Article

Matsuoka N, Aigner TG. D-cycloserine, a partial agonist at the glycine site coupled to N-methyl-D-aspartate receptors, improves visual recognition memory in rhesus monkeys. J Pharmacol Exp Ther 278: 891-897

Laboratory of Neuropsychology, National Institute of Mental Health, Bethesda, Maryland, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 09/1996; 278(2):891-7.
Source: PubMed

ABSTRACT

Strychnine-insensitive glycine binding sites have recently been shown to positively modulate N-methyl-D-aspartate (NMDA) receptors. In the present study, the effects on recognition memory of D-cycloserine, a partial agonist at the glycine modulatory site on the NMDA receptor, were evaluated in rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample (DNMS) with a list length of 20 trail-unique graphic symbols. Single administration of D-cycloserine (100-1000 micrograms/kg i.m.) facilitated DNMS performance significantly with an inverted U-shaped dose-response curve when given 30 min before testing. To assess further the possible neural mechanisms, D-cycloserine was evaluated for its effects on the memory impairments after blockade of the glycine sites by HA-966, N-methyl-D-aspartate receptors by MK-801, or cholinergic receptors by scopolamine. D-Cycloserine completely reversed the visual recognition memory deficits produced by HA-966 (3.2 mg/kg i.m.). D-Cycloserine also dose-dependently and significantly restored the memory deficits produced by MK-801 (32 micrograms/kg i.m.). In addition, D-cycloserine produced a partial, though significant, improvement on the recognition memory deficits after cholinergic blockade with scopolamine (10 micrograms/kg i.m.). From these results, we propose that D-cycloserine has a cognition-enhancing property in non-human primates and that it may have a potential value in treating dementias. Furthermore, the present results provide new evidence for the important role for the glycine sites in the regulation of recognition memory.

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    • "NR2C knockout mice show deficits in tests of fear acquisition and working memory, implying that NMDA receptors consisting of NR2C subunits play a substantial role in fear learning processes (Hillman et al., 2011). In healthy animals, DCS leads to a better extinction of conditioned fears (Walker et al., 2002; Ledgerwood et al., 2003), enhances consolidation and retrieval of memories (Quartermain et al., 1994 ), and improves visual recognition memory (Matsuoka and Aigner, 1996 ). Interestingly, facilitation of the fear extinction process works only once, whereas the retrieval of a previous extinction memory (reextinction) seems not to be influenced by DCS (Langton and Richardson, 2008). "
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    ABSTRACT: D-Cycloserine, known from tuberculosis therapy, has been widely introduced to neuropsychiatric studies, since its central active mechanism as a partial NMDA-agonist has been found. In this review, we evaluate its therapeutic potential in neuropsychological disorders and discuss its pitfalls in terms of dosing and application frequency as well as its safety in low-dose therapy. Therefore, we identified 91 clinical trials by performing a Medline search. We demonstrate in part preliminary but increasing evidence that D-cycloserine may be effective in various psychiatric diseases, including schizophrenia, anxiety disorders, addiction, eating disorders, major depression, and autism as well as in neurological diseases, including dementia, Alzheimer’s disease, and spinocerebellar degeneration. D-Cycloserine in low-dose therapy is safe, but there is still a need for new drugs with higher specificity to the different N-methyl-D-aspartate-receptor subunits.
    Preview · Article · Sep 2015 · The International Journal of Neuropsychopharmacology
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    • "NMDA receptors in the hippocampus not only mediate learning and memory [85e89], but also regulate visuospatial and object recognition [86e89]. Blocking of NMDA receptors results in deterioration not only in learning and memory, but also in visuospatial [90] and object recognition [91]. NMDA receptor antagonists, such as ketamine, MK- 801, and phencyclidine, impair learning and memory and trigger severe dissociative psychosis [92e95]. "
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    ABSTRACT: Hyperactivation of glutamatergic N-methyl-D-aspartate (NMDA) receptors has been implicated in the excitotoxicity and pathophysiology of Parkinson's disease (PD). NMDA receptor blockers have been used clinically to treat dementia, but their efficacy is controversial. Modulation of NMDA receptors might improve neuroinflammation and cognitive deficits in PD. D-cycloserine (DCS), a partial agonist binding to the glycine binding site of NMDA receptors, has been demonstrated to improve cognitive function in primates and rodents. Our previous study showed that DCS can reduce motor, emotional, and cognitive dysfunctions, as well as neuroinflammation and neurodegeneration in a PD animal model and may therefore have potential for the treatment of neuroinflammation and cognitive dysfunction in patients with PD. In addition, increased expression of cyclooxygenase type-2 (COX-2) has been observed in dopaminergic neurons and activated microglia in the brain of both PD patients and PD animal models. COX-2 inhibitors can suppress activation of microglia and protect dopaminergic neurons from degeneration. Thus, a combination of DCS and COX-2 inhibitors might prove useful in suppressing neuroinflammation and cognitive deficits in PD.
    Full-text · Article · Aug 2012 · The Kaohsiung journal of medical sciences
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    • "A question that is often asked is why, if DCS is a cognitive enhancer, does it not stamp in the bad memories brought up during psychotherapy and make patients worse? DCS has been shown to facilitate retention of inhibitory avoidance and spatial learning in rats,88 stimulus attributes in inhibitory avoidance in rats,89 inhibitory avoidance in chicks90 or mice,91,92 thirst-motivated maze learning in mice,93 object location in mice,94 taste aversion in rats,95,96 delayed nonmatching- to-sample in rhesus monkeys,97 and acquisition of eyeblink conditioning in rabbits when trace conditioning was used.98 It also improves memory due to aging in mice,91 spatial memory in rats,99 and eyeblink conditioning in rabbits.100 "
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    ABSTRACT: Based primarily on studies that employ Pavlovian fear conditioning, extinction of conditioned fear has been found to be mediated by N-methyi-D-aspartate (NMDA) receptors in the amygdala and medial prefrontal cortex. This led to the discovery that an NMDA partial agonist, D-cycloserine, could facilitate fear extinction when given systemically or locally into the amygdala. Because many forms of cognitive behavioral therapy depend on fear extinction, this led to the successful use of D-cycloserine as an adjunct to psychotherapy in patients with so-called simple phobias (fear of heights), social phobia, obsessive-compulsive behavior, and panic disorder. Data in support of these conclusions are reviewed, along with some of the possible limitations of D-cycloserine as an adjunct to psychotherapy.
    Full-text · Article · Dec 2011 · Dialogues in clinical neuroscience
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