PM363. The effect of Ketamine: Gunn rat as a Schizophrenia animal model

Objective: Clinical studies have shown that microduplications at 7q36.3, containing VIPR2, confer significant risk for schizophrenia. VIPR2 gene encodes the VPAC2 receptor for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Lymphocytes from patients with these mutations exhibited higher VIPR2 gene expression and VIP responsiveness, but mechanisms by which overactive VPAC2 signaling may lead to these psychiatric disorders are unknown. Here we aimed to determine if the VIPR2-linkage to mental health disorders might be due to overactive VPAC2 receptor signaling during postnatal brain development by daily administration of the highly-selective VPAC2 receptor agonist Ro 25–1553 from postnatal day 1 (P1) to P14 in mice. Results: Western blot analyses on P21 revealed significant reductions of synaptophysin and PSD-95 in the prefrontal cortex, but not in the hippocampus, in Ro 25-1553-treated mice. Furthermore, Golgi staining in adult brain revealed alterations in dendritic morphology of prefrontal cortical neurons in Ro 25-1553-treated mice. The same postnatally-restricted treatment resulted in a disruption in prepulse inhibition of the acoustic startle and cognitive impairment in the novel object recognition task in adult mice. No effects were observed in locomotor activity, sociability in the three-chamber social interaction test, or fear conditioning or extinction. In addition, Ro 25–1553 and VIP, but not PACAP, caused reductions in total numbers and length of neuronal dendrites and length of axon in mouse primary cultured cortical neurons. Conclusions: These results suggest that overactivation of the VPAC2 receptor in the postnatal mouse leads to a reduction in synaptic proteins and alterations in dendritic morphology in the prefrontal cortex and cognitive impairments. These findings imply that the VIPR2-linkage to mental health disorders may be due in part to overactive VPAC2 receptor signaling during a critical time of neuronal maturation. PM361 The hallucinogen D-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT1A, D2 and TAAR1 receptors Danilo De Gregorioa,b, Luca Posaa, Rafael Ochoa-Sancheza, Ryan McLaughlina, Sabatino Maioneb, Stefano Comaia and Gabriella Gobbia. a Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University and McGill University Health Center, Montreal, QC, Canada b Department of Experimental Medicine, Division of Pharmacology, Second University of Naples, Naples, Italy Abstract D-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT1 and 5-HT2 receptors. Little is known about its potential interactions with the dopamine (DA) neurons of the ventral tegmental area (VTA). Using in-vivo electrophysiology in male adult rats, we evaluated the effects of cumulative doses of LSD on VTA DA neuronal activity, we compared these effects to those produced on 5-HT neurons in the dorsal raphe nucleus (DRN), and we attempted to identify the mechanism of action mediating the effects of LSD on VTA DA neurons. We confirmed that low doses of LSD (5–20 μg/kg, i.v.) induce a significant decrease of DRN 5-HT firing activity, but at these doses, it did not alter VTA DA neuronal activity. On the contrary, higher doses of LSD (30–120 μg/kg, i.v.) dose-dependently decreased VTA DA firing activity. The depletion of 5-HT synthesis with p-chlorophenylalanine did not modulate the effects of LSD on DA firing activity. The inhibitory effects of LSD on VTA DA firing activity were prevented by the D2 receptor antagonist haloperidol (50 μg/kg, i.v.) and by the 5-HT1A receptor antagonist WAY-100,635 (500 μg/kg, i.v.). Notably, pretreatment with the novel synthetized trace amine-associate receptor 1 (TAAR1) antagonist EPPTB (5 mg/kg, i.v.) blocked the inhibitory effect of LSD on VTA DA neurons. These results suggest that LSD at high doses strongly affects DA mesolimbic neuronal activity in a 5-HT independent manner and with a pleiotropic mechanism of action involving 5-HT1A, D2 and TAAR1 receptors.D-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT1 and 5-HT2 receptors. Little is known about its potential interactions with the dopamine (DA) neurons of the ventral tegmental area (VTA). Using in-vivo electrophysiology in male adult rats, we evaluated the effects of cumulative doses of LSD on VTA DA neuronal activity, we compared these effects to those produced on 5-HT neurons in the dorsal raphe nucleus (DRN), and we attempted to identify the mechanism of action mediating the effects of LSD on VTA DA neurons. We confirmed that low doses of LSD (5–20 μg/kg, i.v.) induce a significant decrease of DRN 5-HT firing activity, but at these doses, it did not alter VTA DA neuronal activity. On the contrary, higher doses of LSD (30–120 μg/kg, i.v.) dose-dependently decreased VTA DA firing activity. The depletion of 5-HT synthesis with p-chlorophenylalanine did not modulate the effects of LSD on DA firing activity. The inhibitory effects of LSD on VTA DA firing activity were prevented by the D2 receptor antagonist haloperidol (50 μg/kg, i.v.) and by the 5-HT1A receptor antagonist WAY-100,635 (500 μg/kg, i.v.). Notably, pretreatment with the novel synthetized trace amine-associate receptor 1 (TAAR1) antagonist EPPTB (5 mg/kg, i.v.) blocked the inhibitory effect of LSD on VTA DA neurons. These results suggest that LSD at high doses strongly affects DA mesolimbic neuronal activity in a 5-HT independent manner and with a pleiotropic mechanism of action involving 5-HT1A, D2 and TAAR1 receptors. PM362 Social Function of Dopamine D1 Receptor in Nonhuman Primates Yukiori Goto1, Yoshie Yamaguchi1, Young-A Lee2,& Akemi Kato1 1Kyoto University Primate Research Institute, Inuyama, Aichi, 484–8506, Japan 2Catholic University of Daegu, Department of Food Science and Nutrition, Gyeongsan, 712-702, South Korea Abstract Objective: Humans and many animals including non-human primates organize and live in social groups. Although dopamine (DA) has been suggested to play important roles in mediating social behavior, it has remained less clear whether and how DA in each subject consisting of a social group is involved in organization of such a group as social hierarchy and affiliative relationships. In this study, we examined the impacts DA D1 receptor signaling on social relationships of socially housing non-human primates. Methods: The effects of D1 antagonist administration was examined using a group of Japanese macaques consisting of 4 males and 2 females, 3 years old. Chronic administration of D1 receptor antagonist, SCH23390 (~0.1 mg/kg/day) by subcutaneous implantation of an osmotic pump was given to the macaque at second rank in the group, which caused persist decrease of goal-directed actions and increased non-directional agonistic displays in the drug administered subject throughout the behavioral observation period for 1 month. Results: Although social dominance of the drug administered subject was not altered by drug administration, social dominance and affiliative relationships of other subjects in the groups, especially at higher social class, were altered, consequently resulting in stronger social order competitions among higher social class subjects including the drug administered one. However, chronic stress level of subjects, which were assessed by measuring the amount of hair glucocorticoids, were not altered in the drug administered subject as well as others, suggesting little negative consequence of re-organization of social relationships in the group. Conclusions: These results suggest that low D1 receptor signaling, which has been shown to cause detrimental effects on cognitive and affective function, may contradictorily not cause apparent disadvantages in animals such as non-human primates living in ecologically more natural socially groups. This study was supported by Sumitomo Foundation, Institute of Seizon & Life Sciences, and JSPS (26640044, 15J01210).Objective: Humans and many animals including non-human primates organize and live in social groups. Although dopamine (DA) has been suggested to play important roles in mediating social behavior, it has remained less clear whether and how DA in each subject consisting of a social group is involved in organization of such a group as social hierarchy and affiliative relationships. In this study, we examined the impacts DA D1 receptor signaling on social relationships of socially housing non-human primates. Methods: The effects of D1 antagonist administration was examined using a group of Japanese macaques consisting of 4 males and 2 females, 3 years old. Chronic administration of D1 receptor antagonist, SCH23390 (~0.1 mg/kg/day) by subcutaneous implantation of an osmotic pump was given to the macaque at second rank in the group, which caused persist decrease of goal-directed actions and increased non-directional agonistic displays in the drug administered subject throughout the behavioral observation period for 1 month. Results: Although social dominance of the drug administered subject was not altered by drug administration, social dominance and affiliative relationships of other subjects in the groups, especially at higher social class, were altered, consequently resulting in stronger social order competitions among higher social class subjects including the drug administered one. However, chronic stress level of subjects, which were assessed by measuring the amount of hair glucocorticoids, were not altered in the drug administered subject as well as others, suggesting little negative consequence of re-organization of social relationships in the group. Conclusions: These results suggest that low D1 receptor signaling, which has been shown to cause detrimental effects on cognitive and affective function, may contradictorily not cause apparent disadvantages in animals such as non-human primates living in ecologically more natural socially groups. This study was supported by Sumitomo Foundation, Institute of Seizon & Life Sciences, and JSPS (26640044, 15J01210). PM363 The effect of Ketamine: Gunn rat as a Schizophrenia animal model Maiko Hayashida, Tomoko Araki, Sadayuki Hashioka, Jun Horiguchi, Kiminori Kawano, Syoko Miura, Tsuyoshi Miyaoka, Michiaru Nagahama, Keiko Tsuchie, Rei Wake Shimane University, Japan