Reversal of “Schizofrenia-like” and “Dementia-like” MMN deficits induced by blockade of excitatory pathways in humans effects of indirect NMDA-modulators
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1
FORENAP - FRP - Institute for Research in Neuroscience, Neuropharmacology and Psychiatry , France
Disturbances in integrative function have been consistently described in psychotic disorder; for instance the mismatch negativity MMN, belonging to a family of evoked preattentional responses which are an index of automatic context-dependent information processing, has been shown to be deficient in persons with schizophrenia [3]. Age-related decline in MMN has led researchers to associate the ERP-marker with sensory memory, relevant for the study of Alzheimer’s disease. Whereas dysfunction of various receptor systems have been reported in these 2 psychiatric disorders, the neuropharmacology of MMN in healthy volunteers remains poorly understood and is sometimes paradoxical (e.g. [2]). The NMDA antagonist ketamine produces in control subjects a spectrum of neurobehavioral symptoms like encountered in schizophrenia. The muscarinic antagonist scopolamine is capable to induce cognitive impairment accompanied by deteriorated ERP-markers like in elderlies.
Pooled data for acute NMDA-antagonist-induced psychosis in healthy volunteers diminished pitch-deviant MMN responses on electrode Fz from -2.8 ± 0.7 to -0.9 ± 0.4 μV (matched sample t-test p<0.01, N=15) without changing its peak latency of 196 ms. Results on glycine loading, performed as a preliminary proof-of-principle, showed a recovery to -2.3 ± 0.9 μV ; in parallel partial relief from thought disturbances was observed [1] supporting glutamatergic and phencyclidine/NMDA models of schizophrenia disorder. At the same time the result fits with use-dependency concept of NMDA receptors, important for Long-Term Potentiation (LTP) which is considered a substrate for learning and memory. Treatment with various NMDA-receptor modulators and ketamine reversal are discussed in the light of NMDA-boosting results, receptor occupancy, as well as neuropharmacology of age-related aspects, namely experience, though sparse, with MMN changes when manipulating nicotinic/muscarinic transmission pathways.
References
1. Boeijinga PH, Pross N, Luthringer R Fattah S, Danjou P (2008) Novel Prepulse Processing ERP paradigms as marker of experimentally induced psychodysleptic deteriorations : 3 Case Studies of ketamine effects on auditory N100-gating and its reversal in the human brain. Neurol Psychiatry and Brain Res 15(1) ; 51-56
2. Korostenskaja M, Nikulin VV, Kicić D, Nikulina AV, Kähkönen S. (2007) Effects of NMDA receptor antagonist memantine on mismatch negativity. Brain Res Bull; 72(4-6):275-283
3. Umbricht D, Krljes S (2005) Mismatch negativity in schizophrenia: a meta-analysis.
Schizophr Res. 76(1):1-23.
Conference:
MMN 09
Fifth Conference on Mismatch Negativity (MMN) and its Clinical and Scientific Applications, Budapest, Hungary, 4 Apr - 7 Apr, 2009.
Presentation Type:
Poster Presentation
Topic:
Poster Presentations
Citation:
Boeijinga
P,
Santoro
F and
Staner
C
(2009). Reversal of “Schizofrenia-like” and “Dementia-like” MMN deficits induced by blockade of excitatory pathways in humans effects of indirect NMDA-modulators.
Conference Abstract:
MMN 09
Fifth Conference on Mismatch Negativity (MMN) and its Clinical and Scientific Applications.
doi: 10.3389/conf.neuro.09.2009.05.125
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Received:
26 Mar 2009;
Published Online:
26 Mar 2009.
*
Correspondence:
Peter Boeijinga, FORENAP - FRP - Institute for Research in Neuroscience, Neuropharmacology and Psychiatry, Rouffach, France, peterboeijinga@ymail.com