Article

Gunduz-Bruce H. The acute effects of NMDA antagonism: from the rodent to the human brain. Brain Res Rev 60: 279-286

Yale University School of Medicine, VA Medical Center, Psychiatry Service 116A,West Haven, CT 06516, USA.
Brain Research Reviews (Impact Factor: 5.93). 08/2008; 60(2):279-86. DOI: 10.1016/j.brainresrev.2008.07.006
Source: PubMed

ABSTRACT In the past decade, the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia has received support from several lines of clinical evidence, including genetic, postmortem and human psychosis modeling. Recently, superiority of a mGluR2/3 receptor agonist over placebo was demonstrated in a randomized double-blind clinical trial in patients with schizophrenia. Considering the fact that currently available antipsychotics are all dopamine blockers to varying degrees without direct effects on glutamate transmission, this clinical trial highlights the potential utility of glutamatergic agents. In healthy volunteers, the NMDA channel antagonist ketamine induces transient cognitive dysfunction, perceptual aberrations and changes reminiscent of the negative symptoms of schizophrenia. However, how ketamine produces these effects is unclear. Preclinical data on NMDAR hypofunction offer further insights into the pathogenesis of the disorder as it relates to disorganized behavior, stereotypic movements and cognitive dysfunction in the rodent. This review evaluates the existing clinical and preclinical literature in an effort to shed light on the mechanism of action of ketamine as a probe to model NMDAR hypofunction in healthy volunteers. Included in this perspective are direct and indirect effects of ketamine at the neuronal level and in the intact brain. In addition to ketamine's effects on presynaptic and postsynaptic function, effects on glia and other neurotransmitter systems are discussed. While increased extracellular glutamate levels following NMDA antagonist administration stand out as a well replicated finding, evidence suggests that ketamine's effects are not restricted to pyramidal cells, but extend to GABAergic interneurons and the glia. In the glia, ketamine has significant downstream effects on the glutathione metabolism. Further studies are needed to identify the mechanistic connections between ketamine's effects at the cellular and behavioral levels.

Download full-text

Full-text

Available from: Handan Gunduz-Bruce, Oct 01, 2014
1 Follower
 · 
179 Views
  • Source
    • "Moreover, D-serine has emerged as an influential player in the context of psychiatric diseases such as schizophrenia and depression. Indeed, based on the rationale that a common feature of these pathologies might be a dysregulation of glutamatergic system, especially NMDAR-dependent synaptic transmission, an increasing number of studies have investigated D-serine signaling to explore possible causes and potential therapeutic interventions for these diseases (Carlsson and Carlsson, 1990; Adage et al., 2008; Lisman et al., 2008; Gunduz-Bruce, 2009; Hashimoto et al., 2009; Labrie et al., 2012; Balu et al., 2013; Lane et al., 2013; Sacchi et al., 2013). More recently a link between D-serine signaling and cocaine addiction, another neuropsychiatric disorder, has been proposed. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cocaine addiction is characterized by compulsive drug use despite adverse consequences and high rate of relapse during periods of abstinence. Increasing consensus suggests that addiction to drugs of abuse usurps learning and memory mechanisms normally related to natural rewards, ultimately producing long-lasting neuroadaptations in the mesocorticolimbic system. This system, formed in part by the ventral tegmental area and nucleus accumbens (NAc), has a central role in the development and expression of addictive behaviors. In addition to a broad spectrum of changes that affect morphology and function of NAc excitatory circuits in cocaine-treated animals, impaired N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity is a typical feature. D-serine, a D-amino acid that has been found at high levels in mammalian brain, binds with high affinity the co-agonist site of NMDAR and mediates, along with glutamate, several important processes including synaptic plasticity. Here we review recent literature focusing on cocaine-induced impairment in synaptic plasticity mechanisms in the NAc and on the fundamental role of D-serine as co-agonist of NMDAR in functional and dysfunctional synaptic plasticity within this nucleus. The emerging picture is that reduced D-serine levels play a crucial role in synaptic plasticity relevant to cocaine addiction. This finding opens new perspectives for therapeutic approaches to treat this addictive state.
    Frontiers in Synaptic Neuroscience 07/2014; 6:16. DOI:10.3389/fnsyn.2014.00016
  • Source
    • "In fact, synaptic NMDA-R play a key role to trigger different forms of synaptic plasticity that are considered to be the neurophysiological basis of learning and memory (Lynch, 2004; Martin, Grimwood, & Morris, 2000). Additionally, a reduced NMDA-R function also impairs the interactions between multiple brain regions (Fitzgerald, 2012; Greene, 2001; Gunduz-Bruce, 2009); this is a hallmark of the schizophrenic brain, where there is an unbalanced connectivity between different brain regions rather than a locus of dysfunction present in a defined brain region (Field et al., 2011; Lisman et al., 2008). Indeed, the glutamatergic hypofunction in schizophrenia has been particularly explored as a mechanistic basis of alterations in the thalamocortical loop resulting in an exaggerated sensory flooding and psychotic symptoms and the well-known dopaminergic dysfunction (Fitzgerald, 2012; Greene, 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The management of schizophrenia endophenotypes, namely positive, negative, and cognitive symptoms is still an open goal, justifying the search of novel therapeutic avenues. We now review the evidence supporting the interest in targeting the adenosine modulation system to counteract the core features of schizophrenia. This interest is forwarded by the combined ability of strategies aimed at bolstering adenosine levels together with the increasingly recognized impact of adenosine A2A receptors to control dopaminergic signaling, working memory, and behavioral sensitization; this is further heralded by the suggested clinical effectiveness of therapies increasing extracellular adenosine such as dipyridamole and allopurinol and the emergent recognition of a role for adenosine in neurodevelopment. Finally, the combined role of A1 and A2A receptors in assisting the implementation of adaptive changes and encoding of information salience in neuronal circuits together with the adaptive alterations of A1 and A2A receptor density upon brain dysfunction prompts the novel working hypothesis that the parallel imbalance of adenosine formation and of A1 and A2A receptors blurs the adequate encoding of information salience in neuronal circuits, which we propose to be a core pathogenic feature in the development of schizophrenia endophenotypes. This proposal should also provide a rationale to assist the design of future therapeutic intervention targeting the adenosine modulation system to manage schizophrenia endophenotypes: these should not be based only on an attempt to target adenosine kinase-A1 receptors or only A2A receptors, but should instead simultaneously target these two arms of the adenosine modulation system.
    International Review of Neurobiology 01/2014; 119C:395-449. DOI:10.1016/B978-0-12-801022-8.00016-7 · 2.46 Impact Factor
  • Source
    • "Given at a sub-anesthetic dose, NMDA antagonists recapitulate a schizophrenia-like state in healthy human subjects (Coyle, 1996; Javitt and Zukin, 1991; Krystal et al., 1994; Luby et al., 1959). Although the likely mechanism of action may include neuronal dysfunction at many levels (Gunduz-Bruce, 2009), it is clear that NMDA antagonists disrupt the highly specific interactions between cortical GABAergic and glutamatergic neuron networks (Grunze et al., 1996; Homayoun and Moghaddam, 2007; Roopun et al., 2008). A working hypothesis proposes that low-dose NMDA antagonists preferentially target the fast-spiking GABAergic interneurons leading to a disturbed pyramidal firing in key brain regions (Grunze et al., 1996; Jackson et al., 2004; Lisman, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with schizophrenia show marked deficits in processing sensory inputs including a reduction in the generation and synchronization of 40 Hz gamma oscillations in response to steady-state auditory stimulation. Such deficits are not readily demonstrable at other input frequencies. Acute administration of NMDA antagonists to healthy human subjects or laboratory animals is known to reproduce many sensory and cognitive deficits seen in schizophrenia patients. In the following study, we tested the hypothesis that the NMDA antagonist MK-801 would selectively disrupt steady-state gamma entrainment in the auditory cortex of urethane-anesthetized rat. Moreover, we further hypothesized that nicotinic receptor activation would alleviate this disruption. Auditory steady state responses were recorded in response to auditory stimuli delivered over a range of frequencies (10-80 Hz) and averaged over 50 trials. Evoked power was computed under baseline condition and after vehicle or MK-801 (0.03 mg/kg, iv). MK-801 produced a significant attenuation in response to 40 Hz auditory stimuli while entrainment to other frequencies was not affected. Time-frequency analysis revealed deficits in both power and phase-locking to 40 Hz. Nicotine (0.1 mg/kg, iv) administered after MK-801 reversed the attenuation of the 40 Hz response. Administered alone, nicotine augmented 40 Hz steady state power and phase-locking. Nicotine's effects were blocked by simultaneous administration of the 003F4003F2 antagonist DH003FE. Thus we report for the first time, a rodent model that mimics a core neurophysiological deficit seen in patients with schizophrenia and a pharmacological approach to alleviate it.
    Neuropharmacology 05/2013; 73. DOI:10.1016/j.neuropharm.2013.05.006 · 4.82 Impact Factor
Show more