Introduction

D-cycloserine (D-4-amino-3-isoxazolidone; DCS), a partial N-methyl-d-aspartate (NMDA) receptor agonist, might show promise as a cognitive enhancer in humans, as glutamatergic activation of the NMDA receptor influences long-term potentiation-dependent forms of learning and memory. NMDA receptors are widespread in the amygdala, hippocampus, and other brain regions and are critically involved in fear processing and associative learning[1].

History

The clinical development of d-Cycloserine (DCS) has experienced several waves. It was introduced in the 1960s as an antimicrobial agent for the treatment of tuberculosis. DCS was later found centrally active as a selective partial NMDAR agonist, acting at its serine/glycine-binding site. Based on the assumption of glutamatergic deficits in dementia and schizophrenia, several clinical trials examined the treatment of Alzheimer disease and negative symptoms of schizophrenia in the 1990s. However, these treatment approaches largely failed[2]. A third wave was initiated by a seminal study by Ressler et al. in 2004, in which DCS successfully augmented virtual exposure therapy for height phobia. In the following years, DCS has been used in many clinical trials to augment exposure-based cognitive behaviour therapy for anxiety-related disorders, obsessive-compulsive disorder, addiction and posttraumatic stress disorder. However, a meta-analysis revealed only a small and potentially not clinically meaningful augmentation effect of DCS on exposure-based therapy. More recently, the first clinical trials supported an antidepressant effect of DCS.

Neurophysiological Aspects

Drugs like D-cycloserine (DCS), which modulate the NMDA receptor, show promise in treating conditions with neuroplasticity deficits, such as dementia, and in therapies that involve learning, like fear exposure therapy. The NMDA receptor is composed of NR1 and NR2 subunits, and DCS acts as a partial agonist at the glycine-binding site on the NR1 subunit. Its effects vary with dose and receptor subtype, with low doses showing agonistic activity at NR1/NR2C receptors and high doses potentially inhibiting NR1/NR2A and NR1/NR2B receptors.

DCS's impact on NMDA receptors, especially those with NR2C subunits, is significant for fear learning and memory processes. It enhances fear extinction, memory consolidation, and visual recognition memory in animals, but its efficacy may decrease with repeated use. The drug's mechanism may be influenced by stress and neurotransmitter concentrations, and its effects on fear extinction learning were seen in sleep-deprived rats but not replicated in humans with poor sleep quality. DCS is thought to improve cognitive functions by stabilizing NMDA receptors and facilitating cortical neuroplasticity. It may be beneficial in neurorehabilitation, as it has been shown to improve recovery after brain damage in mice[3].

DCS is a typical example of translational research from neurobiochemical considerations to animal experiments and application in various neuropsychiatric diseases. First, the central acting mechanism of DCS was found. DCS acts at the glycine-binding side of the NMDA receptor and thereby modulates its activity. It has been proven that NMDA receptors play a crucial role in the neuroplasticity of the human brain through a mechanism called LTP. This led to the rationale that DCS might modulate neuroplasticity, which has been proven in humans by neurophysiological studies with transcranial direct current stimulation. Neuroplasticity plays a vital role in higher cognitive functions like learning and memory. Therefore, DCS might modulate these processes, which gave the rational of studying the effects of DCS on diseases associated with memory/learning deficits (eg, dementia, autism) on therapies that rely on learning processes (eg, exposure therapy in anxiety disorders or cue exposure therapy in addiction).

References

[1] Ph.D., Stefan G. Hofmann. “d-CYCLOSERINE FOR TREATING ANXIETY DISORDERS: MAKING GOOD EXPOSURES BETTER AND BAD EXPOSURES WORSE.” Depression and Anxiety 31 3 (2014): 175–177.

[2] Stefan Vestring. “D-Cycloserine enhances the bidirectional range of NMDAR-dependent hippocampal synaptic plasticity.” Translational Psychiatry 14 1 (2024): 18.

[3] Sebastian Schade, Walter Paulus. “D-Cycloserine in Neuropsychiatric Diseases: A Systematic Review.” International Journal of Neuropsychopharmacology 19 4 (2016).