title: Psychotomimetic effects of different doses of MK-801 and the underlying mechanisms in a selective memory impairment model.
abstract: Although N-methyl-d-aspartate receptor antagonists-induced hypoglutamate rodent models are the most well-established models for preclinical studies of schizophrenia-related deficits, they also evoke a wide spectrum of psychotomimetic side effects. It is significant to increase the specificity of hypoglutamate rodent models. In this study, the recognition memory was evaluated in rats by object recognition test (ORT), sensorimotor gating was evaluated by prepulse inhibition of the startle reflex (PPI), and locomotor activity was measured using open field test. High-performance liquid chromatography was used to measure neurotransmitters content in the medial prefrontal cortex (mPFC) and thalamus (THA). Total Akt and phospho-Akt protein was measured by Western blots. Results showed that 0.3mg/kg of MK-801 was most effective in inducing locomotion. 0.3mg/kg of MK-801 was most effective in decreasing PPI. 0.03mg/kg of MK-801 was most effective in decreasing object memory while not affecting exploration manners in the training session. 0.03mg/kg of MK-801 significantly increased HVA and Glu content in the mPFC. 0.1mg/kg of MK-801 significantly decreased GABA content in the THA. 0.03mg/kg of MK-801 significantly decreased Akt phosphorylation in the mPFC, which was related to the ORT index. In conclusion, a dose of 0.03mg/kg MK-801 can establish a "pure" memory impairment model without contaminations of sensorimotor gating and locomotor activity. MK-801-induced cognitive deficits is associated with increased DA metabolites and glutamate content in the mPFC and decreased GABA content in the THA as well as decrease in Akt phosphorylation in the mPFC.
authors.affiliation: Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, PR China; Institute of Mental Health, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Liu
authors.affiliation: Institute of Mental Health, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China; Wuxi Mental Health Center, Wuxi, Jiangsu 214151, PR China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, PR China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Hong
authors.affiliation: Institute of Mental Health, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Institute of Mental Health, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, PR China.
authors.forename: Jicai
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, PR China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Xu
authors.affiliation: Institute of Mental Health, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China.
authors.forename: Liwen
authors.initials: L
authors.lastname: Tan
authors.affiliation: Institute of Mental Health, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China. Electronic address: chenxghn@gmail.com.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Chen
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced*; D018377:Neurotransmitter Agents / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D065808:Prepulse Inhibition / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects; D055139:Sensory Gating / Q000187:drug effects; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism
chemical_list: D000596:Amino Acids; D018691:Excitatory Amino Acid Antagonists; D018377:Neurotransmitter Agents; D016291:Dizocilpine Maleate; D051058:Oncogene Protein v-akt
keywords: Akt phosphorylation; Animal model; Dose; Glu; MK-801; Psychotomimetic effects