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NMDA Receptor Interactions
Published by Anonymous on 2007/9/30 (2634 reads)
1: Brain Cogn. 2007 Mar;63(2):94-122. Epub 2007 Jan 3.

Comment in:
Brain Cogn. 2007 Mar;63(2):92-3.

Tuning the engine of cognition: a focus on NMDA/D1 receptor interactions in prefrontal cortex.

Castner SA, Williams GV.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA. stacy.castner@yale.edu

The prefrontal cortex of the primate frontal lobes provides the capacity for judgment which can constantly adapt behavior in order to optimize its outcome. Adjudicating between long-term memory programs and prepotent responses, this capacity reviews all incoming information and provides an interpretation dependent on the events that have just occurred, the events that are predicted to happen, and the alternative response strategies that are available in the given situation. It has been theorized that this function requires two essential integrated components, a central executive which guides selective attention based on mechanisms of associative memory, as well as the second component, working memory buffers, in which information is held online, abstracted, and translated on a mental sketchpad of work in progress. In this review, we critically outline the evidence that the integration of these processes and, in particular, the induction and maintenance of persistent activity in prefrontal cortex and related networks, is dependent upon the interaction of dopamine D1 and glutamate NMDA receptor signaling at critical nodes within local circuits and distributed networks. We argue that this interaction is not only essential for representational memory, but also core to mechanisms of neuroadaptation and learning. Understanding its functional significance promises to reveal major new insights into prefrontal dysfunction in schizophrenia and, hence, to target a new generation of drugs designed to ameliorate the debilitating working memory deficits in this disorder.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

PMID: 17204357 [PubMed - indexed for MEDLINE]


2: Toxicol Sci. 2003 Apr;72(2):185-7.

Comment on:
Toxicol Sci. 2003 Apr;72(2):289-95.

From anticholinesterase toxicity to Alzheimer's disease: important interactions of cholinergic and NMDA receptor systems.

Popke EJ.

Safety Pharmacology, Wyeth Research, 641 Ridge Road Chazy, NY 12921, USA. popkej@wyeth.com

The article highlighted in this issue is "Dizocilpine Improves Beneficial Effects of Cholinergic Antagonists in Anticholinesterase-Treated Mice," by Andrzej Dekundy, Rafal M. Kaminski, and Waldemar A. Turski (pp. 289-295). It explores the relationship between cholinergic and N-methyl-D-aspartate (NMDA) receptors as mediators of anticholinesterase toxicity. The following review summarizes these findings and discusses their broader implications for central nervous system pharmacology. Alzheimer's disease is discussed as an example of how knowledge of the interactions between NMDA and cholinergic receptors may lead to a better understanding of human disease.

Publication Types:

PMID: 12685427 [PubMed - indexed for MEDLINE]


3: Neurosci Biobehav Rev. 2001 Jun;25(4):343-53.

Opioid-NMDA receptor interactions may clarify conditioned (associative) components of opioid analgesic tolerance.

Bespalov AY, Zvartau EE, Beardsley PM.

Department of Psychopharmacology, Valdman Institute of Pharmacology, Pavlov Medical University, 6/8 Lev Tolstoy Str., St Petersburg 197089, Russia. abespalov@spmu.rssi.ru

Recent evidence suggests that acute administration of opioid analgesic drugs (such as morphine or heroin) produces delayed hyperalgesia. This hyperalgesic response is likely to result from hyperactivation of NMDA receptors triggered by stimulation of opioid receptors and may mediate acute tolerance. In support of this hypothesis, blockade of NMDA receptors attenuates opioid-induced delayed hyperalgesia and prolongs the duration of antinociceptive activity of morphine. Furthermore, the NMDA receptor-induced hyperalgesia is likely an unconditioned response to opioid receptor stimulation that becomes spatiotemporally associated with environmental cues accompanying repeated opioid exposure. This hypothesis conforms to the traditional Pavlovian requirement for conditioned and unconditioned responses to be qualitatively similar. In support of the role of NMDA receptor hyperactivation in morphine tolerance, NMDA receptor antagonists have been shown to block development of analgesic tolerance induced by repeated exposures to morphine. The view of the conditioned nature of opioid tolerance may be significantly extended by assuming that upon repeated drug administration an early-onset effect of a drug may become a predictive stimulus for a later-onset effect and, consequentially, it may become empowered to elicit the later-onset effect itself. Such 'intra-drug' conditioning hypothesis is well in line with the current experimental evidence but further studies will be needed to verify it directly.

Publication Types:

PMID: 11445139 [PubMed - indexed for MEDLINE]


4: J Pain Symptom Manage. 2000 Jan;19(1 Suppl):S7-11.

NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance.

Price DD, Mayer DJ, Mao J, Caruso FS.

Department of Oral and Maxillofacial Surgery, University of Florida, USA.

A model proposing that N-methyl-D-aspartate (NMDA) receptor and opioid receptor mechanisms overlap and interact within the same dorsal horn nociceptive neurons makes several predictions. First, hyperalgesia should be associated with opioid tolerance. Second, both hyperalgesia and tolerance to opioid-analgesia should be blocked by an NMDA-receptor antagonist. Results from our laboratory and others support these predictions and point to several clinical implications. One is that, in addition to preventing tolerance and dependence, combining NMDA-receptor antagonists with both opioid and nonopioid analgesics may increase their analgesic potency. Preclinical animal studies demonstrate these advantages and underscore the practicality of the combined administration of nontoxic NMDA-receptor antagonists with various types of analgesic drugs.

Publication Types:

PMID: 10687332 [PubMed - indexed for MEDLINE]

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