsassociated to schizophrenia by restoring the balance of PFC glutamatergic function. Lastly, wewill propose a coherent hypothesis predicting the utility of acamprosate-like compounds asneuroprotective interventions in at-risk adolescents with cognitive and emotional impairmentsor sub-threshold psychotic symptoms.
Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Antipsychotic Drugs and Cognitive Symptoms in Schizophrenia
It is well known that current available antipsychotic drugs have limited effect in treating cognitive and emotional impairments in schizophrenia. In fact, cognitive deficits seem to beassociated with severe reduction in PFC volume in patients treated with haloperidol (Liebermanet al., 2005b), and the initial cognitive improvement observed after olanzapine (10-20 mg/day)and haloperidol (2-20 mg/day) treatment became no longer apparent after 1 year of drugexposure when detectable reductions in PFC volume emerge (Keefe et al., 2006a, Keefe et al.,2006b, Lieberman et al., 2005a). Similar PFC reductions in gray and white matter were foundafter 2 years of olanzapine or haloperidol exposure (Dorph-Petersen et al., 2005). Thus, thelack of cognitive improvement could be due to the anatomical and cellular alterations inducedby prolonged antipsychotic exposure as these changes seem to be positively correlated withthe cumulative doses of antipsychotic exposure (Cahn et al., 2002, Gur et al., 1998).
The mechanisms underlying the anatomical and molecular changes observed after chronicexposure to antipsychotics have yet to be identified. Evidences indicate that thesepathophysiological changes could be due to downregulation of neurotrophic factors inducedby the anti-DA effect of antipsychotic drugs, in particular by interfering signaling pathwaysunderlying D1 receptor activation. Although it is well established that first and secondgeneration antipsychotic drugs exert anti-DA effects, mainly by targeting D2 over D1 receptors(Creese et al., 1976, Seeman and Lee, 1975), prolonged blockade of D2 receptors can also lead to decreased expression of PFC D1 receptors (Castner et al., 2000, Lidow et al., 1997, Lidowand Goldman-Rakic, 1994). Consequently, chronic exposure to antipsychotic drugs mayproduce neuronal atrophy in DA-innervated brain areas by disrupting D1-dependent trophicsignaling (i.e., protein kinase A -PKA-) on growth and maintenance of new dendritic spines(Lisman and Grace, 2005). Indeed, D1 receptor activation increases surface expression ofAMPA receptor subunits in cortical neurons through a PKA-dependent mechanism (Smith etal., 2005, Sun et al., 2005), and alter the strength of synaptic communication induced by long-term potentiation (LTP) (Malenka, 2003), a cellular mechanism for learning and memory(Miles et al., 2005). Similarly, PKA activation facilitate the insertion of brain derivedneurotrophic factor (BDNF) receptor tyrosine kinase B (TrkB) into the dendritic spines (Ji etal., 2005), and favors the arrangement of new dendritic spines (Tyler and Pozzo-Miller,2001). Therefore, D1-mediated PKA signaling may promote the formation of new dendriticspines and synaptic contacts during learning and memory (Jay, 2003, Lisman and Grace,2005), and disruption of D1 receptor-dependent neurotrophic signaling could explain some ofthe cellular and synaptic alterations observed after prolonged exposure to antipsychotic drugs(Konopaske et al., 2007): BDNF protein and mRNA levels were reduced in animals chronicallyexposed to haloperidol (Angelucci et al., 2000, Bai et al., 2003, Chlan-Fourney et al., 2002, Lipska et al., 2001, Pillai et al., 2006b), while downregulation of TrkB receptors in the PFCwas correlated with the duration and doses of antipsychotic treatment in schizophrenia patients(Weickert et al., 2005). Overall, these results indicate that first and second generationantipsychotic drugs may alter cortical levels of neurotrophic factors by antagonizing DAsignaling.
On the other hand, it has been proposed that the progressive cortical atrophy observed inschizophrenia patients with first psychotic episode could be triggered by psychosis itself(Lieberman, 1999, Lieberman et al., 2001, Lieberman et al., 2005b), whereas the delayedanatomical changes found in olanzapine-treated patients reflect a pro-neurotrophic effect thatcounter-balance the effect of first psychotic episode-induced neurotoxicity (Lieberman et al.,2005a, Lieberman et al., 2005b). However, neuropathological and gene expression studiesaimed to support the existence of first psychosis-induced neurotoxicity have yielded negativeresults (Benes et al., 2006, Benes et al., 2003, Damadzic et al., 2001, Harrison, 1999). Somestudies found reduction of BDNF expression (Lipska et al., 2001) whereas no change (Pillai Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
et al., 2006a) or even increased levels of BDNF were observed after chronic exposure toolanzapine and clozapine (Bai et al., 2003). A likely explanation for these contrasting results may be the duration of antipsychotic exposure. For example, it is well known that acuteadministration of second-generation antipsychotic drugs increases DA release in the medialPFC (Diaz-Mataix et al., 2005, Ichikawa et al., 2002, Li et al., 2005, Li et al., 2004, Li et al.,2003), an effect that could potentially lead to higher levels of BDNF (Bai et al., 2003). Incontrast, 180 days treatment with olanzapine showed no major effects on BDNF protein levels,but decreased significantly the activity and the levels of the neuroprotective enzymemanganese-superoxide dismutase in the cortex (Pillai et al., 2006a, Pillai et al., 2006b).
Similarly, a reduction of cortical gray and white matter was observed after two years ofolanzapine treatment in non-human primates (Dorph-Petersen et al., 2005). Interestingly,similar anatomical changes in the PFC were observed after twelve but not six-month exposureto olanzapine in schizophrenia patients exhibiting first psychotic episode (Lieberman et al.,2005b). Taken together, these findings suggest that prolonged treatments with second-generation antipsychotic drugs may alter PFC structure and function. Consistent with thishypothesis, a progressive decline in cognitive performance in a group of 80 schizophreniapatients (many of them treated with olanzapine or clozapine) was observed only after a two-year period of antipsychotic exposure (Andreasen et al., 2005). Studies exploring whetherprolonged exposure to second generation antipsychotic drugs increase DA release in the PFCmay shed some light on the mechanisms underlying the delayed cortical atrophy and cognitive deterioration associated with chronic exposure to antipsychotics. New therapeutic strategieswith better neuroprotective and neurocognitive profiles need to be examined, particularly infirst psychotic episode patients.
New Hypothesis for Addressing New Problems
Growing evidence indicates that abnormalities in glutamatergic neurotransmission mayunderlie some of the core psychopathological phenomena observed in schizophrenia (Harrisonand Weinberger, 2005). The glutamatergic hypothesis of schizophrenia was originally basedupon clinical observations of chronic abusers of the NMDA receptor antagonist phencyclidine(PCP). Similar to the symptoms observed in schizophrenia, PCP exposure elicits thoughtdisorder, emotional blunting, working memory disturbances and auditory hallucinations (Javittand Zukin, 1991, Luby et al., 1959). The observation that acute administration of anotherNMDA receptor antagonist, that is, sub-anesthetic doses of ketamine, induces similarpsychopathological effects in healthy volunteers (Adler et al., 1999, Krystal et al., 1994,Malhotra et al., 1996) supported the hypothesis that hypofunctional NMDA receptors may playa critical role in the pathophysiology of schizophrenia. Consequently, anti-DA drugs combinedwith agents that enhance NMDA function might ameliorate the residual cognitive, emotional and psychotic symptoms in schizophrenia (Goff and Coyle, 2001, Goff et al., 1999). However,a recent multicentric study failed to provide evidence in favor of this therapeutic intervention(Carpenter and Thaker, 2007).
A re-formulation of the glutamatergic hypothesis of schizophrenia has emerged. According tothis new paradigm, hyperactive glutamatergic neurons in several brain regions including thePFC may underlie the psychotic, cognitive and emotional manifestations in schizophrenia(Krystal et al., 2003, Moghaddam, 2003). Several pieces of converging evidence havecontributed to establish this reformulation: 1) Microdialysis studies showing that glutamatelevels are increased in the striatum (Bustos et al., 1992) and PFC (Moghaddam et al., 1997) ofanimals acutely treated with psychotomimetic doses of NMDA antagonists; 2) Behavioralstudies showing that hyperlocomotion and working memory impairments induced by PCP arecorrelated with increased glutamate levels in the PFC (Adams and Moghaddam, 1998); 3)Pharmacological studies showing that glutamate release inhibitors such as lamotrigine (Anandet al., 2000) and mGluR 2 agonists (Moghaddam and Adams, 1998) ameliorate the cognitive Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
and behavioral abnormalities induced by acute exposure to psychotomimetic doses of NMDAantagonists; 4) In vivo electrophysiological recordings in freely moving animals revealing that acute administration of NMDA antagonists is associated with PFC pyramidal neuronsexcitation (Jackson et al., 2004), an effect that could be triggered by an increased tonicexcitatory inputs from the ventral hippocampus (Jodo et al., 2005); 5) In vitroelectrophysiological studies showing that hippocampal GABAergic interneurons that controlpyramidal neuron firing are particularly sensitive to psychotomimetic doses of NMDAantagonists (Grunze et al., 1996); 6) Neuroimaging studies indicating that psychotic symptomsand cognitive abnormalities elicited by acute administration of ketamine in healthy volunteersconcur with an enhancement of PFC metabolic activity (Breier et al., 1997, Holcomb et al.,2005, Holcomb et al., 2001); 7) Proton magnetic resonance spectroscopy studies showing thatglutamine levels, an indicator of synaptic glutamate recycling activity (Rothman et al., 1999),are increased in the medial PFC of healthy volunteers acutely exposed to sub-anesthetic dosesof ketamine (Rowland et al., 2005), antipsychotic naïve first psychotic episode schizophreniapatients (Bartha et al., 1997, Theberge et al., 2002), and adolescents at-risk of developingschizophrenia (Tibbo et al., 2004). Thus, despite binding at different receptors in dendriticspines, psychotomimetic drugs such as LSD, amphetamine and PCP may trigger signaltransduction pathways that converge to potentiate glutamatergic excitability via inhibition ofprotein phosphatase 1, an enzyme that normally downregulates excitatory synapses(Svenningsson et al., 2003). At the network level, psychotomimetic doses of NMDA antagonist may favor the balance of excitation over inhibition by blocking NMDA-dependent excitatoryinputs to GABAergic interneurons. Overall, these results indicate that a dysfunctionalenhancement of cortical excitatory transmission maybe the common synaptic effect ofpsychotomimetic drugs that induced schizophrenia-like symptoms.
How a primary dysregulation of glutamatergic neurotransmission may explain the fact that
most cases of schizophrenia emerge after puberty?
Electrophysiological recordings of PFC pyramidal neurons at different maturational stageshave revealed that DA-glutamate interactions in the PFC mature after puberty (Tseng andO'Donnell, 2004, Tseng and O'Donnell, 2005). Therefore, a cortical disruption of NMDAfunction may contribute to establish the pathophysiological changes observed in schizophreniaby altering the acquisition of mature DA responses in the PFC. For example, glutamatergicplateau depolarizations induced by co-activation of NMDA and D1 receptors isdevelopmentally regulated in a manner that a D1-dependent enhancement of NMDA functionin the PFC can be observed only in post-pubertal, but not pre-pubertal animals (Tseng andO'Donnell, 2005). This is consistent with previous studies showing a delayed acquisition ofadult levels of DA receptors (Leslie et al., 1991, Tarazi et al., 1999) and NMDA receptorsubunits (Monyer et al., 1994, Williams et al., 1993) around puberty. Furthermore, the expression of BDNF mRNA, which is tightly dependent on the activation of intra-synapticNMDA receptors (Hardingham et al., 2002), reaches its maximum level in the PFC during lateadolescence and young adulthood (Webster et al., 2002). Thus, subtle changes in glutamatergicexcitability determined by genetic and environmental factors may drive some of the mildcognitive, emotional and motor abnormalities observed in pre-psychotic children andadolescents (Lewis and Levitt, 2002, Lewis and Murray, 1987, Murray and Waddington,1990, Weinberger, 1987). These changes may remain relatively silent until the acquisition ofmature cognitive abilities dependent on D1-NMDA interactions that emerge around puberty(Tseng and O'Donnell, 2005). A developmental disruption of either or both the glutamatergicand the DA systems may therefore lead to the cognitive and emotional manifestations ofprodromal schizophrenia (Lencz et al., 2006, Reichenberg et al., 2005, Weiser et al., 2001).
Without treatment, post-pubertal hyperglutamatergic states may escalate until full psychoticepisodes emerge during late adolescence and early adulthood.
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The Glutamatergic Hypothesis for Psychosis: addressing the objections
Could the hyperglutamatergic neurotransmission, exacerbated by an abnormal D1-NMDA
co-activation during late adolescence underlie the core of early pathophysiological events
This hypothesis may appear at odds by the fact that antipsychotic drugs have been shown totarget mainly D2 over D1 receptors (Tauscher et al., 2004). If an exaggerated PFC D1-NMDA-dependent excitation plays a role in psychosis, it may seem unlikely that D2 antagonists wouldexert any antipsychotic effects. However, it is well known that prolonged exposure to D2antagonists are typically associated with a series of changes including downregulation of PFCD1 receptors (Castner et al., 2000, Lidow et al., 1997, Lidow and Goldman-Rakic, 1994) andDA cell firing (Bai et al., 2003, Boye and Rompre, 2000, Bunney and Grace, 1978, Di Giovanniet al., 1998, Grace et al., 1997, Moore et al., 1998), which in turn may decrease DA synthesis(Grunder et al., 2003) and impair prefrontal D1-dependent functioning. On the other hand, ithas been documented that some of the behavioral effects of DA are dependent on co-activationof D1 and D2 receptors within the cortico-basal ganglia loop (Kita et al., 1999, Waszczak etal., 2002). Both D1 and D2 DA receptors are co-expressed in single striatal neurons and theirco-activation can lead to calcium release from internal stores (Aizman et al., 2000, Lee et al.,2004, So et al., 2005) and increase neuronal activity (Hopf et al., 2003). It is possible that D2antagonists prevent D1 mediated potentiation of NMDA response within the PFC by decreasing the D2-dependent calcium release from internal stores. Although this hypothesis awaitsconfirmation in cortical neurons, it seems likely that chronic blockade of D2 receptors couldultimately compromise cognitive performance by disrupting PFC D1-dependent signaling.
Why selective D1 antagonists failed to elicit significant therapeutic effects in schizophrenia?
Several factors may explain the lack of effectiveness of selective D1 antagonists in treatingsymptoms associated to schizophrenia (de Beaurepaire et al., 1995, Den Boer et al., 1995,Karlsson et al., 1995). First, the therapeutic effects of D1 antagonists were initially tested inpatients exposed to prolonged antipsychotic drugs treatment, a stage where therehyperglutamatergic state may not longer present in the PFC (Bartha et al., 1997, Theberge etal., 2002, Tibbo et al., 2004). Secondly, it has been suggested that a proper balance of PFC D1receptor activation (i.e., invert U curve) is required for supporting optimal working memoryperformance (Arnsten and Li, 2005). Several studies have also highlighted the need of DA-glutamate co-activation for a number of prefrontal functions including appetitive instrumentallearning, memory retrieval and enhancement of hippocampal-PFC synaptic plasticity (Baldwinet al., 2002, Gurden et al., 1999, Jay, 2003). Thus, potent D1 antagonists may not only reducethe hyperglutamatergic state but also impair PFC functioning in schizophrenia. Two trials using full D1 antagonists have to be aborted as result of the emergence of severe psychosisexacerbation (de Beaurepaire et al., 1995, Karlsson et al., 1995).
Finally, it is not clear whether cognitive and emotional deterioration putatively driven bychronic hypoglutamatergic states are the result of prolonged antipsychotic exposure sincesimilar deficits were reported in schizophrenia subjects before the introduction of anti-DAdrugs (Kraepelin, 1919; Bleuler, 1911). It has been documented that chronic exposure to lowdoses of NMDA antagonist significantly decrease PFC DA and glutamate turnover (Jentschand Roth, 1999, Kondziella et al., 2005) and elicit PFC-related behavioral deficits resemblingthe cognitive deterioration observed in chronic stages of schizophrenia (Jentsch et al., 1997,Jentsch and Roth, 1999). Taken together, these findings suggest that repetitive episodes ofhyperglutamatergic activity may trigger compensatory mechanisms that would in turndownregulate PFC excitatory transmission. Thus, even in the absence of D2 antagonists, ahypoglutamatergic PFC may emerge resulting from repetitive untreated hyperglutamatergicstate as seen after chronic exposure to PCP.
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In summary, it is possible that the emergence of an abnormal PFC D1-NMDA co-activationduring late adolescence could exacerbate the hyperglutamatergic state that underlies the early pathophysiological events in schizophrenia. If the model proposed here capture at least part ofwhat is really occurring in early stages of schizophrenia, we predict that the earlier theintroduction of non-DA therapeutic interventions, the higher the probability of preventingcompensatory changes associated with a hypoactive PFC.
Cellular Mechanisms Underlying the Hyperglutamatergic State
Several DA-dependent and DA-independent factors could contribute to elicit the hyperactiveNMDA state in schizophrenia. At cellular level, an increase expression of calcyon (Koh et al.,2003), a D1 receptor interacting protein that allows calcium release from internal stores(Bergson et al., 2003), may potentiate NMDA function in a manner independent from D2receptor activation. Similarly, reduction of calcineurin levels (Eastwood et al., 2005, Gerberet al., 2003), a phosphatase that normally reduces the excitability of NMDA receptors (Rycroftand Gibb, 2004, Smith et al., 2006), may also enhance NMDA function and promote workingmemory deficits in response to low doses of the NMDA antagonist MK801 (Miyakawa et al.,2003). Furthermore, a reduced expression of the RSG4 gene (Chowdari et al., 2002, Erdely etal., 2006, Prasad et al., 2005, Saugstad et al., 1998), which encodes a protein product thatnormally decreases the activation of mGluR5, may result in over-activation of NMDAreceptors. This change at mGluR5 function might ultimately increase PFC pyramidal neurons bursting activity through an NMDA-dependent mechanism (Homayoun et al., 2004). Finally,a recent study has identified a genetic defect affecting the expression of the phosphodiesterase4B gene (PDE4B) in schizophrenia and mood disorders. This gene product plays a critical rolein maintaining the normal D1-dependent protein kinase A signal transduction pathway. Moreimportantly, it was found that the PDE4B enzyme interacts with the disrupted in schizophrenia1 (DISC 1) gene in a manner that PDE4B can be released from DISC 1 when the dendriticlevels of cyclic adenosine monophosphate (cAMP) are elevated (Millar et al., 2005). Thus,abnormalities in the expression or activity of different gene products such as calcyon,calcineurin, PDE4B and DISC 1 may lead to hyper-excitable signal transduction pathwaysdependent on D1-NMDA receptor activation.
Disruption of GABAergic interneurons function may also contribute to initiate and sustain ahyperglutamatergic state in schizophrenia. PFC GABAergic interneurons play an importantrole in determining the responses of pyramidal neurons to glutamatergic and DA inputs (Tsenget al., 2006b, Tseng and O'Donnell, 2004, Tseng and O'Donnell, 2007a, Tseng and O'Donnell,2007b) and functional disruption of this selective neuronal population could ultimately lead tothe altered cognitive performances observed in schizophrenia (Lewis et al., 2005). Because DA-dependent attenuation of PFC NMDA responses involves activation of local GABAergicinterneurons (Tseng and O'Donnell, 2004), a reduction of this inhibitory tone may alsocontribute to trigger and sustain the hyperglutamatergic state in the PFC. Although an overallenhancement of PFC activity may appear at odds with the traditional concept of hypofrontality(Manoach, 2003), recent studies conducted in a developmental animal model that exhibitscortical deficits resembling to those observed in schizophrenia indicate that the hypofrontalstate could be associated with an hyperactive PFC. The characteristic post-pubertal emergenceof PFC glutamatergic hyperactivity (O'Donnell et al., 2002, Tseng et al., 2007) andhyperreactive PFC metabolic response to mesocortical stimulation (Tseng et al., 2006a) arecorrelated with a selective down regulation of PFC glutamate decarboxylase-67 mRNA, aneuronal marker for GABA interneurons (Lipska et al., 2003). Furthermore, a postpubertaldisruption of D2 receptor function that normally regulate PFC excitatory responses throughseveral pre- and postsynaptic mechanisms (Tseng and O'Donnell, 2004, Tseng and O'Donnell,2007a) combined with an abnormal response to D1 activation may also serve to increasepyramidal neurons excitability to NMDA (Tseng et al., 2007) and yield the concurrent hyper- Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
reactive and hypofunctional state in the PFC (Tseng et al., 2006a). Finally, it is also possiblethat other monoamines may potentiate this abnormal enhancement of NMDA function, particularly the cortical norepinephrine system. Stress-dependent increases of norepinephrinerelease sustaining the hyperactive NMDA state through activation of α1 adrenergic receptorsand upregulation of postsynaptic protein kinase C signaling pathways in the PFC (Arnsten,2004) may underlie the hyperreactive response to stress observed in schizophrenia.
In summary, cortical deficits in schizophrenia (i.e., hypofrontality) could be thereforecompounded by a hyperglutamatergic PFC state elicited by a reduction of PFC GABAergicfunction concurrent with a disruption of D2 modulation and an abnormal potentiation of D1and NMDA-mediated responses. These two pathophysiological conditions are not mutuallyexclusive and may not be restricted to the PFC since markers of increased glutamatergic activitydependent on NMDA receptors concurs with those indicative of decreased GABAergicfunction such as of GAD-67, GAD-65 and GAT1 in the cerebellar cortex of patients withschizophrenia (Paz et al., 2006).
Searching for New Psychopharmacological Targets to Restore the Balance
of Glutamatergic Neurotransmission: a lesson from acamprosate
Acamprosate is a derivative of the amino acid taurine and despite its low intestinal absorption, it has been used for more than two decades in Europe to prevent relapse in alcoholic patients(Buonopane and Petrakis, 2005, Room et al., 2005, Williams, 2005). Recently, the FDAapproved the use of acamprosate for detoxified alcohol-dependent patients in USA. Althoughits mechanism of action has not been completely identified, preclinical studies suggest thatacamprosate normalizes glutamate release and NMDA receptors function without altering thenormal glutamatergic neurotransmission (De Witte et al., 2005). Several cellular mechanismsmay account for the therapeutic effect of acamprosate, particularly by interfering mGluR5-dependent regulation of glutamate release (De Witte et al., 2005). Metabotropic GluR5 is anexcitatory G-protein coupled receptor located at both pre- and postsynaptic sites ofglutamatergic synapses as well as in glia and astrocytes (Swanson et al., 2005). Activation ofpresynaptic mGluR5 facilitates synaptic glutamate release whereas postsynaptic mGluR5increase neuronal excitability by facilitating NMDA currents. Consequently, a reduction of thehyperglutamatergic PFC state could be achieved with acamprosate by attenuating the excitatoryeffect of mGluR5 on presynaptic glutamate release and by decreasing NMDA-dependentpostsynaptic excitability. On the other hand, mGluR5 also regulates non-synaptic release ofglutamate from glia and astrocytes via stimulation of the cystine-glutamate antiporter (Xc-)(Melendez et al., 2005, Moran et al., 2005). The Xc- is a non-vesicular transporter that mediatessodium-independent exchange of one intracellular glutamate for one extracellular molecule of cystine, and is responsible for around 50 to 70 % of basal extracellular glutamate in the nucleusaccumbens (Baker et al., 2002), but not in the PFC (Melendez et al., 2005). In the PFC, however,Xc- stimulation increases the concentration of non-synaptic, extracellular glutamate, andreduces excitatory synaptic transmission resulting from activation of the inhibitory presynapticmGluR2/3 (Moran et al., 2005). Accordingly, acamprosate would prevent activation of the Xc-antiporter by antagonizing mGluR5, which in turn would reduce the non-synaptic extracellularglutamate levels and remove the presynaptic mGluR2/3-dependent inhibitory tone atglutamatergic synapses. Removing the mGluR2/3-dependent inhibitory tone on glutamaterelease might actually contribute to balance the decrease in glutamatergic synaptic transmissioninduced by presynaptic mGluR5 blockade. It is predicted that by acting on both synaptic andnon-synaptic mechanisms underlying glutamate release and its interactions with postsynapticNMDA receptors, acamprosate-like compounds may restore PFC hyperglutamatergic statewithout altering the balance of excitatory neurotransmission Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Acamprosate also binds the spermidine site of NMDA receptors (Mayer et al., 2002, Naassilaet al., 1998) and it is thought to exert a partial agonistic effect acting as an agonist or antagonist depending on the activity of NMDA receptors. For example, acamprosate potentiates theexcitatory action induced by low concentration of NMDA and reduced the excitatory effectelicited by higher concentrations of NMDA (Pierrefiche et al., 2004). Accordingly, studies inhyperglutamatergic mutant mice (a rodent model of increased alcohol consumption) revealedthat acamprosate normalize glutamate levels and ethanol intake without affecting glutamatelevels of control animals (Spanagel et al., 2005). A similar effect was observed in thehippocampus of ethanol-withdrawn rats treated with acamprosate as compared to controlanimals (Room et al., 2005). Because repetitive exposure to ethanol and withdrawal increasesglutamatergic transmission and glutamate release (De Witte, 2004, Krystal et al., 2003), theincreased glutamate would reach the extrasynaptic space, which in turn would stimulate moremGluR5 receptors and cause even more glutamate release and abnormal NMDA activation(De Witte et al., 2005). Therefore, acamprosate may effectively block this vicious cycle bynormalizing and restoring the balance of glutamatergic neurotransmission across several brainregions through its combined action on mGluR5 and NMDA receptor functions. Furthermore,the increased ethanol intake observed in the hyperglutamatergic mice (Spanagel et al., 2005)raises the intriguing possibility that similar exacerbated glutamatergic condition may bedriving, at least in part, the increased prevalence of ethanol abuse and dependence observed inschizophrenia. Interestingly, glutamate-dependent neurotoxicity induced by acute exposure to intermediate doses of NMDA antagonists could be prevented by ethanol exposure in rats(Farber et al., 2004).
Overall, it is tempting to speculate that the modulatory action of compounds that block mGluR5and exert a partial agonistic effect on NMDA receptors (e.g., acamprosate-like compounds andpossibly others) could provide a much better result in restoring altered glutamatergicneurotransmission than that produced by NMDA agonists and antagonists, and that obtainedwith D2 antagonists, in particular during early stages of the disorder.
Advantages of Using Acamprosate-like Drugs in Prodromal Stages of
It has been proposed that anti-DA treatments during the early stages of first-episode psychosesmay be effective to prevent cognitive and emotional decline in schizophrenia (Lieberman,1999, Wyatt, 1991). However, recent studies indicate that this strategy does not truly improvethe cognitive and emotional outcomes(Ho et al., 2003, Hoff et al., 2000, Marshall et al.,2005, Perkins et al., 2005, Rund et al., 2004), perhaps because cognitive deficits inschizophrenia occurs during late adolescence, before the emergence of psychotic episodes (Perkins et al., 2005). In fact, several retrospective studies have found that cognitive andemotional deterioration in a subgroup of schizophrenia patients become evident when post-pubertal social and cognitive performances are compared with those exhibited in prepubertalages (Ang and Tan, 2004, Cosway et al., 2000, Fuller et al., 2002, Rabinowitz et al., 2002,Reichenberg et al., 2005, van Oel et al., 2002). Although limited by their retrospective nature,these studies are consistent with the idea that profound changes occurring in the adolescentbrain make this neural development period vulnerable. Accelerated pruning of redundantconnections in the PFC occurs during this developmental stage (Bourgeois et al., 1994,Huttenlocher, 1979, Huttenlocher and Dabholkar, 1997, Zecevic et al., 1989, Zecevic andRakic, 1991), while the myelination of axons projecting from the PFC is particularly intenseduring adolescence and young adulthood (Giedd et al., 1999, Gogtay et al., 2004, Jernigan etal., 1991, Paus et al., 1999, Sowell et al., 2003, Sowell et al., 1999, Toga et al., 2006). Sincethese events are probably dependent on plastic changes affecting the glutamatergic (Monyeret al., 1994, Williams et al., 1993) and the DA systems (Leslie et al., 1991, Tarazi et al.,1999), it is not surprising that PFC pyramidal neuron response to DA acquire a mature profile Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
at early postpubertal stages of neural development (Tarazi et al., 1999, Tseng et al., 2006a,Tseng and O'Donnell, 2005, Tseng and O'Donnell, 2007a, Tseng and O'Donnell, 2007b). A similar delayed acquisition of mature responses to DA has been recently observed in PFCinterneurons (Tseng and O'Donnell, 2007a, Tseng and O'Donnell, 2007b). All theseinteractions will ultimately determine the normal balance of excitation and inhibition that isneeded for optimal cognitive performances including those dependent on PFC functioningduring adulthood. Thus, several abnormalities at cellular and network levels compromisingboth glutamatergic and GABAergic systems may produce dramatic effects during criticalperiods of neural development that could potentially lead to permanent loss of synapticconnections resulting in cognitive and emotional alterations in adulthood. Consequently, acuteexposure to low doses of NMDA antagonists induces psychotic symptoms and cognitivedysfunctions in pubertal/postpubertal rather than prepubertal ages (Olney and Farber, 1995).
Modulation of glutamatergic neurotransmission within the mesocorticolimbic-PFC networkby drugs acting on metabotropic and NMDA glutamate receptors may allow a better controlof persistent hyperglutamatergic states that are not affected by D2 receptor blockade. In thisregard, it is appealing that clozapine binds D1 receptors with a higher affinity than D2 receptors(Chou et al., 2006, Tauscher et al., 2004). Therefore, clozapine may exert a more directinteraction with NMDA receptors than other antipsychotic drugs, in particular if thehyperglutamatergic state is exacerbated by an abnormal PFC D1-NMDA co-activation. In fact, the response to clozapine can be predicted by polymorphisms within the D1 receptor gene inschizophrenia subjects. Patients with the 2,2, but not with the 1,2 D1 genotype exhibiteddecrements in psychotic symptoms after clozapine treatment, a therapeutic effect associatedwith a reduction in PFC metabolism that was not observed in the 1,2 D1 group (Potkin et al.,2003). Furthermore, prolonged clozapine exposure (i.e., 21 days) decreased NMDA-dependentsynaptic function (i.e., LTP) (Gemperle and Olpe, 2004). Thus, the therapeutic effects ofclozapine in patients with refractory psychotic symptoms might be obtained by decreasing theabnormal PFC D1-NMDA-dependent excitation.
A narrow window of NMDA activation mediated by D1 receptors and α adrenergic receptorsis needed to maintain appropriate working memory performance. An excessive stimulation ofD1 receptors lead to cognitive dysfunction (Arnsten and Goldman-Rakic, 1998, Cai andArnsten, 1997, Zahrt et al., 1997) whereas insufficient recruitment of these receptors isassociated with working memory deficits (Castner et al., 2000, Sawaguchi and Goldman-Rakic,1994). Interestingly, a similar inverted U-shape response has been reported for noradrenergicmanipulations (Arnsten and Li, 2005). Therefore, drugs with anti-mGluR5 and partial NMDAagonist properties (e.g., acamprosate) might produce better outcomes in patients with severecognitive dysfunction. Along with this hypothesis, transgenic mice overexpressing D2 receptors in the striatum exhibit severe deficits in working memory-dependent tasks inassociation with increased D1 receptor responses in the PFC (Kellendonk et al., 2006).
Decreasing the expression of D2 receptors in the striatum failed to restore the increased PFCresponse. This suggests that blocking D2 receptors in the striatum does not prevent workingmemory impairments secondary to neurodevelopmentally-induced abnormalities of D1-NMDA interactions within the PFC. Thus, direct modulation of hyperactive NMDA receptorsby drugs like acamprosate may allow targeting microcircuits within the mesocortico-PFC thatare not accessible to conventional D2-based treatments.
Because suicide is a major cause of mortality in schizophrenia and a risk factor for youngadults, a note of caution should be mentioned concerning the use of acamprosate in alcoholicpatients with suicidal ideation and suicide attempts. Although infrequent, acamprosate seemsto induce a relatively higher risk of suicidal thoughts and attempted suicide (2.4 %) whencompared to placebo (0.8 %) (2005, Bouza et al., 2004, Chick et al., 2000, Sher, 2006a).
However, the incidence of completed suicide in patients receiving acamprosate (0.13 %) Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
resembled to that observed in the placebo group (0.10 %)). Because many of these suicidal-related events occurred in the context of alcohol dependence and relapse, the relationship betweenacamprosate and the emergence of suicidality remains unclear (Sher, 2006b).
Summary and Conclusions
Overall, it becomes clear that the vulnerability of the periadolescence brain to environmentallyand genetically driven events that could potentially disrupt the balance of excitation andinhibition in cortical circuits should be taken into consideration when planningpsychopharmacological treatments in at-risk adolescent patients exhibiting cognitive andemotional deterioration. Drugs with similar acamprosate-like profile on metabotropicglutamate (e.g., mGluR5) and NMDA receptors may provide a better and safer therapeuticstrategy for early stages schizophrenia as compared to risperidone (McGorry et al., 2002),olanzapine (McGlashan et al., 2006, McGlashan et al., 2003) or D-cycloserine (Buchanan etal., 2007). The development of drugs that restore the hyperglutamatergic state by virtue ofnormalizing the abnormal NMDA function without altering the balance of synaptic andextrasynaptic glutamatergic transmission may be useful for schizophrenia patients withpersistent and residual psychotic symptoms as well as cognitive and emotional deficits.
Supported by NIDCD 1R01-DC005986-01A1 and NARSAD foundation/Sidney Baer Trust (MA) and RFUMS-TheChicago Medical School Start-up Funds (KYT) References
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OBJECTIVES: SCIENTIFIC PROGRAMME: 25 th September 2009. of Molecular Biology Severo Ochoa. University Autónoma of ˜ Announce the actual state in the investigation of recessive 08,45-09,00 Data collection. Madrid. “Human neuronal cell models and gene therapy and dominant ataxias in Europe and all over the world” ˜ Keep in touch those Scientifics who work with ataxias i