Head movement: a novel serotonin-sensitive behavioral endpoint for tail suspension test analysis.

The tail suspension test (TST) as an antidepressant and depression-related behavior screen, has many advantages over the forced swim test (FST) in terms of procedural simplicity and consistent SSRI response. However, the FST has traditionally offered more specific neuromodulatory information by differentiating between serotonin (5-HT) and norepinephrine sensitive behavior categories. Head movement is a newly characterized behavior endpoint in the FST and TST with a selective 5-HT sensitivity. In this investigation, we show that the baseline and drug response profile of head movement previously found in the 129S6 strain of mice (Lockridge et al., 2010) is reproducible in the C57 strain. Head movement is inversely correlated to FST swimming and elevated in the TST by SSRI administration. The use of a weighted bin sample analysis method differentiates TST behaviors into fluoxetine-responsive head movement and desipramine-responsive struggling. The use of 5-HT subtype receptor agonists, after depleting endogenous 5-HT with pCPA, shows the head movement suppressing effect of 5-HT2A and 5-HT2C postsynaptic receptor activation. 5-HT1A and 5-HT1B agonists were ineffective. We propose that a head movement focused analysis can add sensitive and reliable 5-HT detection capability to mouse TST testing with minimal effort but significant reward.

Timing-dependent reduction in ethanol sedation and drinking preference by NMDA receptor co-agonist d-serine.

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.