title: Importance of inter-hemispheric prefrontal connection in the effects of non-competitive NMDA receptor antagonists.
abstract: Previous studies have shown that systemic, but not unilateral intra-prefrontal cortex administration of non-competitive NMDA antagonists, increased prefrontal activity, the cortical efflux of serotonin, and induced stereotypies. In this work we used in-vivo microdialysis and immunohistochemistry to test the hypothesis as to whether MK-801 and ketamine need to act on both prefrontal cortices to reproduce these neurochemical and behavioural changes. Dialysis probes were implanted in the medial prefrontal cortex, and extracellular serotonin as well as behavioural stereotypies was measured after systemic administration of MK-801 and ketamine (1 mg/kg and 25 mg/kg, respectively), and unilateral and bilateral perfusion of both drugs (300 μm and 3 mm, respectively). Additionally, the prefrontal (glutamatergic) level of activity was measured using c-Fos immunohistochemistry. Systemic and bilateral (but not unilateral) prefrontal administration of MK-801 and ketamine increased serotonin efflux whereas only systemic administration of both drugs produced hyperlocomotion and stereotypies. The unilateral perfusion of 1 μm tetrodotoxin in the medial prefrontal cortex reduced increases of serotonin in both hemispheres, the expression of c-Fos in the contralateral side, and stereotypy scores after systemic NMDA antagonists. Our results support the hypothesis that a bilateral impairment of cortical inhibition in the medial prefrontal cortex is needed for non-competitive NMDA antagonists to induce the state of pyramidal cell hyperactivity and concurrent efflux of serotonin. Furthermore, hyperlocomotion and stereotypies produced by MK-801 and ketamine do not appear to result from changes in the activity of prefrontal cortex although this structure exerts some control over these behaviours.
authors: Department of Neurochemistry and Neuropharmacology, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, IDIBAPS, Barcelona, Spain.
authors: Xavier
authors: X
authors: López-Gil
authors: Laura
authors: L
authors: Jiménez-Sánchez
authors: Tamara
authors: T
authors: Romón
authors: Leticia
authors: L
authors: Campa
authors: Francesc
authors: F
authors: Artigas
authors: Albert
authors: A
authors: Adell
mesh_terms: D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004333:Drug Administration Routes; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007839:Functional Laterality / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009434:Neural Pathways / Q000187:drug effects* / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: D000779:Anesthetics, Local; D018691:Excitatory Amino Acid Antagonists; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; C493466:Slc17a7 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; D012701:Serotonin; D013779:Tetrodotoxin; D007649:Ketamine; D016291:Dizocilpine Maleate