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


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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    • "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.
    The Kaohsiung journal of medical sciences 08/2012; 28(8):407-17. DOI:10.1016/j.kjms.2012.02.010 · 0.80 Impact Factor
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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.
    Dialogues in clinical neuroscience 12/2011; 13(4):463-74.
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    • "Much success has been reported with D-cycloserine (DCS), a partial agonist at the glycine site of the NMDA receptor (Hood et al. 1989). In the animal literature, DCS has been shown to improve learning and memory in rats (Land and Riccio 1999; Pussinen and Sirvio 1999; Lelong et al, 2001) and monkeys (Matsuoka and Aigner 1996; Schneider et al. 2000), as well as facilitating fear extinction learning (Davis et al. 2006; Vervliet 2008). "
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    ABSTRACT: Given the success of cue exposure (extinction) therapy combined with a cognitive enhancer for reducing anxiety, it is anticipated that this approach will prove more efficacious than exposure therapy alone in preventing relapse in individuals with substance use disorders. Several factors may undermine the efficacy of exposure therapy for substance use disorders, but we suspect that neurocognitive impairments associated with chronic drug use are an important contributing factor. Numerous insights on these issues are gained from research using animal models of addiction. In this review, the relationship between brain sites whose learning, memory and executive functions are impaired by chronic drug use and brain sites that are important for effective drug cue extinction learning is explored first. This is followed by an overview of animal research showing improved treatment outcome for drug addiction (e.g. alcohol, amphetamine, cocaine, heroin) when explicit extinction training is conducted in combination with acute dosing of a cognitive-enhancing drug. The mechanism by which cognitive enhancers are thought to exert their benefits is by facilitating consolidation of drug cue extinction memory after activation of glutamatergic receptors. Based on the encouraging work in animals, factors that may be important for the treatment of drug addiction are considered.
    Pharmacology Biochemistry and Behavior 02/2011; 99(2):229-44. DOI:10.1016/j.pbb.2011.01.018 · 2.78 Impact Factor
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