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Poster #223 GENDER DIFFERENCES AND EFFECTS OF ACUTE AND CHRONIC OXYTOCIN ON SOCIAL INTERACTION IN MICE
Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
divided into two groups, high and low, according to their level of experience of filling out more than 10 prescriptions for LAI to patients with schizophrenia. The two groups did not differ significantly in terms of sociodemographic characteristics. However, it was shown that the highly experienced group recommended more and gave explanations in more detail about LAI, compared to the other group with less experience. Also, they showed more satisfaction with using LAI, while the less experienced group expressed greater negativity towards LAI. Discussion: Attitudes of Korean psychiatrists towards LAI were closely related to the frequency of LAI use. To enhance the use of LAI in Korea, more information based on scientific evidence should be provided to psychiatrists, and the positive experiences of colleagues should be shared with others.
Poster #222 DELAYED “EUREKA” OF ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR KNOCKOUT MICE IN A PROBABILISTIC REVERSAL LEARNING PARADIGM Jared W. Young, Mary E. Kamenski, Mark A. Geyer University of California San Diego, La Jolla, California, USA Background: Evidence that functional outcome in patients with schizophrenia correlates most strongly with cognitive performance has galvanized research to identify pro-cognitive treatments. The development of a procognitive drug has been unsuccessful so far however. Given the vast number of neurodevelopmental abnormalities that exist in patients with schizophrenia, it has been proposed that psychosocial intervention along with pro-cognitive drug treatment will be required to improve their cognitive capabilities. Therefore, developing treatments that improve rewardrelated learning – used in psychosocial intervention studies – may offer the best opportunity at maximizing cognitive improvement in these patients. Nicotine improves reward related learning across species in a variety of paradigms. Among other receptors, nicotine is an agonist at alpha 7 nAChRs. We have demonstrated that mice lacking this receptor exhibit delayed learning across various deterministic reward paradigms. Learning is commonly tested in humans using probabilistic reward paradigms however and it is unclear whether these mice exhibit altered learning in such a setting. We therefore assessed the simple and reversal learning rates of alpha 7 nAChR knockout (KO) mice and their wildtype (WT) littermates. We hypothesized that the KO mice would exhibit impaired initial learning in this task but that their reversal learning would be unimpaired. Methods: The reward-related learning of male alpha 7 nAChR WT (n=12) and KO (n=15) mice were assessed in a probabilistic reward paradigm. In 5-hole chambers, mice were presented with two stimuli illuminating apertures. A nose-poke in one of the apertures resulted in mice being rewarded (with strawberry milkshake) 80% of the time, and punished (lights on for 4 s) 20%. Conversely, a response in the other aperture resulted in a reward 20%, and punishment 80% of the time. The reward contingencies were then reversed when the mice responded 85% of the time in the aperture more often associated with reward for 2 consecutive days. The number of sessions required to attain criterion for simple and reversal learning was calculated and compared between genotypes using a 2-way ANOVA, with learning stage as a within subjects factor and gene as a between subjects factor. Planned comparison t-tests compared learning rates of WT and KO mice in each stage Results: Reversal learning took longer to acquire than simple learning (F(1,23)=15.5, p<0.005). When assessed by stage, alpha 7 nAChR KO mice required more sessions to attain criterion in the initial learning phase when compared with their WT littermates (p<0.05). The number of sessions required to attain the reversal stage was no different between the two groups (p>0.05). Discussion: We have demonstrated that alpha 7 nAChR KO mice exhibited delayed probabilistic learning. Reversal learning was unaffected in these mice however. Importantly, the delayed “eureka” of the KO mice is observed in a learning paradigm that is consistent with the methodology for assessing learning in humans i.e. probabilistic. These data support previously published evidence that the alpha 7 nAChR is involved in reward-related learning. Moreover, once these mice acquire the nuances of a rule-set, they can apply such nuances to other situations, such as the reversal learning described here. Future studies using nicotine and more selective alpha 7 nAChR agonists will determine whether activating this receptor can
S361
improve reward-related learning, with the possible development of such drugs as pharmacological augments to psychosocial therapy for patients with schizophrenia.
Poster #223 GENDER DIFFERENCES AND EFFECTS OF ACUTE AND CHRONIC OXYTOCIN ON SOCIAL INTERACTION IN MICE Xiaofan Zhang 1 , Qi Li 1 , Sylvia Lam 1 , Siew Chua 1 , Grainne McAlonan 2 Department of Psychiatry Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong; 2 Department of Forensic and Neurodevelopmental Sciences Institute of Psychiatry, King’s College, London, United Kingdom
1
Background: Understanding emotion from others is an essential ability for the healthy development of all mammals. Anomalies in emotion processing are associated with developmental disorders such as schizophrenia and autism. Oxytocin is a nine amino-acid peptide (nonapeptide) hormone. It is well-known for its role in lactation and parturition, but it also has a key role in social recognition. Oxytocin has been suggested as a potential therapy in neurodevelopmental disorders such as schizophrenia and autism spectrum, however direct experimental investigation of the action of oxytocin is still limited. The aim of the present study was to explore acute and chronic dose-related effects of oxytocin on social interaction activity in male and female mice. Methods: 8 week old adult C57BL/6N mice were obtained from the Laboratory Animal Unit at The University of Hong Kong. The experimental protocol was approved by the Committee on the Use of Live Animals for teaching and Research, University of Hong Kong (CULATR case NO: 2152-10). In the chronic administration group, a single injection of 10ug/kg, 100ug/kg, or 1000ug/kg oxytocin (Sigam-Aldrich) was given subcutaneously once a week for two weeks as part of a larger study on chronic effects of oxytocin. Social interaction test was conducted one week after the last oxytocin exposure. Mice received oxytocin injection 30min before test. In the acute administration group, another batch of mice was tested in the same way without previous exposure to oxytocin. Additional untreated mice received saline injection 30min before the social interaction test and were included as controls. The social interaction test conducted followed standard protocols in our lab. An experimental mouse paired with a “neutral” stimulus mouse from the same gender are tested together and scored as a single unit. The mice are put in opposite corners of the arena facing away from each other before the start of the 10-min social interaction test. Mice social interaction times were scored manually. Results: In the control group, the male mice had longer social interaction time with strangers than female mice (P<0.05). In the oxytocin acute administration group, the social interaction time was increased with the increasing oxytocin doses in the female mice (P<0.05). There was a significant linear relationship between social interaction time and oxytocin doses. However, the oxytocin dose-effect curve showed an inverted U shape in the male mice. Both 100ug/kg and 1000ug/kg oxytocin increased social interaction activity in the male mice, but the maximal effect was obtained at 100ug/kg of oxytocin administration. In the oxytocin chronic administration, previous oxytocin exposures increased social interaction time in the female mice for all doses of oxytocin (P<0.05). The oxytocin dose-effect curve for the male mice in the chronic administration group had a similar inverted U shape as the acute administration, with the peak effect at 100ug/kg oxytocin administration (P<0.05). Discussion: The social interaction measure in C57BL/6N mice is gender dependent. Male and female mice also have different responses to acute and chronic administration of oxytocin. Therefore, gender differences need to be carefully considered for further investigations into the utility of oxytocin.
divided into two groups, high and low, according to their level of experience of filling out more than 10 prescriptions for LAI to patients with schizophrenia. The two groups did not differ significantly in terms of sociodemographic characteristics. However, it was shown that the highly experienced group recommended more and gave explanations in more detail about LAI, compared to the other group with less experience. Also, they showed more satisfaction with using LAI, while the less experienced group expressed greater negativity towards LAI. Discussion: Attitudes of Korean psychiatrists towards LAI were closely related to the frequency of LAI use. To enhance the use of LAI in Korea, more information based on scientific evidence should be provided to psychiatrists, and the positive experiences of colleagues should be shared with others.
Poster #222 DELAYED “EUREKA” OF ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR KNOCKOUT MICE IN A PROBABILISTIC REVERSAL LEARNING PARADIGM Jared W. Young, Mary E. Kamenski, Mark A. Geyer University of California San Diego, La Jolla, California, USA Background: Evidence that functional outcome in patients with schizophrenia correlates most strongly with cognitive performance has galvanized research to identify pro-cognitive treatments. The development of a procognitive drug has been unsuccessful so far however. Given the vast number of neurodevelopmental abnormalities that exist in patients with schizophrenia, it has been proposed that psychosocial intervention along with pro-cognitive drug treatment will be required to improve their cognitive capabilities. Therefore, developing treatments that improve rewardrelated learning – used in psychosocial intervention studies – may offer the best opportunity at maximizing cognitive improvement in these patients. Nicotine improves reward related learning across species in a variety of paradigms. Among other receptors, nicotine is an agonist at alpha 7 nAChRs. We have demonstrated that mice lacking this receptor exhibit delayed learning across various deterministic reward paradigms. Learning is commonly tested in humans using probabilistic reward paradigms however and it is unclear whether these mice exhibit altered learning in such a setting. We therefore assessed the simple and reversal learning rates of alpha 7 nAChR knockout (KO) mice and their wildtype (WT) littermates. We hypothesized that the KO mice would exhibit impaired initial learning in this task but that their reversal learning would be unimpaired. Methods: The reward-related learning of male alpha 7 nAChR WT (n=12) and KO (n=15) mice were assessed in a probabilistic reward paradigm. In 5-hole chambers, mice were presented with two stimuli illuminating apertures. A nose-poke in one of the apertures resulted in mice being rewarded (with strawberry milkshake) 80% of the time, and punished (lights on for 4 s) 20%. Conversely, a response in the other aperture resulted in a reward 20%, and punishment 80% of the time. The reward contingencies were then reversed when the mice responded 85% of the time in the aperture more often associated with reward for 2 consecutive days. The number of sessions required to attain criterion for simple and reversal learning was calculated and compared between genotypes using a 2-way ANOVA, with learning stage as a within subjects factor and gene as a between subjects factor. Planned comparison t-tests compared learning rates of WT and KO mice in each stage Results: Reversal learning took longer to acquire than simple learning (F(1,23)=15.5, p<0.005). When assessed by stage, alpha 7 nAChR KO mice required more sessions to attain criterion in the initial learning phase when compared with their WT littermates (p<0.05). The number of sessions required to attain the reversal stage was no different between the two groups (p>0.05). Discussion: We have demonstrated that alpha 7 nAChR KO mice exhibited delayed probabilistic learning. Reversal learning was unaffected in these mice however. Importantly, the delayed “eureka” of the KO mice is observed in a learning paradigm that is consistent with the methodology for assessing learning in humans i.e. probabilistic. These data support previously published evidence that the alpha 7 nAChR is involved in reward-related learning. Moreover, once these mice acquire the nuances of a rule-set, they can apply such nuances to other situations, such as the reversal learning described here. Future studies using nicotine and more selective alpha 7 nAChR agonists will determine whether activating this receptor can
S361
improve reward-related learning, with the possible development of such drugs as pharmacological augments to psychosocial therapy for patients with schizophrenia.
Poster #223 GENDER DIFFERENCES AND EFFECTS OF ACUTE AND CHRONIC OXYTOCIN ON SOCIAL INTERACTION IN MICE Xiaofan Zhang 1 , Qi Li 1 , Sylvia Lam 1 , Siew Chua 1 , Grainne McAlonan 2 Department of Psychiatry Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong; 2 Department of Forensic and Neurodevelopmental Sciences Institute of Psychiatry, King’s College, London, United Kingdom
1
Background: Understanding emotion from others is an essential ability for the healthy development of all mammals. Anomalies in emotion processing are associated with developmental disorders such as schizophrenia and autism. Oxytocin is a nine amino-acid peptide (nonapeptide) hormone. It is well-known for its role in lactation and parturition, but it also has a key role in social recognition. Oxytocin has been suggested as a potential therapy in neurodevelopmental disorders such as schizophrenia and autism spectrum, however direct experimental investigation of the action of oxytocin is still limited. The aim of the present study was to explore acute and chronic dose-related effects of oxytocin on social interaction activity in male and female mice. Methods: 8 week old adult C57BL/6N mice were obtained from the Laboratory Animal Unit at The University of Hong Kong. The experimental protocol was approved by the Committee on the Use of Live Animals for teaching and Research, University of Hong Kong (CULATR case NO: 2152-10). In the chronic administration group, a single injection of 10ug/kg, 100ug/kg, or 1000ug/kg oxytocin (Sigam-Aldrich) was given subcutaneously once a week for two weeks as part of a larger study on chronic effects of oxytocin. Social interaction test was conducted one week after the last oxytocin exposure. Mice received oxytocin injection 30min before test. In the acute administration group, another batch of mice was tested in the same way without previous exposure to oxytocin. Additional untreated mice received saline injection 30min before the social interaction test and were included as controls. The social interaction test conducted followed standard protocols in our lab. An experimental mouse paired with a “neutral” stimulus mouse from the same gender are tested together and scored as a single unit. The mice are put in opposite corners of the arena facing away from each other before the start of the 10-min social interaction test. Mice social interaction times were scored manually. Results: In the control group, the male mice had longer social interaction time with strangers than female mice (P<0.05). In the oxytocin acute administration group, the social interaction time was increased with the increasing oxytocin doses in the female mice (P<0.05). There was a significant linear relationship between social interaction time and oxytocin doses. However, the oxytocin dose-effect curve showed an inverted U shape in the male mice. Both 100ug/kg and 1000ug/kg oxytocin increased social interaction activity in the male mice, but the maximal effect was obtained at 100ug/kg of oxytocin administration. In the oxytocin chronic administration, previous oxytocin exposures increased social interaction time in the female mice for all doses of oxytocin (P<0.05). The oxytocin dose-effect curve for the male mice in the chronic administration group had a similar inverted U shape as the acute administration, with the peak effect at 100ug/kg oxytocin administration (P<0.05). Discussion: The social interaction measure in C57BL/6N mice is gender dependent. Male and female mice also have different responses to acute and chronic administration of oxytocin. Therefore, gender differences need to be carefully considered for further investigations into the utility of oxytocin.