PT688. PKCδ gene facilitates cognitive impairment induced by low doses of methamphetamine (MA) in mice

Objective: Our pilot study showed that 5-HT1A receptor mainly contributed to DM-induced serotonin syndrome in mice. Earlier reports suggested that 5-HT1A receptor can activate protein kinase C (PKC) in vitro. In the present study, we investigated whether the up-regulation of 5-HT1A receptor induced by DM requires specific induction of PKC isoform. Methods: Mice were pretreated with rottlerin, a pharmacological inhibitor of PKC-δ, 30 min before DM administration. Scores of serotonin syndrome (i.e. reciprocal forepaw treading, lateral head-weaving, hind-limb abduction, tremor, Straub tail and flat body posture) were assessed during 30 min after DM. In addition, rectal temperature was measured 30 min after DM. Serotonin levels and 5-HT1A receptor mRNA expression were examined in the hypothalamus 2 h after DM. Results: A high dose of DM resulted in a specific induction of PKC-δ out of PKC-α, PKC-β1, PKC-β2, PKC-ξ, PKC-δ in the hypothalamus of mice. Rottlerin significantly attenuated serotonergic behaviors induced by DM. In addition, rottlerin protected increases in 5-HT1A receptor mRNA expression and serotonin level induced by DM in wild-type mice. Consistently, genetic inhibition of PKC-δ protected serotonergic behaviors and increases in serotonin level, mRNA expression of 5-HT1A receptor induced by DM. Conclusion: Endogenous PKC-δ gene mediates serotonin syndrome induced by DM in mice [This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea]. PT688 PKCδ gene facilitates cognitive impairment induced by low doses of methamphetamine (MA) in mice The-Vinh Tran1, Hai-Quyen Tran1, Thu-Hien Thi Tu1, Eun-Joo Shin1, Choon-Gon Jang2, Kiyofumi Yamada3, Toshitaka Nabeshima4, HyoungChun Kim1 1Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200–701, Republic of Korea; 2Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea; 3Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine; 4Department of Regional Pharmaceutical Care and Sciences, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan Abstract Objective: We suggested that the cognitive impairment induced by repeated MA treatment in mice is a useful model of the cognitive deficits in schizophrenia and MA psychosis. We also demonstrated that minocycline, an antibiotic possessing antiinflammatory activity, improves cognitive impairment induced by MA. It is well-known that protein kinase C (PKC) mediates neuroinflammation. Therefore, we investigated a specific role of PKC in response to cognitive impairment induced by MA. Method: To achieve a better understanding whether PKC expression can be altered by repeated treatment with MA. We examined changes in the expression of PKCα, PKCβ1, PKCβ2, PKCζ, and PKCδ in the prefrontal cortex (PFC) after the final MA treatment. Because PKCδ expression is selectively increased after the last MA, we applied PKCδ knock-out (KO) mice in this study. We evaluated relationship between novel object recognition test (NORT), phosphorylation of extracellular signal-regulated kinase 1⁄2 (p-ERK1⁄2), and phosphorylation of PKCδ (p-PKCδ) in the PFC. Result: Repeated treatment with MA resulted in cognitive impairment as evaluated by NORT. This effect lasted, at least, for 28 days after the final MA treatment. Correlation study indicated that cognitive impairment parallels p-PKCδ expression. P-ERK1⁄2 expression increased in the mice exposed to the novel objects in the absence of MA, but it was decreased in the presence of MA. Genetic inhibition of PKCδ attenuated MA-induced decrease in p-ERK1⁄2 expression. Posttreatment with antipsychotic clozapine significantly protected cognitive impairment and alteration in p-ERK1⁄2 and p-PKCδ. Conclusion: PKCδ gene is an endogenous neuropsychostimulant for behavioral side effects and cognitive impairment induced by MA. Interestingly, clozapine positively modulated p-ERK1⁄2 and p-PKCδ induced by MA in the PFC of mice [This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea].Objective: We suggested that the cognitive impairment induced by repeated MA treatment in mice is a useful model of the cognitive deficits in schizophrenia and MA psychosis. We also demonstrated that minocycline, an antibiotic possessing antiinflammatory activity, improves cognitive impairment induced by MA. It is well-known that protein kinase C (PKC) mediates neuroinflammation. Therefore, we investigated a specific role of PKC in response to cognitive impairment induced by MA. Method: To achieve a better understanding whether PKC expression can be altered by repeated treatment with MA. We examined changes in the expression of PKCα, PKCβ1, PKCβ2, PKCζ, and PKCδ in the prefrontal cortex (PFC) after the final MA treatment. Because PKCδ expression is selectively increased after the last MA, we applied PKCδ knock-out (KO) mice in this study. We evaluated relationship between novel object recognition test (NORT), phosphorylation of extracellular signal-regulated kinase 1⁄2 (p-ERK1⁄2), and phosphorylation of PKCδ (p-PKCδ) in the PFC. Result: Repeated treatment with MA resulted in cognitive impairment as evaluated by NORT. This effect lasted, at least, for 28 days after the final MA treatment. Correlation study indicated that cognitive impairment parallels p-PKCδ expression. P-ERK1⁄2 expression increased in the mice exposed to the novel objects in the absence of MA, but it was decreased in the presence of MA. Genetic inhibition of PKCδ attenuated MA-induced decrease in p-ERK1⁄2 expression. Posttreatment with antipsychotic clozapine significantly protected cognitive impairment and alteration in p-ERK1⁄2 and p-PKCδ. Conclusion: PKCδ gene is an endogenous neuropsychostimulant for behavioral side effects and cognitive impairment induced by MA. Interestingly, clozapine positively modulated p-ERK1⁄2 and p-PKCδ induced by MA in the PFC of mice [This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea]. PT689 Utilization of Psychotic Drugs in Taiwan: An Overview of Outpatient Sector in 2010 Wei-Chen Lina,b,c, Wen-Han Changa, Ya-Mei Baia,b, Cheng-Ta Lia,b,c, Mu-Hong Chena,b, Tung-Ping Sua,b,c,d aDepartment of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; bDivision of Psychiatry, Faculty of Medicine, National YangMing University, Taipei, Taiwan; cInstitute of Brain Science, National Yang-Ming University, Taipei, Taiwan; dDepartment of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan Abstract Objective: Pharmacological treatment in mental disorder has been getting popular over decades in Taiwan. Our aims are 1) to survey the utilization of psychotropic drugs in outpatient psychiatric services, 2) to know the difference of antipsychotic drugs prescriptions among psychiatrists and non-psychiatrists. Methods: The sampling datasets from the Taiwan National Health Insurance Research Data base (NHIRD) served as data sources. We performed a survey comprising 886,219 participantsObjective: Pharmacological treatment in mental disorder has been getting popular over decades in Taiwan. Our aims are 1) to survey the utilization of psychotropic drugs in outpatient psychiatric services, 2) to know the difference of antipsychotic drugs prescriptions among psychiatrists and non-psychiatrists. Methods: The sampling datasets from the Taiwan National Health Insurance Research Data base (NHIRD) served as data sources. We performed a survey comprising 886,219 participants