The effects of an acute challenge with the NMDA receptor antagonists, MK-801, PEAQX, and ifenprodil, on social inhibition in adolescent and adult male rats

Abstract

Rationale NMDA antagonists consistently produce social inhibition in adult animals, although effects of these manipulations on social behavior of adolescents are relatively unknown. Objectives The aim of this study was to assess potential age differences in the socially inhibitory effects of the non-competitive NMDA antagonist, MK-801, as well as NR2 subunit selective effects, given the regional and developmental differences that exist for the NR2 subunit during ontogeny. Methods In separate experiments, adolescent and adult male Sprague–Dawley rats were treated acutely with MK-801 (0, 0.05, 0.1, 0.2 mg/kg, i.p.), the NR2A antagonist, PEAQX (2.5, 5, 10, 20 mg/kg, s.c.), or the NR2B antagonist, ifenprodil (1.5, 3, 6, 12 mg/kg, i.p.), 10 min prior to a social interaction test. Results Adolescents required higher doses of MK-801 (0.1 and 0.2 mg/kg) to induce social suppression, whereas adults demonstrated reductions in social activity after all doses. Likewise, adolescents required higher doses of ifenprodil (6 and 12 mg/kg) to produce social inhibitory effects relative to adults (all doses). In contrast, adults were less sensitive to PEAQX than adolescents, with adults showing social inhibition after 20 mg/kg whereas adolescents showed this effect following 10 and 20 mg/kg. Although locomotor activity was generally reduced at both ages by all drugs tested, ANCOVAs using locomotor activity as a covariate revealed similar patterns of social inhibitory effects. Conclusions Adolescents are less sensitive than adults to the disruption of social behavior by NMDA and NR2B-selective receptor antagonism, but not by an NR2A antagonist—age differences that may be related to different subunit expression patterns during development.

Pre-pubertal gonadectomy and the social consequences of acute ethanol in adolescent male and female rats

“…Gonadectomy also had no effect on the social preference/avoidance coefficient, likely because this measure was found to be insensitive to ethanol under the present test circumstances. The lack of ethanol-induced social avoidance in the current study may be attributed to the 2-day, repeated measures test procedure used—a procedural difference that appears to affect the social preference/avoidance coefficient differently than other social behaviors when compared to between subjects, single day test (Morales and Spear, 2013b; Morales et al, 2013). …”

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

“…In rodents, acute MK-801 treatment demonstrates face validity as a model of schizophrenia as its administration produces behavioral changes similar to those observed in the disease (Nestler and Hyman 2010). The acute administration of MK-801 results in locomotor hyperactivity (Howland et al 2012;Mahmood et al 2016), reduced sociability (Morales and Spear 2014), and performance deficits on touchscreen-based (Kumar et al 2015b;Kumar et al 2015a;Lins et al 2015;Lins and Howland 2016) and working memory (Homayoun et al 2004;Galizio et al 2012) tasks. One published study has explored the changes following acute MK-801 (0.05 mg/kg) administration in the TUNL task (Kumar et al 2015a).…”

“…Similarly, non-competitive NMDA receptor antagonism in rodents produces behaviors analogous to the positive, negative, and cognitive symptoms of schizophrenia (Moghaddam and Krystal 2012). For example, locomotor hyperactivity (Manahan-Vaughan et al 2008;Howland et al 2012;Zemanova et al 2013;Mahmood et al 2016), reduced sociability (Morales and Spear 2014), and performance deficits on visual learning and working memory tasks (Brown et al 2013;Zemanova et al 2013;Kumar et al 2015b;Kumar et al 2015a;Lins and Howland 2016) are observed following MK-801 administration, mirroring the positive, negative, and cognitive symptoms respectively. Beyond its direct effect on NMDA receptors, MK-801 administration indirectly mimics other pathophysiological features of the disease (Lewis et al 2005).…”

Ifenprodil infusion in agranular insular cortex alters social behavior and vocalizations in rats exposed to moderate levels of ethanol during prenatal development

“…Based on this conclusion, systemic ifenprodil treatment could be a useful tool for normalizing some of the social behavior deficits seen in rats following moderate PAE. Low dose (0.75 mg/kg) systemic ifenprodil treatment increases social activity (play, social investigation, and social contact) in naïve adolescent (P35) male rats [92], while higher doses (6–12 mg/kg) cause a decrease in social activity in adulthood (P68) [93]. The differences in the effect of ifenprodil at different doses and ages could be partially explained by the normal time course of NMDA subunit expression in rats and other mammals.…”