The effects of a single memantine treatment on behavioral alterations associated with binge alcohol exposure in neonatal rats

Abstract

Background The third trimester in human fetal development represents a critical time of brain maturation referred to as the “brain growth spurt”. This period occurs in rats postnatally, and exposure to ethanol during this time can increase the risk of impairments on a variety of cognitive and motor tasks. It has been proposed that one potential mechanism for the teratogenic effects of ethanol is NMDA receptor-mediated excitotoxicity during periods of ethanol withdrawal. In neonatal rats, antagonism of NMDA receptors during ethanol withdrawal, with drugs such as MK-801 and eliprodil, has been shown to mitigate some of the behavioral deficits induced by developmental ethanol exposure. The current study examined whether memantine, an NMDA receptor antagonist and a drug used clinically in Alzheimer’s patients, would attenuate impairments associated with binge ethanol exposure in neonatal rats. Methods On postnatal day 6, rats were exposed to 6 g/kg ethanol via intubation with controls receiving an isocaloric maltose dextrin solution. Twenty-one hours following the ethanol binge, rats received intraperitoneal injections of memantine at 0, 10, 15, or 20 mg/kg. Ethanol’s teratogenic effects were assessed using multiple behavioral tasks: open field activity, parallel bars and spatial discrimination reversal learning. Results Ethanol-treated rats were overactive in the open field and were impaired on both reversal learning and motor performance. Administration of 15 or 20 mg/kg memantine during withdrawal significantly attenuated ethanol’s adverse effects on motor coordination, but did not significantly alter activity levels or improve the spatial learning deficits associated with neonatal alcohol exposure. Conclusion These results indicate that a single memantine administration during ethanol withdrawal can mitigate motor impairments but not spatial learning impairments or overactivity observed following a binge ethanol exposure during development in the rat.

Administration of Memantine During Withdrawal Mitigates Overactivity and Spatial Learning Impairments Associated with Neonatal Alcohol Exposure in Rats

“…For example, no significant effect of ethanol was observed on the number of trials to the first successful criterion. Such results are consistent with previous studies (Idrus et al, 2011b). This measure of spatial learning is thought to be less sensitive to developmental alcohol exposure in comparison to the more robust measure of the number of errors committed (e.g.…”

“…On PD 40–43, subjects were tested on a serial spatial discrimination reversal task (Idrus et al, 2011b, Thomas et al, 1997). This task required the subject to escape from a Plexiglas T-maze (19-cm-wide passages, 71-cm-long stem and a 91-cm arm span with 10-cm-wide cul-de-sac at each end) that was partially submerged in a 121-cm diameter tank of water.…”

“…In addition, memantine is neuroprotective, blocking ethanol withdrawal neurotoxicity in fetal hippocampal cultures (Stepanyan et al, 2008). We have already demonstrated the mitigation of long-lasting alcohol-induced motor coordination deficits, although hippocampal-based effects were not observed when 10, 15, or 20 mg/kg single memantine doses were administered 24 hours after an ethanol binge (Idrus et al, 2011b). This may be due, in part, to memantine concentrations peaking 20–30 minutes after injection and its relatively short half life (4–12 hours) (Beconi et al, 2011, Parsons et al, 2007, Wesemann et al, 1982).…”

An animal model of fetal alcohol spectrum disorder: Trace conditioning as a window to inform memory deficits and intervention tactics

“…Cognitive enhancers (cholinesterase inhibitors, memantine; Disterhoft & Oh, 2003; Idrus et al, 2011) can also improve performance on hippocampal tasks. A preliminary study described above (Figure 4) suggests that the cholinesterase inhibitor physiostimine reduced the ethanol mediated impairment in trace conditioning in a dose dependent manner.…”

“Killing Two Birds with One Stone”: Alcohol Use Reduction Interventions with Potential Efficacy at Enhancing Self-control

“…Further, memantine improved performance among gamblers on the intradimensional/extradimensional set-shifting task, a measure of cognitive flexibility (i.e., avoidance of perseveration) [88]. In contrast to these human findings, basic science findings with memantine have been largely negative in terms of benefit to impulsivity [53] and other self-control deficits (e.g., overactivity; [89]),…”