title: Differential effects of early-life NMDA receptor antagonism on aspartame-impaired insulin tolerance and behavior.
abstract: We have previously showed that lifetime exposure to aspartame, commencing in utero via the mother's diet, may impair insulin tolerance and cause behavioral deficits in adulthood via mechanisms which are incompletely understood. The role of the CNS in regulating glucose homeostasis has been highlighted by recent delineation of the gut-brain axis, in which N-methyl-d-aspartic acid receptors (NMDARs) are important in maintaining glucose homeostasis, in addition to regulating certain aspects of behavior. Since the gut-brain axis can be modulated by fetal programming, we hypothesized that early-life NMDAR antagonism may affect aspartame-induced glucose deregulation in adulthood, and may alter the aspartame behavioral phenotype. Accordingly, C57Bl/6J mice were chronically exposed to aspartame commencing in utero, in the presence and absence of maternal administration of the competitive NMDAR antagonist CGP 39551, from conception until weaning. Drug/diet interactions in adulthood glucocentric and behavioral parameters were assessed. Aspartame exposure elevated blood glucose and impaired insulin-induced glucose disposal during an insulin tolerance test, which could be normalized by NMDAR antagonism. The same effects were not observed in control diet mice, suggesting an early-life drug/diet interaction. Behavioral analysis of adult offspring indicated that NMDAR antagonism of control diet mice caused hyperlocomotion and impaired spatial navigation. Conversely hypolocomotion, reduced exploratory activity and increased anxiety-related behavior were apparent in aspartame diet mice with early-life NMDAR antagonism.
  
  
  
  significant drug/diet interactions in glucocentric and behavioral parameters were identified in aspartame-exposed mice with early-life NMDAR antagonism. This suggests a possible involvement of early NMDAR interactions in aspartame-impaired glucose homeostasis and behavioral deficits.
authors.affiliation: Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia. Electronic address: kate@kfshrc.edu.sa.
authors.forename: Kate S
authors.initials: KS
authors.lastname: Collison
authors.affiliation: Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Angela
authors.initials: A
authors.lastname: Inglis
authors.affiliation: Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Sherin
authors.initials: S
authors.lastname: Shibin
authors.affiliation: Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Bernard
authors.initials: B
authors.lastname: Andres
authors.affiliation: Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Rosario
authors.initials: R
authors.lastname: Ubungen
authors.affiliation: Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thiam
authors.affiliation: Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Princess
authors.initials: P
authors.lastname: Mata
authors.affiliation: Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Futwan A
authors.initials: FA
authors.lastname: Al-Mohanna
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001218:Aspartame / Q000009:adverse effects*; D001522:Behavior, Animal / Q000187:drug effects*; D001786:Blood Glucose / Q000187:drug effects; D003623:Dark Adaptation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000503:physiopathology*; D021641:Recognition, Psychology / Q000187:drug effects; D018709:Statistics, Nonparametric; D013549:Sweetening Agents / Q000009:adverse effects*
chemical_list: D001786:Blood Glucose; D018691:Excitatory Amino Acid Antagonists; D013549:Sweetening Agents; C064540:CGP 39551; D015763:2-Amino-5-phosphonovalerate; D001218:Aspartame
keywords: Aspartame; Behavior; Gut-brain axis; Insulin tolerance; NMDA receptor antagonism