Differential effects of early-life NMDA receptor antagonism on aspartame-impaired insulin tolerance and behavior

Effect of developmental NMDAR antagonism with CGP 39551 on aspartame-induced hypothalamic and adrenal gene expression

“…A second finding from our study was that the behavior of ASP-fed mice with early-life NMDAR antagonism differed from control-diet mice receiving NMDAR antagonism under identical experimental conditions, suggesting a drug/diet interaction occurring early in life with long term consequences. Specifically, whereas control diet mice with NMDAR antagonism exhibited hyperlocomotor behavior consistent with previous reports [ 21 , 54 ], ASP-diet mice with NMDAR antagonism were hypolocomotive, more immobile, and showed less exploratory behavior than aspartame-diet mice without NMDAR modulation [ 53 ]. Markers of anxiety-based behavior were also differentially affected by diet and drug treatment.…”

“…Food and fluid intake in the male offspring were measured at 7 weeks of age as previously described [ 5 ]. Between weeks 14 and 18 of age, experimental offspring mice took part in behavioral testing, the results of which have been presented in a prior publication [ 53 ]. The behavioral testing commenced at 14 weeks of age and comprised of Open Field, Object recognition, Light-Dark transition, and the Morris Water Maze for spatial cognition.…”

“…Food and fluid intake in the offspring were not significantly affected by either diet or drug ( Table 1 ). Detailed analysis of the effects of chronic ASP exposure and NMDAR antagonism on the physiological and behavioral characteristics of adult mice were reported in a previous publication [ 53 ], which indicated that the effects of ASP may impact on components of the Hypothalamic Pituitary Adrenal (HPA) axis. Table 1 summarizes the effect of chronic ASP exposure and/or CGP 39551 on overnight fasting serum adrenocorticotropic hormone (ACTH), growth hormone (GH), corticosterone and epinephrine.…”

“…Our previous studies have shown that chronic ASP exposure commencing in utero may detrimentally affect adulthood glucose metabolism and aspects of cognition and behavior [ 5 ], and that this can be modulated by developmental NMDAR blockade with the anticonvulsant NMDAR antagonist CGP 39551 [ 53 ]. Because glucose homeostasis and anxiety-related behavior are coordinated in part by the HPA axis [ 6 , 74 ], and since augmented hypothalamic NMDAR activity has been shown to contribute to hyperactivation of the HPA axis [ 75 ], which can be modulated by NMDAR antagonism [ 76 ], we elected to examine changes in global gene expression in the hypothalamus and adrenal gland of these animals.…”

“…In view of the above, and because metabolic and behavioral phenotypes are influenced by environmental variables during perinatal development, we hypothesized that NMDARs may play a role in the ASP-induced perturbations in glucose homeostasis and behavior previously reported by us [ 5 ] and others [ 22 – 24 , 50 , 51 ]. Accordingly we found that early-life treatment with the NMDAR antagonist CGP 39551 [ 52 ] normalized the ASP-induced insulin intolerance seen in adult mice exposed to ASP from conception onwards, whilst not altering glucose homeostasis in control diet mice to any significant degree [ 53 ]. A second finding from our study was that the behavior of ASP-fed mice with early-life NMDAR antagonism differed from control-diet mice receiving NMDAR antagonism under identical experimental conditions, suggesting a drug/diet interaction occurring early in life with long term consequences.…”