title: Developmental GABAergic deficit enhances methamphetamine-induced apoptosis.
abstract: BACKGROUND
  Neuroanatomical evidence suggests that GABAergic deficits and progressive cortical atrophy occur with schizophrenia.
  
  
  OBJECTIVE
  To evaluate the hypothesis that neurodevelopmental deficits affect neurodegeneration occurring with schizophrenia, this study examined a novel animal model for schizophrenia-related neurodevelopmental GABAergic deficit in neurodegenerative progression.
  
  
  METHODS
  The prenatal N-methyl-D-aspartate (NMDA) receptor hypofunction model that induces neurodevelopmental GABAergic deficit in the medial prefrontal cortex (mPFC) was used to examine whether adult offspring of Sprague-Dawley rats exhibited disruption of prepulse inhibition (PPI), enhancement of methamphetamine (METH) (2.5 mg/kg)-induced glutamate release in the mPFC and the emergence of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive neurons in this brain region.
  
  
  RESULTS
  Offspring of dams exposed to NMDA receptor antagonist MK-801 on days 15-18 of pregnancy (MK-801 offspring) showed reduced density of parvalbumin-immunoreactive GABAergic interneurons in the mPFC, PPI disruption on postnatal days 63 (P63) and 35 (P35) and an enhanced METH (2.5 mg/kg)-induced glutamate release. Repeated administration of this psychostimulant increased the emergence of TUNEL-positive cells.
  
  
  CONCLUSIONS
  These findings suggest that prenatal blockade of NMDA receptors induces a neurodevelopmental GABAergic deficit. The decrease in the density of GABAergic neurons might be related to disruption of sensorimotor gating (PPI), enhanced METH-induced release of glutamate in the mPFC and a repeated METH injection-induced increase in apoptosis in this region of the brain in adult animals.
authors.affiliation: Kotoku-kai Aiko Hospital, Atsugi, Japan. spg35k69@opal.ocn.ne.jp
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Abekawa
authors.forename: Koki
authors.initials: K
authors.lastname: Ito
authors.forename: Yasuya
authors.initials: Y
authors.lastname: Nakato
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Koyama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000503:physiopathology*; D055139:Sensory Gating / Q000187:drug effects; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D008694:Methamphetamine; D005680:gamma-Aminobutyric Acid; D016291:Dizocilpine Maleate