Behavioral and cognitive effects of the N-methyl-D-aspartate receptor co-agonist D-serine in healthy humans: initial findings.

The efficacy of compounds having agonistic activity at the glycine site associated with the N-methyl-D-aspartate receptor (NMDAR) is presently assessed in psychiatric disorders. In contrast to NMDAR antagonists, the neuropsychiatric effects of NMDAR agonists in the healthy human organism are not known. We studied neuropsychiatric and neurochemical effects of the NMDAR-glycine site obligatory co-agonist d-serine (DSR) in healthy subjects using a randomized, controlled crossover challenge design including a baseline assessment day and two DSR/placebo administration days. Thirty-five subjects aged 23-29 years participated in the study and received a 2.1 g orally administered DSR dose. The main outcome measures were the changes in scores of mood-related Visual Analogue Scale (VAS), Continuous Performance Test-Identical Pairs (CPT-IP), and Rey Auditory Verbal Learning Test (RAVLT). DSR acute administration: (1) was well tolerated and resulted at 2 h in ≥ 200 times increase in DSR serum levels; (2) elicited reduced VAS-measured depression and anxiety feelings; (3) improved attention and vigilance as measured by CPT-IP D-prime score; (4) preferentially improved performance in RAVLT list 7 reflecting ability to retain information over interference; (5) had significant but nonspecific effects on Category Fluency and Benton Visual Retention tests; and (6) did not affect glycine and glutamate serum levels. These data indicate that in healthy subjects, DSR reduces subjective feelings of sadness and anxiety and has procognitive effects that are overall opposed to the known effects of NMDAR antagonists. The findings are relevant to translational research of NMDAR function and the development of NMDAR-glycine site treatments for specific psychiatric entities. ClinicalTrials.gov: Behavioral and Cognitive Effects of the N-methyl-D-aspartate Receptor (NMDAR) Co-agonist D-serine in Healthy Humans; http://www.clinicaltrials.gov/ct2/show/NCT02051426?term=NCT02051426&rank=1; NCT02051426.

Autoimmune-induced glutamatergic receptor dysfunctions: conceptual and psychiatric practice implications.

Glutamatergic neurotransmission is mediated via complex receptorial systems including N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) and metabotropic receptor subtypes and plays a critical role in the modulation of synaptic plasticity, mood, cognitive processes and motor behavior. Glutamatergic function deficits are hypothesized to contribute to the pathogenesis of neuropsychiatric disorders, including schizophrenia, mood and movement disorders. Accumulating data are rapidly leading to the characterization of specific types of autoimmune encephalitis in which the receptors and proteins critically involved in glutamatergic neurotransmission, e.g., NMDA, AMPA receptors, are antigen targets. Characteristic of these syndromes, antibodies alter the structure and/or function of the corresponding neuronal antigen resulting in clinical pictures that resemble pharmacological disease models. Presently the best characterized autoimmune glutamatergic disorder is anti-NMDA receptor encephalitis. This disorder manifests with intertwined psychiatric and neurological features, defines a new syndrome, reclassifies poorly defined clinical states and extends previous hypotheses, such as hypo-NMDA receptor function in schizophrenia. The characterization of autoimmune-induced glutamatergic receptor dysfunctions (AGRD) is likely to have a substantial conceptual impact upon our understanding of neuropsychiatric disorders including schizophrenia, affective and movement dysfunctions. Further definition of AGRD will provide additional guidelines for psychiatric diagnoses, identification of homogeneous patient subtypes within broad phenomenological classifications and will contribute to the development of personalized treatments. The body of knowledge already accumulated on anti-NMDA receptor encephalitis highlights the need for wide dissemination of these concepts among psychiatrists, and in suspected cases, for early recognition, prompt clinical and laboratory investigation and efficient interface between mental health and medical teams.

Serum cholinesterases are differentially regulated in normal and dystrophin-deficient mutant mice.

The cholinesterases, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) (pseudocholinesterase), are abundant in the nervous system and in other tissues. The role of AChE in terminating transmitter action in the peripheral and central nervous system is well understood. However, both knowledge of the function(s) of the cholinesterases in serum, and of their metabolic and endocrine regulation under normal and pathological conditions, is limited. This study investigates AChE and BChE in sera of dystrophin-deficient mdx mutant mice, an animal model for the human Duchenne muscular dystrophy (DMD) and in control healthy mice. The data show systematic and differential variations in the concentrations of both enzymes in the sera, and specific changes dictated by alteration of hormonal balance in both healthy and dystrophic mice. While AChE in mdx-sera is elevated, BChE is markedly diminished, resulting in an overall cholinesterase decrease compared to sera of healthy controls. The androgen testosterone (T) is a negative modulator of BChE, but not of AChE, in male mouse sera. T-removal elevated both BChE activity and the BChE/AChE ratio in mdx male sera to values resembling those in healthy control male mice. Mechanisms of regulation of the circulating cholinesterases and their impairment in the dystrophic mice are suggested, and clinical implications for diagnosis and treatment are considered.