D-cycloserine, a positive modulator of the N-methyl-D-aspartate receptor, enhances performance of learning tasks in rats

doi:10.1016/0091-3057(89)90571-6

Pharmacology Biochemistry and Behavior

Volume 34, Issue 3, November 1989, Pages 649-653

https://doi.org/10.1016/0091-3057(89)90571-6 Get rights and content

Abstract

Glycine has recently been shown to positively modulate the N-methyl-D-aspartate (NMDA) subclass of acidic amino acid receptors which are important in neural pathways involved in learning and memory. We report that d-cycloserine (DCS), an antimycobacterial agent known to cross the blood-brain barrier, binds with high affinity to this glycine modulatory site, functions as a positive modulator, and facilitates performance of learning tasks in rats. In addition, DCS appears to be a potent cognitive enhancer at doses lower than those required for antibacterial activity. Based on these data, we propose that modulation of NMDA receptors via glycinergic mechanisms may be a means of influencing cognitive processes.

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Cue-exposure therapy (CET) is an effective approach for anxiety-related disorders, but its effectiveness for substance use disorders is less clear. One potential means of improving CET outcomes is to include a cognitive-enhancing pharmacotherapy. This study evaluated d-cycloserine (DCS) and RY-023, putative cognitive enhancers targeting glutamate and GABA systems, respectively, in a monkey model of CET for alcohol use disorder.
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Through multiple cycles, self-administration remained stable. Compared to vehicle, DCS facilitated extinction of ethanol seeking (Phase 2) and delayed reacquisition of ethanol self-administration (Phase 4). In contrast, RY-023 facilitated extinction (Phase 2) and reduced cue reactivity (Phase 3).
Adjunctive pharmacotherapy can improve CET outcomes, but the choice of pharmacotherapy should be dependent on the outcome of interest.
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Cognitive flexibility facilitates adaptions to a changing environment in humans and animals and can be assessed with the attentional set shifting task (ASST). In various learning paradigms for laboratory rodents, the partial NMDA receptor agonist D-cycloserine has been found to have pro-cognitive effects. However, D-cycloserine has not yet been investigated for its effects on cognitive flexibility. The aim of the present study was to determine whether D-cycloserine is able to improve cognitive flexibility measured by the ASST in rats. Rats were first pre-treated with the muscarinic antagonist scopolamine (0.5 mg/kg) before the D-cycloserine administrations (20 mg/kg) to induce deficits in ASST performance. Our findings showed impaired ASST performance after scopolamine administration with significant effects on reversal phases and extra-dimensional shift. D-cycloserine treatment selectively improved the performance in the extra-dimensional shift and the last reversal phase, where scopolamine effects were most pronounced. These findings suggest that D-cycloserine can rescue deficits in cognitive flexibility.
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Traumatic brain injury is the leading cause of death and disability in the United States, and may be associated with long lasting impairments into adulthood. The multitude of ongoing neurobiological processes that occur during brain maturation confer both considerable vulnerability to TBI but may also provide adaptability and potential for recovery. This review will examine and synthesize our current understanding of developmental neurobiology in the context of pediatric TBI. Delineating this biology will facilitate more targeted initial care, mechanism-based therapeutic interventions and better long-term prognostication and follow-up.

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Pharmacology Biochemistry and Behavior

Abstract

References (26)

Biochemical evidence that glycine allosterically regulates an NMDA receptor-coupled ion channel

Eur. J. Pharmacol.

NMDA receptors—their role in long term potentiation

Trends Neurosci.

Anatomical organization of excitatory amino acid receptors and their pathways

Trends Neurosci.

Long term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors

Brain Res.

Blockage of long-term potentiation by phencyclidine and σ-opiates in the hippocampus in vivo and in vitro

Brain Res.

Glycine modulation of the phencyclidine binding site in mammalian brain

Brain Res.

Glycine modulates [³H]MK-801 binding to the NMDA receptor in rat brain

Eur. J. Pharmacol.

Long term potentiation and NMDA receptors in rat visual cortex

Nature

Light microscopic autoradiographic localization of [³H]strychnine binding sites in rat brain

Eur. J. Pharmacol.

Do passive avoidance tasks permit assessment of retrograde amnesia in rats?

J. Comp. Physiol. Psychol.

Learning impairment in rats by N-methyl-D-aspartate receptor antagonists

Neuropharmacology

Anatomical and behavioral analysis of hippocampal cell fields in rats

J. Comp. Physiol. Psychol.

Glycine potentiates the NMDA response in cultured mouse brain neurons

Nature

Cited by (249)

Modeling cue-exposure therapy for alcohol use disorder in rhesus monkeys: Effects of putative cognitive enhancers

D-cycloserine rescues scopolamine-induced deficits in cognitive flexibility in rats measured by the attentional set-shifting task

Fear-related anxiety disorders and posttraumatic stress disorder

Pharmacological assistance for psychotherapy

D-Cycloserine reverses scopolamine-induced object and place memory deficits in a spontaneous recognition paradigm in rats

Bridging the gap: Mechanisms of plasticity and repair after pediatric TBI

D-cycloserine, a positive modulator of the N-methyl-D-aspartate receptor, enhances performance of learning tasks in rats

Abstract

Eur. J. Pharmacol.

Trends Neurosci.

Trends Neurosci.

Brain Res.

Brain Res.

Brain Res.

Eur. J. Pharmacol.

Long term potentiation and NMDA receptors in rat visual cortex

Nature

Light microscopic autoradiographic localization of [3H]strychnine binding sites in rat brain

Eur. J. Pharmacol.

Do passive avoidance tasks permit assessment of retrograde amnesia in rats?

J. Comp. Physiol. Psychol.

Learning impairment in rats by N-methyl-D-aspartate receptor antagonists

Neuropharmacology

Anatomical and behavioral analysis of hippocampal cell fields in rats

J. Comp. Physiol. Psychol.

Glycine potentiates the NMDA response in cultured mouse brain neurons

Nature

Light microscopic autoradiographic localization of [³H]strychnine binding sites in rat brain