title: Acute D-serine treatment produces antidepressant-like effects in rodents.
abstract: Research suggests that dysfunctional glutamatergic signalling may contribute to depression, a debilitating mood disorder affecting millions of individuals worldwide. Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects in approximately 70% of patients. Glutamate evokes the release of D-serine from astrocytes and neurons, which then acts as a co-agonist and binds at the glycine site on the NR1 subunit of NMDA receptors. Several studies have implicated glial deficits as one of the underlying facets of the neurobiology of depression. The present study tested the hypothesis that D-serine modulates behaviours related to depression. The behavioural effects of a single, acute D-serine administration were examined in several rodent tests of antidepressant-like effects, including the forced swim test (FST), the female urine sniffing test (FUST) following serotonin depletion, and the learned helplessness (LH) paradigm. D-serine significantly reduced immobility in the FST without affecting general motor function. Both D-serine and ketamine significantly rescued sexual reward-seeking deficits caused by serotonin depletion in the FUST. Finally, D-serine reversed LH behaviour, as measured by escape latency, number of escapes, and percentage of mice developing LH. Mice lacking NR1 expression in forebrain excitatory neurons exhibited a depression-like phenotype in the same behavioural tests, and did not respond to D-serine treatment. These findings suggest that D-serine produces antidepressant-like effects and support the notion of complex glutamatergic dysfunction in depression. It is unclear whether D-serine has a convergent influence on downstream synaptic plasticity cascades that may yield a similar therapeutic profile to NMDA antagonists like ketamine.
authors: Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors: Oz
authors: O
authors: Malkesman
authors: Daniel R
authors: DR
authors: Austin
authors: Tyson
authors: T
authors: Tragon
authors: Gang
authors: G
authors: Wang
authors: Gregory
authors: G
authors: Rompala
authors: Anahita B
authors: AB
authors: Hamidi
authors: Zhenzhong
authors: Z
authors: Cui
authors: W Scott
authors: WS
authors: Young
authors: Kazu
authors: K
authors: Nakazawa
authors: Carlos A
authors: CA
authors: Zarate
authors: Husseini K
authors: HK
authors: Manji
authors: Guang
authors: G
authors: Chen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004924:Escape Reaction / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006380:Helplessness, Learned; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D046353:Immobility Response, Tonic / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D010655:Phenylenediamines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency / Q000235:genetics; D012694:Serine / Q000008:administration & dosage*; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; D010655:Phenylenediamines; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D007649:Ketamine; C015060:4-chloro-1,2-diaminobenzene; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2