Comments on News and Primary Papers
Comment by: Patricia Estani
Submitted 21 May 2007
Posted 21 May 2007
In the field of the psychopharmacology of schizophrenia, a lot of research work has been done on dopaminergic systems. Thus, this research news is excellent news because it explores an alternative neurotransmission system in schizophrenia, the glutamatergic system. Since the work of Dr. Bita Moghaddam in 1998, published in Science, a lot of research studies have turned to the important role of glutamate in schizophrenia. More studies are needed to focus on the exact role of this neurotransmitter.
View all comments by Patricia EstaniComment by: Joseph Neale
Submitted 14 July 2007
Posted 14 July 2007
The pioneering research over the past decade on group II metabotropic glutamate receptor (mGluR) agonists from the Lilly Labs and Bita Moghaddam's research group has provided a strong foundation for the view that activation of these receptors reduces schizophrenia-like behaviors in the PCP and amphetamine models. These phase 2 clinical trials bring mGluR agonists one step closer to clinical use as therapy or co-therapy.
These same data provide the foundation for current and future research aimed at increasing the concentration of the peptide transmitter, N-acetylaspartylglutamate (NAAG) in the synaptic cleft by systemic administration of NAAG peptidase inhibitors. NAAG is the third most prevalent transmitter in the mammalian nervous system and a selective group II mGluR agonist with preference for mGluR3 (Neale et al., 2005). Our research group demonstrated that a NAAG peptidase inhibitor substantially reduces positive and negative behaviors induced in PCP models of schizophrenia (Olszewski et al., 2007; Olszewski et al., 2004). These NAAG peptidase inhibition studies parallel the preclinical studies from Lilly and Bita Moghaddam on mGluR agonists in animal models of schizophrenia.
Since NAAG is an endogenous transmitter, it can be argued that elevating its levels following synaptic release by reducing the rate of its inactivation (analogous to SSRI and serotonin) is a more physiologic means of activating the mGluR, and thus this may be better tolerated with fewer side effects than the continuous receptor activation that is obtained via systemic administration of a receptor agonist.
These phase 2 clinical trials clearly brighten the prospects for both lines of new drug development for treatment of schizophrenia.
Neale JH, Olszewski RT, Gehl LM, Wroblewska B, Bzdega T. The neurotransmitter N-acetylaspartylglutamate in models of pain, ALS, diabetic neuropathy, CNS injury and schizophrenia. Trends Pharmacol Sci. 2005 Sep;26(9):477-84. Review. Abstract
Olszewski RT, Wegorzewska MM, Monteiro AC, Krolikowski K, Zhou
J, Kozikowski AP, Long K, Mastropaolo J, Deutsch S, Neale JH. PCP and MK-801 induced behaviors reduced by NAAG peptidase inhibition via metabotropic glutamate receptors. E-pub in advance of print, Biological Psychiatry, 2007.
Olszewski RT, Bukhari N, Zhou J, Kozikowski AP, Wroblewski JT, Shamimi-Noori S, Wroblewska B, Bzdega T, Vicini S, Barton FB, Neale JH. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. J Neurochem. 2004 May;89(4):876-85.
View all comments by Joseph Neale
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Related News: Studies Explore Glutamate Receptors as Target for Schizophrenia MonotherapyComment by: Dan Javitt, SRF Advisor
Submitted 3 September 2007
Posted 3 September 2007
A toast to success, or new wine in an old skin?
Patil et al. present a landmark study. It is the kind of study that represents the best of how science should work. It pulls together the numerous strands of schizophrenia research from the last 50 years, from the development of PCP psychosis as a model for schizophrenia in the late 1950s, through the links to glutamate, the discovery of metabotropic receptors, and the seminal discovery in 1998 by Moghaddam and Adams that metabotropic glutamate 2/3 receptor (mGluR2/3) agonists reverse the neurochemical and behavioral effects of PCP in rodents (Moghaddam and Adams, 1998. The story would not be possible without the elegant medicinal chemistry of Eli Lilly, which provided the compounds needed to test the theories; the research support of NIMH and NIDA, who have been consistent supporters of the “PCP theory”; or the hard work of academic investigators, who provided the theories and the platforms for testing. The study is large and the effects robust. Assuming they replicate (and there is no reason to suspect that they will not), this compound, and others like it, will represent the first rationally developed drugs for schizophrenia. Patients will benefit, drug companies will benefit, and academic investigators and NIH can feel that they have played their role in new treatment development.
Nevertheless, it is always the prerogative of the academic investigator to ask for more. In this case, we do not yet know if this will be a revolution in the treatment of schizophrenia, or merely a platform shift. What is striking about the study, aside from the effectiveness of LY2140023, is the extremely close parallel in both cross-sectional and temporal pattern of response between it and olanzapine. Both drugs change positive and negative symptoms in roughly equal proportions, despite their different pharmacological targets. Both drugs show approximately equal slopes over a 4-week period. There is no intrinsic reason why symptoms should require 4 or more weeks to resolve, or why negative and positive symptoms should change in roughly the same proportion with two medications from two such different categories, except that evidently they do.
There are many things about mGluR2/3 agonists that we do not yet know. The medication used here was administered at a single, fixed dose. It is possible that a higher dose might have been better, and that optimal results have not yet been achieved. The medications were used in parallel. It is possible that combined medication might be more effective than treatment with either class alone. The study was stopped at 4 weeks, with the trend lines still going down. It is possible that longer treatment duration in future studies might lead to even more marked improvement and that the LY and olanzapine lines might separate. No cognitive data are reported. It is possible that marked cognitive improvement will be observed with these compounds when cognition is finally tested, in which case a breakthrough in pharmacotherapy will clearly have been achieved.
If one were to look at the glass as half empty, then the question is why the metabotropic agonist did not beat olanzapine, and why the profiles of response were so similar. If these compounds work, as suggested in the article by modulating mesolimbic dopamine, then it is possible that metabotropic agonists will share the same therapeutic limitations as current antipsychotics—good drugs certainly and without the metabolic side effects of olanzapine, but not “cures.” The recent study with the glycine transport inhibitor sarcosine by Lane and colleagues showed roughly similar overall change in PANSS total (-17.1 pts) to that reported in this study, but larger change in negative symptoms (-5.5 pts), and less change in positive symptoms (-2.3 pts) in a similar type of patient population. Onset of effect in the sarcosine study also appeared somewhat faster. The sarcosine study was smaller (n = 20) and did not include a true placebo group. As with the Lilly study, it was only 4 weeks in duration, and did not include cognitive measures. It also included only two, possibly non-optimized doses. As medications become increasingly available to test a variety of mechanisms, side-by-side comparisons will become increasingly important.
There are also causes for concern and effects to be watched. For example, a side effect signal was observed for affect lability in the LY group, at about the same prevalence rate as weight increase in the olanzapine group. What this means for the mechanism and how this will effect treatment remains to be determined. Since these medications are agonists, there is concern that metabotropic receptors may downregulate over time. Thus, whether treatment effects increase, decrease, or remain constant over the course of long-term treatment will need to be determined. Nevertheless, 50 years since the near-contemporaneous discovery of both PCP and chlorpromazine, it appears that glutamatergic drugs for schizophrenia may finally be on the horizon.
Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science. 1998 Aug 28;281(5381):1349-52. Abstract
View all comments by Dan Javitt
Related News: Studies Explore Glutamate Receptors as Target for Schizophrenia Monotherapy
Comment by: Gulraj Grewal
Submitted 4 September 2007
Posted 4 September 2007
I recommend the Primary Papers
Related News: Studies Explore Glutamate Receptors as Target for Schizophrenia Monotherapy
Comment by: Shoreh Ershadi
Submitted 8 June 2008
Posted 9 June 2008
I recommend the Primary Papers
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
Related News: Learning from Drug Candidates—New Kid Targets Same Block
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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2. Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D: Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am. J. Psychiatry 1997; 154:805-811. Abstract
3. Farber NB, Kim SH, Dikranian K, Jiang XP, Heinkel C: Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity. Mol. Psychiatry 2002; 7:32-43. Abstract
4. Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC: Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 2008; 452:93-97. Abstract
5. Gouzoulis-Mayfrank E, Schreckenberger M, Sabri O, Arning C, Thelen B, Spitzer M, Kovar KA, Hermle L, Bull U, Sass H: Neurometabolic effects of psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and d-methamphetamine in healthy volunteers. A double-blind, placebo-controlled PET study with [18F]FDG. Neuropsychopharmacology 1999; 20:565-581. Abstract
6. Holcomb HH, Lahti AC, Medoff DR, Cullen T, Tamminga CA: Effects of noncompetitive NMDA receptor blockade on anterior cingulate cerebral blood flow in volunteers with schizophrenia. Neuropsychopharmacology 2005; 30:2275-2282. Abstract
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10. Moghaddam B, Adams BW: Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 1998; 281:1349-1352. Abstract
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13. 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; 13:1102-1107. Abstract
14. Rothman DL, Sibson NR, Hyder F, Shen J, Behar KL, Shulman RG: In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycle and functional neuroenergetics. Philos. Trans. R. Soc. Lond B Biol. Sci. 1999; 354:1165-1177. Abstract
15. Rowland, L. M., Bustillo, J. R., Mullins, P. G., Jung, R. E., Lenroot, R., Landgraf, E., Barrow, R, Yeo, R, Lauriello, J, and Brooks, W. M. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T Proton MRS study. Am. J. Psychiatry 162(2), 394-396. 2005. Abstract
16. Soyka M, Koch W, Moller HJ, Ruther T, Tatsch K: Hypermetabolic pattern in frontal cortex and other brain regions in unmedicated schizophrenia patients. Results from a FDG-PET study. Eur. Arch. Psychiatry Clin.Neurosci. 2005; 255:308-312. Abstract
17. Tamminga CA, Tanimoto K, Kuo S, Chase TN, Contreras PC, Rice KC, Jackson AE, O'Donohue TL: PCP-induced alterations in cerebral glucose utilization in rat brain: blockade by metaphit, a PCP-receptor-acylating agent. Synapse 1987; 1:497-504. Abstract
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View all comments by Henry Holcomb
Related News: ICOSR 2011—Some Hope for Alleviating Negative Symptoms
Comment by: Kimberly E. Vanover
Submitted 20 June 2011
Posted 20 June 2011
Thank you for your summary of the presentations from the New Drug Session at ICOSR 2011 on the Schizophrenia Research Forum. The Forum is a helpful and important resource.
I just wanted to clarify your description of ITI-007’s properties at the D2 site. As a dopamine phosphorylation modulator, ITI-007 acts as a pre-synaptic partial agonist and a post-synaptic antagonist with mesolimbic/mesocortical selectivity (Wennogle et al., 2008). In addition to its antagonism of 5-HT2A receptors and unique interaction with D2 receptors, it has affinity for D1 receptors, consistent with partial agonism linked to downstream increases in NMDA NR2B receptor phosphorylation (Zhu et al., 2008), and it is a serotonin reuptake inhibitor (Wennogle et al., 2008). Unfortunately, the short, 10-minute talk during the ICOSR session wasn’t sufficient time to go into the details of the mechanism and supporting preclinical data.
I did notice that a brief description for the mode of action for ITI-007 is listed as “5-HT2A antagonist + dopamine phosphoprotein modulator” with a role in schizophrenia listed as “DA stabilizer + 5hT-T inhibitor” in the Forum’s Drugs in Clinical Trials section. This is a nice, brief way to describe a rather complex mechanism.
Wennogle LP, Snyder GL, Hendrick JP, Vanover KE, Tomesch JT, Li P, O’Callaghan JP, Miller DB, Fienberg AA, Davis RE, Mates S (2008) Unique antipsychotic profile of a novel 5-HT2A receptor antagonist and dopamine receptor protein phosphorylation modulator. Schizophrenia Research 98:Suppl1:15.
Zhu H, Snyder GL, Vanover KE, Rana M, Tsui T, Hendrick JP, Li P, Tomesch J, O’Brien JJ, Guo H, Davis RE, Fienberg AA, Wennogle LP, Mates S (2008) ITI-007: A novel 5-HT2A antagonist and dopamine protein phosphorylation modulator (DPPM) induces a distinct NR2B expression pattern in mouse brain. Program No. 155.14 2008 Neuroscience Meeting Planner. Washington, DC Society for Neuroscience, 2008. Online.
View all comments by Kimberly E. Vanover