title: Timing-dependent reduction in ethanol sedation and drinking preference by NMDA receptor co-agonist d-serine.
abstract: NMDA receptors become a major contributor to acute ethanol intoxication effects at high concentrations as ethanol binds to a unique site on the receptor and inhibits glutamatergic activity in multiple brain areas. Although a convincing body of literature exists on the ability of NMDA receptor antagonists to mimic and worsen cellular and behavioral ethanol effects, receptor agonists have been less well-studied. In addition to a primary agonist site for glutamate, the NMDA receptor contains a separate co-agonist site that responds to endogenous amino acids glycine and d-serine. d-serine is both selective for this co-agonist site and potent in boosting NMDA dependent activity even after systemic administration. In this study, we hypothesized that exogenous d-serine might ameliorate some acute ethanol behaviors by opposing NMDA receptor inhibition. We injected adult male C57 mice with a high concentration of d-serine at various time windows relative to ethanol administration and monitored sedation, motor coordination and voluntary ethanol drinking. d-serine (2.7 g/kg, ip) prolonged latency to a loss of righting reflex (LoRR) and shortened LoRR duration when given 15 min before ethanol (3 g/kg) but not when it was injected with or shortly after ethanol. Blood samples taken at sedative recovery and at fixed time intervals revealed no effect of d-serine on ethanol concentration but an ethanol-induced decrease in l-serine and glycine content was prevented by acute d-serine pre-administration. d-serine had no effect on ethanol-induced (2 g/kg) rotarod deficits in young adult animals but independently and interactively degraded motor performance in a subset of older mice. Finally, a week-long series of daily ip injections resulted in a 50% decrease in free choice ethanol preference for d-serine treated animals compared to saline-injected controls in a two-bottle choice experiment.
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Lockridge
authors.forename: Gabriel
authors.initials: G
authors.lastname: Romero
authors.forename: Justin
authors.initials: J
authors.lastname: Harrington
authors.forename: Brett
authors.initials: B
authors.lastname: Newland
authors.forename: Zi
authors.initials: Z
authors.lastname: Gong
authors.forename: Andrew
authors.initials: A
authors.lastname: Cameron
authors.forename: Li-Lian
authors.initials: LL
authors.lastname: Yuan
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects* / Q000503:physiopathology; D000435:Alcoholic Intoxication / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D016202:N-Methylaspartate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism; D012694:Serine / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D018698:Glutamic Acid; D012694:Serine; D016202:N-Methylaspartate; D005998:Glycine