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P.1.g.015 Effects of atypical antipsychotics aripiprazole and olanzapine on active avoidance test in rats with tryptamine-induced behavior
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P.1.g. Basic and clinical neuroscience − Neuropharmacology
Conclusions: Patients with a period off trial medication (prior placebo treated patients) showed substantial efficacy in the extension study and patients continuously exposed to MPH-LA maintained efficacy over duration of up to 12 months. MPH-LA was well tolerated with no unexpected adverse events. References [1] Huss M, Ginsberg Y, Tvedten T, et al., 2014. Methylphenidate hydrochloride modified-release in adults with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial. Adv Ther 31, 44−65.
P.1.g.014 Added benefits of long-term treatment of methylphenidate modified-release long-acting formulation in adults with ADHD M. Huss1 ° , Y. Ginsberg2 , T. Arngrim3 , A. Philipsen4 , P. Gandhi5 , C.W. Chen6 , V. Kumar6 1 University Medicine, Department of Child and Adolescent Psychiatry, Mainz, Germany; 2 Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden; 3 Private Clinic, Aarhus, Denmark; 4 University Medical Centre, Freiburg, Germany; 5 Novartis Healthcare Pvt. Ltd, Hyderabad, India; 6 Novartis Pharmaceuticals Corporation, East Hanover NJ, USA Purpose: Response to Methylphenidate modified release longacting formulation (MPH-LA) in the treatment of adult ADHD is variable and the predictors to nonresponse are unclear. Previously, a 40-week, randomized, double-blind placebo controlled core study comprising 3 phases (9-week dose confirmation phase, 5-week open-label dose optimization phase and 6-month maintenance of effectphase) reported that MPH-LA (40−80 mg/day) in adults, controlled ADHD symptoms as well as reduced functional impairment, with a good tolerability profile [1]. There was a population of patients who did not respond to MPH-LA during the maintenance of effect phase of the core study and had to leave the study. These patients (non-responders) were then allowed to join the 26-week flexible dose open label extension study to the core study. Here, we report long-term efficacy from the extension phase in these responders and non-responders identified in the maintenance of effectphase of the core study. Methods: Non-responders (treatment failures in maintenance of effect phase of the core study) were defined as patients with 30% worsening from maintenance of effect phasebaseline and <30% remaining improvement from dose confirmation phase baseline score on the DSM-IV ADHD rating scale (RS). All patients (responders and non-responders of maintenanceof effectphase) entering extension phase were initiated treatment with MPH-LA (20 mg/day) and up-titrated in increments of 20 mg/week to reach the individual patient’s optimal dose of 40, 60 or 80 mg. The investigator had the flexibility to readjust the doses as necessary within the dose range of 40−80 mg/day. Efficacy of MPH-LA in responders and non-responders was determined by the mean change in DSM-IV ADHD RS and SDS total scores from extensionphase baselineto the end of extension study. Further efficacy analyses were done on these responders and nonresponders based on treatment received (MPH-LA/placebo) in the maintenance of effect phase. From the maintenance phase, 46 patients treated with MPH-LA and 45 patients given placebo met the criteria for non-responders; 132 patients treated with MPH-LA and 24 given placebo were responders.
Results: The mean improvement in total score of DSM-IV ADHD RS at the end of extension study from the extension baseline was 18.2 and 0.9 for the maintenance of effect phase nonresponders (N = 91) and responders (N = 156), respectively. Similarly, mean improvement in SDS total score for non-responders and responders was 9.7 and 1.8, respectively. Non-responders showed symptomatic and functional improvement at the end of extension phase, irrespective of the treatment received in maintenance of effect phase (MPH-LA/placebo) as showed by the mean change in DSM-IV ADHD RS and SDS total score (Table). Overall MPH-LA was well tolerated. Conclusions: Responders to MPH-LA in the maintenance of effect phase continued to maintain efficacy in the extension phase. Non-responders to both MPH-LA and placebo in the maintenancephase showed marked symptomatic improvement. Re-titration and re-optimization of the dose for a longer duration in the extension study could possibly explain this improvement. Table: Mean improvement in DSM-IV ADHD RS and SDS total scores from extension baseline to end of extension phase Treatment received in maintenance of effect phase MPH-LA
DSM-IV ADHD RS SDS
Placebo
Non-responders (N = 46)
Responders (N = 132)
Non-responders (N = 45)
Responders (N = 24)
16.6 9.2
0.8 1.7
19.8 10.2
1.7 2.2
References [1] Huss M, Ginsberg Y, Tvedten T, et al., 2014. Methylphenidate hydrochloride modified-release in adults with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial. Adv Ther 31, 44−65.
P.1.g.015 Effects of atypical antipsychotics aripiprazole and olanzapine on active avoidance test in rats with tryptamine-induced behavior D. Getova1 ° , M. Topolov2 , K. Dzenis3 1 Medical University, Department of Pharmacology and Clinical Pharmacology, Plovdiv, Bulgaria; 2 Medical University, Department of Pharmacology and Toxicology, Plovdiv, Bulgaria; 3 Medical University, Department of Pharmacology, Riga, Latvia Purpose: Tryptamine induces neurodegeneration as axonopathy manifested by vesicularization of inner and outer mitochondrial membranes, axonal and cell membranes. Tyiptamine produced a decreased density of somatic mitochondria in mouse hippocampus causing axonal swellings and mitochondrialdamage mimicking neurodegenerative diseases [1]. Aripiprazole is a new antipsychotic drug with unique mechanism of action, which is an alternative to current antipsychotic drugs that adversely affect cognitive processes [2]. Atypical antipsychotic olanzapine acts as dopamine, serotonin and muscarinic antagonist and these transmitters could account for memory impairment in working memory tasks [3]. Our aim was to assess the impact of aripiprazole and olanzapine on behavioral functions of rats with tryptamine-induced behavior after multiple dosing. Methods: Male Wistar rats (n = 8), divided in 4 groups were treated intraperitoneally (i.p.) with: 1st saline (controls) 0.1 ml/100 g; 2nd group with tryptamine 5 mg/kg i.p.; 3rd group with tryptamine 5 mg/kg and aripiprazole 1 mg/kg; 4th group
P.1.g. Basic and clinical neuroscience − Neuropharmacology with tryptamine 5 mg/kg and olanzapine 1 mg/kg i.p. For active avoidance test rats were trained in an automatic reflex conditioner (shuttle box) with 5 days learning session and on the 12th day a memory retention test. The following parameters were observed: number of avoidances, number of escapes from foot shock and number of inter-trial crossings. The statistic evaluation was done by ANOVA for repeated measurments. Results: In active avoidance test the control rats significantly increased the number of avoidances on learning and memory retention, compared to the 1st day. Rats with tryptamine alone showed similar tendency, but less number of avoidances, compared to the same day controls. Rats with tryptamine and aripiprazol decreased the number of avoidances on learning session and on memory retention test, compared to the tryptamine group and control group. Rats with olanzapine and tryptamine decreased the number of avoidances during the learning session and on memory retention test, compared to the tryptamine and control group. Controls, tryptamine-treated group and both groups with respective neuroleptics and tryptamine showed the tendency to decrease the number of escapes during learning and memory tests and only group with olanzapine and tryptamine significantly decreased it during both learning and memory retention sessions. Conclusion: The study reveals that tryptamine, as a drug easily crossing brain blood barrier, induced slight deteriorating changes in the ability of rats to lean and memorize the task. Many research data has suggested that cognitive disorders are persistent trait of mental illness such as schizophrenia. Antipsychotic drugs aripiprazol and olanzapine applied together with tryptamine showed additive effect of impaired learning and memory in active avoidance test compared to that found with tryptamine group. The observed effects are probably due to the fact, that tryptamine is implicated as a causative agent in neurodegeneration, resembling that defining a number of human diseases, including schizophrenia. References [1] Paley EL, Perry G, Sokolova O. 2013 Tryptamine induces axonopathy and mitochondrial mimicking neurodegenerative disease via triptophanyl-tRNA deficiency. Curr Alzheimer Res, 10: 987–1004. [2] Burda, K., Czubak, A., Kus, K., et al, 2011 Influence of aripiprazole on the antidepressant, anxiolytic and cognitive functions of rats. Pharmacological reports 63, 898–907. [3] Ortega-Alvaro, A., Gibert-Rahola, J., Mico, J., 2006 Influence of chronic treatment with olanzapine, clozapine and scopolamine on performance of a learned 8-arm radial maze task in rats. Progress in Neuro-Psychopharmacology & Biological Psychiatry 30, 104–111.
P.1.g.016 Basolateral amygdala 5-HT1A receptors mediate stress-induced state-dependent learning in rats A. Rezayof1 ° , M. Sardari1 1 University of Tehran College of Science School of Biology, Animal Biology, Tehran, Iran Evidence suggests that exposure to stress, which is associated with increased levels of stress hormones, affects learning and memory processes [1]. The basolateral amygdala (BLA) is one of the most well understood brain regions that has critical roles in emotional behaviors. It has been shown that the facilitation of serotonin neurotransmission in the BLA may lead to adaptation to stress [2]. The 5-HT1A receptor, a G protein-coupled receptor (GPCR) that is coupled to Gi/Go, may be implicated in stress,
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learning and memory. On the other hand, it is well known that if the animal learns new information under the influence of emotional and physiological states, memory retrieval will be improved in the same conditions as were present during the acquisition of the information [3]. Considering the above-mentioned points and findings, the present study was designed with the following three aims: (1) to investigate the effect of acute stress on memory consolidation and retrieval of passive avoidance learning; (2) to examine whether stress can induce state-dependent learning; (3) to evaluate the possible role of the BLA 5-HT1A receptors in stress-induced state-dependent learning. Adult male Wistar rats weighing 220–250 g at the time of surgery were used in this study. The animals were anesthetized with an intraperitoneal injection of ketamine-xylazine mixture, placed in a stereotaxic apparatus and implanted bilaterally with two guide cannulas into the BLAs. The cannula placements were verified using the rat brain atlas of Paxinos and Watson. The animals were allowed to recover 1-week before experimental procedures. The memory retrieval was measured in a step-through type of passive avoidance apparatus. In order to induce the acute stress, the animals placed on an elevated platform for 10, 20 and 30 min. The statistical analyses were performed using one- and two-way analysis of variance (ANOVA). Our results showed that post-training exposure to 30 min stress, but not 10 or 20 min, induced the memory consolidation impairment. Moreover, pre-test exposure to 20 or 30 min stress, but not 10 min, decreased step-through latency, indicating the memory retrieval impairment. The memory impairment induced by post-training exposure to stress was restored in the animals which received pre-test exposure to 30 min stress, suggesting stress-induced state-dependent learning. On the other hand, pretest intra-BLA microinjection of different doses of a selective antagonist of 5-HT1A receptors, (S)-WAY100135 (0.5−2 mg/rat) inhibited the stress-induced state-dependent learning. It should be considered that, pre-test intra-BLA injection of same doses of (S)-WAY-100135 without stress had no effect on memory retrieval. These results provide evidence that post-training exposure to acute stress impairs memory consolidation and the impairment of memory retrieval can also be produced by pre-test exposure to stress in a time-dependent manner. Moreover, acute stress induces state-dependent learning. The serotonergic system of the BLA via 5-HT1A receptors may also be involved in stress-induced statedependent learning. References [1] Sardari, M., Rezayof, A., Khodagholi, F., Zarrindast, M.R., 2014. Basolateral amygdala GABA-A receptors mediate stress-induced memory retrieval impairment in rats. Int J Neuropsychopharmacol. 17, 603–612. [2] Christianson, J.P., Ragole, T., Amat, J., Greenwood, B.N., et al., 2010. 5-hydroxytryptamine 2C receptors in the basolateral amygdala are involved in the expression of anxiety after uncontrollable traumatic stress. Biol Psychiatry 67, 339–345. [3] Alijanpour, S., Rezayof, A., 2013. Involvement of dorsal hippocampal and medial septal nicotinic receptors in cross state-dependent memory between WIN55, 212−2 and nicotine or ethanol in mice. Neuroscience 245, 61−73.
P.1.g. Basic and clinical neuroscience − Neuropharmacology
Conclusions: Patients with a period off trial medication (prior placebo treated patients) showed substantial efficacy in the extension study and patients continuously exposed to MPH-LA maintained efficacy over duration of up to 12 months. MPH-LA was well tolerated with no unexpected adverse events. References [1] Huss M, Ginsberg Y, Tvedten T, et al., 2014. Methylphenidate hydrochloride modified-release in adults with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial. Adv Ther 31, 44−65.
P.1.g.014 Added benefits of long-term treatment of methylphenidate modified-release long-acting formulation in adults with ADHD M. Huss1 ° , Y. Ginsberg2 , T. Arngrim3 , A. Philipsen4 , P. Gandhi5 , C.W. Chen6 , V. Kumar6 1 University Medicine, Department of Child and Adolescent Psychiatry, Mainz, Germany; 2 Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden; 3 Private Clinic, Aarhus, Denmark; 4 University Medical Centre, Freiburg, Germany; 5 Novartis Healthcare Pvt. Ltd, Hyderabad, India; 6 Novartis Pharmaceuticals Corporation, East Hanover NJ, USA Purpose: Response to Methylphenidate modified release longacting formulation (MPH-LA) in the treatment of adult ADHD is variable and the predictors to nonresponse are unclear. Previously, a 40-week, randomized, double-blind placebo controlled core study comprising 3 phases (9-week dose confirmation phase, 5-week open-label dose optimization phase and 6-month maintenance of effectphase) reported that MPH-LA (40−80 mg/day) in adults, controlled ADHD symptoms as well as reduced functional impairment, with a good tolerability profile [1]. There was a population of patients who did not respond to MPH-LA during the maintenance of effect phase of the core study and had to leave the study. These patients (non-responders) were then allowed to join the 26-week flexible dose open label extension study to the core study. Here, we report long-term efficacy from the extension phase in these responders and non-responders identified in the maintenance of effectphase of the core study. Methods: Non-responders (treatment failures in maintenance of effect phase of the core study) were defined as patients with 30% worsening from maintenance of effect phasebaseline and <30% remaining improvement from dose confirmation phase baseline score on the DSM-IV ADHD rating scale (RS). All patients (responders and non-responders of maintenanceof effectphase) entering extension phase were initiated treatment with MPH-LA (20 mg/day) and up-titrated in increments of 20 mg/week to reach the individual patient’s optimal dose of 40, 60 or 80 mg. The investigator had the flexibility to readjust the doses as necessary within the dose range of 40−80 mg/day. Efficacy of MPH-LA in responders and non-responders was determined by the mean change in DSM-IV ADHD RS and SDS total scores from extensionphase baselineto the end of extension study. Further efficacy analyses were done on these responders and nonresponders based on treatment received (MPH-LA/placebo) in the maintenance of effect phase. From the maintenance phase, 46 patients treated with MPH-LA and 45 patients given placebo met the criteria for non-responders; 132 patients treated with MPH-LA and 24 given placebo were responders.
Results: The mean improvement in total score of DSM-IV ADHD RS at the end of extension study from the extension baseline was 18.2 and 0.9 for the maintenance of effect phase nonresponders (N = 91) and responders (N = 156), respectively. Similarly, mean improvement in SDS total score for non-responders and responders was 9.7 and 1.8, respectively. Non-responders showed symptomatic and functional improvement at the end of extension phase, irrespective of the treatment received in maintenance of effect phase (MPH-LA/placebo) as showed by the mean change in DSM-IV ADHD RS and SDS total score (Table). Overall MPH-LA was well tolerated. Conclusions: Responders to MPH-LA in the maintenance of effect phase continued to maintain efficacy in the extension phase. Non-responders to both MPH-LA and placebo in the maintenancephase showed marked symptomatic improvement. Re-titration and re-optimization of the dose for a longer duration in the extension study could possibly explain this improvement. Table: Mean improvement in DSM-IV ADHD RS and SDS total scores from extension baseline to end of extension phase Treatment received in maintenance of effect phase MPH-LA
DSM-IV ADHD RS SDS
Placebo
Non-responders (N = 46)
Responders (N = 132)
Non-responders (N = 45)
Responders (N = 24)
16.6 9.2
0.8 1.7
19.8 10.2
1.7 2.2
References [1] Huss M, Ginsberg Y, Tvedten T, et al., 2014. Methylphenidate hydrochloride modified-release in adults with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial. Adv Ther 31, 44−65.
P.1.g.015 Effects of atypical antipsychotics aripiprazole and olanzapine on active avoidance test in rats with tryptamine-induced behavior D. Getova1 ° , M. Topolov2 , K. Dzenis3 1 Medical University, Department of Pharmacology and Clinical Pharmacology, Plovdiv, Bulgaria; 2 Medical University, Department of Pharmacology and Toxicology, Plovdiv, Bulgaria; 3 Medical University, Department of Pharmacology, Riga, Latvia Purpose: Tryptamine induces neurodegeneration as axonopathy manifested by vesicularization of inner and outer mitochondrial membranes, axonal and cell membranes. Tyiptamine produced a decreased density of somatic mitochondria in mouse hippocampus causing axonal swellings and mitochondrialdamage mimicking neurodegenerative diseases [1]. Aripiprazole is a new antipsychotic drug with unique mechanism of action, which is an alternative to current antipsychotic drugs that adversely affect cognitive processes [2]. Atypical antipsychotic olanzapine acts as dopamine, serotonin and muscarinic antagonist and these transmitters could account for memory impairment in working memory tasks [3]. Our aim was to assess the impact of aripiprazole and olanzapine on behavioral functions of rats with tryptamine-induced behavior after multiple dosing. Methods: Male Wistar rats (n = 8), divided in 4 groups were treated intraperitoneally (i.p.) with: 1st saline (controls) 0.1 ml/100 g; 2nd group with tryptamine 5 mg/kg i.p.; 3rd group with tryptamine 5 mg/kg and aripiprazole 1 mg/kg; 4th group
P.1.g. Basic and clinical neuroscience − Neuropharmacology with tryptamine 5 mg/kg and olanzapine 1 mg/kg i.p. For active avoidance test rats were trained in an automatic reflex conditioner (shuttle box) with 5 days learning session and on the 12th day a memory retention test. The following parameters were observed: number of avoidances, number of escapes from foot shock and number of inter-trial crossings. The statistic evaluation was done by ANOVA for repeated measurments. Results: In active avoidance test the control rats significantly increased the number of avoidances on learning and memory retention, compared to the 1st day. Rats with tryptamine alone showed similar tendency, but less number of avoidances, compared to the same day controls. Rats with tryptamine and aripiprazol decreased the number of avoidances on learning session and on memory retention test, compared to the tryptamine group and control group. Rats with olanzapine and tryptamine decreased the number of avoidances during the learning session and on memory retention test, compared to the tryptamine and control group. Controls, tryptamine-treated group and both groups with respective neuroleptics and tryptamine showed the tendency to decrease the number of escapes during learning and memory tests and only group with olanzapine and tryptamine significantly decreased it during both learning and memory retention sessions. Conclusion: The study reveals that tryptamine, as a drug easily crossing brain blood barrier, induced slight deteriorating changes in the ability of rats to lean and memorize the task. Many research data has suggested that cognitive disorders are persistent trait of mental illness such as schizophrenia. Antipsychotic drugs aripiprazol and olanzapine applied together with tryptamine showed additive effect of impaired learning and memory in active avoidance test compared to that found with tryptamine group. The observed effects are probably due to the fact, that tryptamine is implicated as a causative agent in neurodegeneration, resembling that defining a number of human diseases, including schizophrenia. References [1] Paley EL, Perry G, Sokolova O. 2013 Tryptamine induces axonopathy and mitochondrial mimicking neurodegenerative disease via triptophanyl-tRNA deficiency. Curr Alzheimer Res, 10: 987–1004. [2] Burda, K., Czubak, A., Kus, K., et al, 2011 Influence of aripiprazole on the antidepressant, anxiolytic and cognitive functions of rats. Pharmacological reports 63, 898–907. [3] Ortega-Alvaro, A., Gibert-Rahola, J., Mico, J., 2006 Influence of chronic treatment with olanzapine, clozapine and scopolamine on performance of a learned 8-arm radial maze task in rats. Progress in Neuro-Psychopharmacology & Biological Psychiatry 30, 104–111.
P.1.g.016 Basolateral amygdala 5-HT1A receptors mediate stress-induced state-dependent learning in rats A. Rezayof1 ° , M. Sardari1 1 University of Tehran College of Science School of Biology, Animal Biology, Tehran, Iran Evidence suggests that exposure to stress, which is associated with increased levels of stress hormones, affects learning and memory processes [1]. The basolateral amygdala (BLA) is one of the most well understood brain regions that has critical roles in emotional behaviors. It has been shown that the facilitation of serotonin neurotransmission in the BLA may lead to adaptation to stress [2]. The 5-HT1A receptor, a G protein-coupled receptor (GPCR) that is coupled to Gi/Go, may be implicated in stress,
S211
learning and memory. On the other hand, it is well known that if the animal learns new information under the influence of emotional and physiological states, memory retrieval will be improved in the same conditions as were present during the acquisition of the information [3]. Considering the above-mentioned points and findings, the present study was designed with the following three aims: (1) to investigate the effect of acute stress on memory consolidation and retrieval of passive avoidance learning; (2) to examine whether stress can induce state-dependent learning; (3) to evaluate the possible role of the BLA 5-HT1A receptors in stress-induced state-dependent learning. Adult male Wistar rats weighing 220–250 g at the time of surgery were used in this study. The animals were anesthetized with an intraperitoneal injection of ketamine-xylazine mixture, placed in a stereotaxic apparatus and implanted bilaterally with two guide cannulas into the BLAs. The cannula placements were verified using the rat brain atlas of Paxinos and Watson. The animals were allowed to recover 1-week before experimental procedures. The memory retrieval was measured in a step-through type of passive avoidance apparatus. In order to induce the acute stress, the animals placed on an elevated platform for 10, 20 and 30 min. The statistical analyses were performed using one- and two-way analysis of variance (ANOVA). Our results showed that post-training exposure to 30 min stress, but not 10 or 20 min, induced the memory consolidation impairment. Moreover, pre-test exposure to 20 or 30 min stress, but not 10 min, decreased step-through latency, indicating the memory retrieval impairment. The memory impairment induced by post-training exposure to stress was restored in the animals which received pre-test exposure to 30 min stress, suggesting stress-induced state-dependent learning. On the other hand, pretest intra-BLA microinjection of different doses of a selective antagonist of 5-HT1A receptors, (S)-WAY100135 (0.5−2 mg/rat) inhibited the stress-induced state-dependent learning. It should be considered that, pre-test intra-BLA injection of same doses of (S)-WAY-100135 without stress had no effect on memory retrieval. These results provide evidence that post-training exposure to acute stress impairs memory consolidation and the impairment of memory retrieval can also be produced by pre-test exposure to stress in a time-dependent manner. Moreover, acute stress induces state-dependent learning. The serotonergic system of the BLA via 5-HT1A receptors may also be involved in stress-induced statedependent learning. References [1] Sardari, M., Rezayof, A., Khodagholi, F., Zarrindast, M.R., 2014. Basolateral amygdala GABA-A receptors mediate stress-induced memory retrieval impairment in rats. Int J Neuropsychopharmacol. 17, 603–612. [2] Christianson, J.P., Ragole, T., Amat, J., Greenwood, B.N., et al., 2010. 5-hydroxytryptamine 2C receptors in the basolateral amygdala are involved in the expression of anxiety after uncontrollable traumatic stress. Biol Psychiatry 67, 339–345. [3] Alijanpour, S., Rezayof, A., 2013. Involvement of dorsal hippocampal and medial septal nicotinic receptors in cross state-dependent memory between WIN55, 212−2 and nicotine or ethanol in mice. Neuroscience 245, 61−73.