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The impact of antipsychotic drugs on behaviour: new perspectives from the methylazoxymethanol rodent model of schizophrenia
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P.2.e. Mood disorders and treatment − Treatment (basic)
appropriate risk/benefit ratios. Therefore the aim of this study was to evaluate the effect of chronic unpredictable stress and/or venlafaxine treatment on maternal behavior of dams as well as on emotional behavior of the females after the weaning period. Female Wistar rats were subjected to 2-week chronic unpredictable stress induced by random stressors and treated with venlafaxine orally injected in cookies at a dose of 5 mg/kg twice a day. Maternal behavior was evaluated within 5-min observations twice a day. Mothers were also tested in the open field 8 weeks after chronic unpredictable stress procedure in a single 15-min session. Immunohistochemistry essay using DCX staining was performed on brain sections of these animals. Results of the present study showed altered maternal and emotional behavior of the dams. Cognitive behavior of the females was not affected, yet stressed dams showed lower level of hippocampal neurogenesis, while venlafaxine treatment reversed this condition. These results suggest that stress and antidepressant therapy can have significant impact on neurobehavioral outcomes in rat dams. Disclosure statement: Acknowledgement VEGA 2/0168/15
P.2.e.008 Chronic electroconvulsive stimulation in rats induces alterations in the miRNome that are hippocampal specific K.M. Ryan1,2 ° , P. Smyth3 , G. Blackshields3 , O. Sheils3 , D.M. McLoughlin1,2 1 Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland; 2 Dept. of Psychiatry, Trinity College Dublin St. Patrick’s University Hospital, Dublin 8, Ireland; 3 Dept. of Histopathology Sir Patrick Dun Research Laboratory, Trinity College Dublin St. James’s Hospital, Dublin 8, Ireland Background: MicroRNAs (miRNAs), a class of endogenous small RNA species, may contribute to the development of complex brain disorders, such as depression [1], and their treatment [2]. MiRNAs control about half of all protein-coding genes in mammals and are found in abundance in the brain where they play a role in a variety of functions such as neurogenesis, cell specification, apoptosis and synaptic plasticity. We have previously reported that chronic treatment with electroconvulsive stimulation (ECS), the animal model equivalent of electroconvulsive therapy (ECT), alters the expression of miRNAs associated with the neurotrophin brain derived neurotrophic factor (BDNF) in rat brain and blood [3]. To gain further understanding of the effects of chronic ECS on miRNAs in rat hippocampus the hypothesis neutral approach of next-generation deep sequencing is used here. Methods: Male Sprague-Dawley rats (n = 8 per group) were randomised to receive either “sham” or “real” ECS. ECS (100 pulses/s; 0.5 ms; 0.7 s; 75 mA) was administered daily for 10 days. Total RNA was extracted from hippocampal tissue and samples were run on a SOLiDTM sequencing platform (Life Technologies). The accuracy of each base-call from the SOLiD sequencer was verified and enhanced using Applied Biosystems’s proprietary SOLiD Accuracy Enhancement Tool (SAET) software. Read-mapping was performed using SHRiMP, an alignment program that natively supports the Applied Biosystems colorspace format. Reads were filtered to remove adapter sequences, mitochondrial DNA and unwanted RNA species. Filtered reads were then mapped to a database of miRNA sequences derived from ENSEMBL. The number of reads mapping to individual transcripts was calculated by HTSeq, and differential expression analysis
between groups of samples was performed by its companion program, DESeq2. Confirmation and specificity studies were carried out using individual stem-loop primers and quantitative real-time polymerase chain reaction (qRT-PCR). Drosha and Dicer1 mRNA levels were assessed using qRT-PCR. mRNA targets of confirmed miRNAs were identified using miRWalk and pathway analysis was carried out using DAVID. Results: The SOLiD sequencing platform generated several gigabases of high-quality DNA sequence across all samples. Results generated using the Bioconductor library DESeq showed that nine transcripts were significantly differentially expressed (p < 0.001) in the hippocampus following ECS after correcting for multiple comparisons. These include six known mature miRNA species, one of which we previously reported to be altered following ECS [3]. Confirmation studies using qRT-PCR identified changes in four out of the six mature miRNAs and these changes were shown to be hippocampal specific. Hippocampal levels of Drosha and Dicer1, which regulate production of mature miRNAs, were unaltered. Preliminary miRWalk and DAVID analyses predict that these miRNAs target mRNA species involved in inflammatory, glutamatergic, neurotrophic and intracellular signalling pathways, cytoskeletal regulation, axon guidance and long-term potentiation. Conclusion: Overall, alterations in miRNA expression may be informative about the mechanism of action of ECS/ECT and in turn may give insight into the neurobiology of depression. MiRNAs have already shown tremendous promise in treating other diseases such as Hepatitis C [4]. Thus, a better understanding of the role of miRNAs in depression and its treatments may also lead to novel therapeutic targets. References [1] Kolshus, E., Dalton, V.S., Ryan, K.M., McLoughlin, D.M., 2014. When less is more − microRNAs and psychiatric disorders. Acta Psychiatr Scand 129(4), 241–256. [2] O’Connor, R.M., Grenham, S., Dinan, T.G., Cryan, J.F., 2013. microRNAs as novel antidepressant targets: converging effects of ketamine and electroconvulsive shock therapy in the rat hippocampus. Int J Neuropsychopharmacol 16(8), 1885–1892. [3] Ryan, K.M., O’Donovan, S.M., McLoughlin, D.M., 2013. Electroconvulsive stimulation alters levels of BDNF-associated microRNAs. Neurosci Lett 549, 125–129. [4] Janssen, H.L., Reesink, H.W., Lawitz, E.J., et al., 2013. Treatment of HCV infection by targeting microRNA. N Engl J Med 368(18):1685– 1694. Disclosure statement: This work was funded by the Health Research Board, Ireland and a NARSAD P&S Fund Young Investigator Award 2014.
P.2.e.009 The impact of antipsychotic drugs on behaviour: new perspectives from the methylazoxymethanol rodent model of schizophrenia M. Morais1 ° , J. Pereira1 , S. Aslani1 , P. Patricio1 , N. Alves1 , J. Correia1 , A.R. Machado-Santos1 , A. Mateus-Pinheiro1 , C. Portugal1 , L. Pinto1 , J. Palha1 , N. Sousa1 , J.M. Bessa1 1 Life and Health Sciences Research Institute ICVS- School of Health Sciences- University of Minho- Campus de Gualtar- 4710–057Braga- Portugal, Neuroscience Research Domain NeRD, Braga, Portugal Schizophrenia is a complex neurodevelopmental psychiatric disorder of unknown etiology involving gene-environment interactions that affects about 1% of the population worldwide [1]. In the 1950’s, the serendipitous discovery of drugs with antipsychotic effects revolutionized the treatment and outcome of
P.2.e. Mood disorders and treatment − Treatment (basic) schizophrenia. However, drug treatment of schizophrenia remains problematic; and the therapeutic effects of antipsychotic drugs in the different behavioral dimensions of schizophrenia are still largely unknown [2]. To address this question, an animal model of schizophrenia with prenatal neurogenesis disruption with methylazoxymethanol (MAM) was used. To induce this model, MAM was administrated in pregnant dams (Wistar rats prenatally treated at gestational day 17, 20 mg/kg) [3]. Schizophrenia-like phenotype was evaluated in the male offspring (3 months old) using the pre-pulse inhibition (PPI) test. These animals were subsequently treated (intraperitoneal injection) with the classic antipsychotic drug haloperidol (0.05 mg/kg/day), and three different atypical antipsychotics clozapine (2.5 mg/kg/day), risperidone (0.25 mg/kg/day) and aripiprazole (1 mg/kg/day) for a period of five weeks. During the last two weeks of treatment a battery of behavior tests to assess mood (forced swimming test (FST)), anxiety (elevated-plus maze test (EPM)), cognition (Morris water maze (MWM) and novel object recognition (NOR) test) and social interaction (three-chamber sociability test) were performed. After confirmation of homogeneity, appropriate statistical tests were applied to the data. Repeated measures ANOVA were used to analyze the MWM. Two-factor ANOVA was used to evaluate the remaining behavioral data. Differences between groups were then determined by Tukey’s honestly significant difference test (Tukey HSD) post hoc analysis. Statistical significance was accepted for P < 0.05. Our data indicates that animals exposed to MAM in utero present no alterations in the FST and EPM and also in the different tasks of the MWM. Regarding social interaction using the three chamber test, MAM animals present a decrease in the time spend interacting (time spent with another rodent). The classical antipsychotic drug haloperidol had no significant effects on sociability. The atypical antipsychotic drugs clozapine, risperidone and aripiprazole were able to revert the impairment on sociability induced by MAM exposure. Regarding cognition, animals exposed to MAM in the prenatal period reveal impairment in the novel object recognition task, spending less time exploring the novel object (revealing impairments in discrimination). The classical antipsychotic drug haloperidol had no significant cognitive effects in these animals. The atypical antipsychotic drugs clozapine and risperidone were able to revert the cognitive impairment induced by mam exposure. The effects of aripiprazole on cognition were not significant. In summary, using a neurodevelopmental animal model of schizophrenia (MAM model) we identify specific cognitive deficits and social interaction impairments that are differentially modulated by different antipsychotic drugs. The classical haloperidol presents no beneficial effects in these behavior dimensions. On the other hand, the atypical clozapine and risperidone have a positive effect on both dimensions with aripiprazole presenting only a significant effect in the social measure References [1] Os, J.V., 2009. Clinical overview “Salience syndrome” replaces schizophrenia in DSM-V and ICD-11 : psychiatrys evidence-based entry into the 21st century ? Acta Psychiatrica Scandinavica 120, 363–372. [2] Miyamoto, S., Miyake, N., Jarskog, L.F., Fleischhacker, W.W., Lieberman, J.A., 2012. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry 17, 1206–1227. [3] Le Pen, G., Gourevitch, R., Hazane, F., Hoareau, C., Jay, T.M., Krebs, M.O., 2006. Peri-pubertal maturation after developmental disturbance: a model for psychosis onset in the rat. Neuroscience 143, 395–405.
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P.2.e.010 Effects of maternal depression and venlafaxine treatment on the neurobehavioural development of the juvenile rat offspring E. Cs´asz´ar1 ° , K. Beloviˇcov´a1 , E. Ujhazy1 , M. Mach1 , M. Dubovick´y1 1 Institute of experimental pharmacology and toxicology, Department of developmental and behavioral toxicology, Bratislava, Slovak Republic Depression during pregnancy and in the post partum period is a growing health issue in modern society. An important question is whether to treat or not to treat depression during gestation and lactation. However previous preclinical and clinical studies have shown that the consequences of not treated depression can be so serious that the benefit from antidepressant therapy may overweight the possible risk for neonatal and/or postnatal development of the offspring. Venlafaxine, a representative of serotonine and noradrenaline reuptake inhibitors, is used to treat a wide spectrum of mood disorders. Thus, the limited number of prenatal and perinatal studies raises the question about the safety of venlafaxine therapy during gestation and lactation. Our previous experimental studies showed that pre- and early postnatal exposure to venlafaxine alone affected anxiety- and depressionlike behavior in adult rat offspring of both sexes, though not necessarily in a negative way. However, we did not evaluated the action of venlafaxine in conditions of maternal depression. Unpredictable chronic mild stress before mating is commonly used in experimental animals to induce maternal adversity manifested by signs similar to depression. In the present study, we investigated the effect of venlafaxine treatment on selected reproductive and neurobehavioral variables of the juvenile offspring using a model of maternal adversity. Stressed and non-stressed Wistar rat dams were treated with either venlafaxine (10 mg/kg/day) or vehicle. Dams were divided into four groups: (1) Control + Vehicle, (2) Control + Venlafaxine, (3) Stress + Vehicle and (4) Stress + Venlafaxine. Venlafaxine was administered to the dams from day 15 of gestation to day 20 post partum via cookies. The results of the present study showed that mild maternal stress and/or administration of venlafaxine during gestation and lactation did not cause any major alterations in reproductive variables of the newborn offspring right after the birth. There were no differences in the duration of the pregnancy, litter weight of the offspring after the birth and also no alterations in the number of the living born pups. Nevertheless, dams previously exposed to stress had higher incidence of spontaneous abortions compare to non-stressed mothers. Moreover offspring of stressed mothers showed higher weight gain in the age of 35 days post partum. Maternal stress and venlafaxine do not affect play behavior of juvenile offspring in their familiar environment. However pups exposed to venlafaxine via their mother showed increased anxiety-like behavior in the new unfamiliar environment. In conclusion, we suggest that exposure to maternal stress and venlafaxine treatment during gestation and lactation may interfere with functional development of the brain and can cause neurobehavioral alterations. However these functional changes may not occur immediately after birth. They can manifest later during adolescence or even in adulthood and senescence as delayed and/or long-term neurobehavioral dysfunctions.
P.2.e. Mood disorders and treatment − Treatment (basic)
appropriate risk/benefit ratios. Therefore the aim of this study was to evaluate the effect of chronic unpredictable stress and/or venlafaxine treatment on maternal behavior of dams as well as on emotional behavior of the females after the weaning period. Female Wistar rats were subjected to 2-week chronic unpredictable stress induced by random stressors and treated with venlafaxine orally injected in cookies at a dose of 5 mg/kg twice a day. Maternal behavior was evaluated within 5-min observations twice a day. Mothers were also tested in the open field 8 weeks after chronic unpredictable stress procedure in a single 15-min session. Immunohistochemistry essay using DCX staining was performed on brain sections of these animals. Results of the present study showed altered maternal and emotional behavior of the dams. Cognitive behavior of the females was not affected, yet stressed dams showed lower level of hippocampal neurogenesis, while venlafaxine treatment reversed this condition. These results suggest that stress and antidepressant therapy can have significant impact on neurobehavioral outcomes in rat dams. Disclosure statement: Acknowledgement VEGA 2/0168/15
P.2.e.008 Chronic electroconvulsive stimulation in rats induces alterations in the miRNome that are hippocampal specific K.M. Ryan1,2 ° , P. Smyth3 , G. Blackshields3 , O. Sheils3 , D.M. McLoughlin1,2 1 Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland; 2 Dept. of Psychiatry, Trinity College Dublin St. Patrick’s University Hospital, Dublin 8, Ireland; 3 Dept. of Histopathology Sir Patrick Dun Research Laboratory, Trinity College Dublin St. James’s Hospital, Dublin 8, Ireland Background: MicroRNAs (miRNAs), a class of endogenous small RNA species, may contribute to the development of complex brain disorders, such as depression [1], and their treatment [2]. MiRNAs control about half of all protein-coding genes in mammals and are found in abundance in the brain where they play a role in a variety of functions such as neurogenesis, cell specification, apoptosis and synaptic plasticity. We have previously reported that chronic treatment with electroconvulsive stimulation (ECS), the animal model equivalent of electroconvulsive therapy (ECT), alters the expression of miRNAs associated with the neurotrophin brain derived neurotrophic factor (BDNF) in rat brain and blood [3]. To gain further understanding of the effects of chronic ECS on miRNAs in rat hippocampus the hypothesis neutral approach of next-generation deep sequencing is used here. Methods: Male Sprague-Dawley rats (n = 8 per group) were randomised to receive either “sham” or “real” ECS. ECS (100 pulses/s; 0.5 ms; 0.7 s; 75 mA) was administered daily for 10 days. Total RNA was extracted from hippocampal tissue and samples were run on a SOLiDTM sequencing platform (Life Technologies). The accuracy of each base-call from the SOLiD sequencer was verified and enhanced using Applied Biosystems’s proprietary SOLiD Accuracy Enhancement Tool (SAET) software. Read-mapping was performed using SHRiMP, an alignment program that natively supports the Applied Biosystems colorspace format. Reads were filtered to remove adapter sequences, mitochondrial DNA and unwanted RNA species. Filtered reads were then mapped to a database of miRNA sequences derived from ENSEMBL. The number of reads mapping to individual transcripts was calculated by HTSeq, and differential expression analysis
between groups of samples was performed by its companion program, DESeq2. Confirmation and specificity studies were carried out using individual stem-loop primers and quantitative real-time polymerase chain reaction (qRT-PCR). Drosha and Dicer1 mRNA levels were assessed using qRT-PCR. mRNA targets of confirmed miRNAs were identified using miRWalk and pathway analysis was carried out using DAVID. Results: The SOLiD sequencing platform generated several gigabases of high-quality DNA sequence across all samples. Results generated using the Bioconductor library DESeq showed that nine transcripts were significantly differentially expressed (p < 0.001) in the hippocampus following ECS after correcting for multiple comparisons. These include six known mature miRNA species, one of which we previously reported to be altered following ECS [3]. Confirmation studies using qRT-PCR identified changes in four out of the six mature miRNAs and these changes were shown to be hippocampal specific. Hippocampal levels of Drosha and Dicer1, which regulate production of mature miRNAs, were unaltered. Preliminary miRWalk and DAVID analyses predict that these miRNAs target mRNA species involved in inflammatory, glutamatergic, neurotrophic and intracellular signalling pathways, cytoskeletal regulation, axon guidance and long-term potentiation. Conclusion: Overall, alterations in miRNA expression may be informative about the mechanism of action of ECS/ECT and in turn may give insight into the neurobiology of depression. MiRNAs have already shown tremendous promise in treating other diseases such as Hepatitis C [4]. Thus, a better understanding of the role of miRNAs in depression and its treatments may also lead to novel therapeutic targets. References [1] Kolshus, E., Dalton, V.S., Ryan, K.M., McLoughlin, D.M., 2014. When less is more − microRNAs and psychiatric disorders. Acta Psychiatr Scand 129(4), 241–256. [2] O’Connor, R.M., Grenham, S., Dinan, T.G., Cryan, J.F., 2013. microRNAs as novel antidepressant targets: converging effects of ketamine and electroconvulsive shock therapy in the rat hippocampus. Int J Neuropsychopharmacol 16(8), 1885–1892. [3] Ryan, K.M., O’Donovan, S.M., McLoughlin, D.M., 2013. Electroconvulsive stimulation alters levels of BDNF-associated microRNAs. Neurosci Lett 549, 125–129. [4] Janssen, H.L., Reesink, H.W., Lawitz, E.J., et al., 2013. Treatment of HCV infection by targeting microRNA. N Engl J Med 368(18):1685– 1694. Disclosure statement: This work was funded by the Health Research Board, Ireland and a NARSAD P&S Fund Young Investigator Award 2014.
P.2.e.009 The impact of antipsychotic drugs on behaviour: new perspectives from the methylazoxymethanol rodent model of schizophrenia M. Morais1 ° , J. Pereira1 , S. Aslani1 , P. Patricio1 , N. Alves1 , J. Correia1 , A.R. Machado-Santos1 , A. Mateus-Pinheiro1 , C. Portugal1 , L. Pinto1 , J. Palha1 , N. Sousa1 , J.M. Bessa1 1 Life and Health Sciences Research Institute ICVS- School of Health Sciences- University of Minho- Campus de Gualtar- 4710–057Braga- Portugal, Neuroscience Research Domain NeRD, Braga, Portugal Schizophrenia is a complex neurodevelopmental psychiatric disorder of unknown etiology involving gene-environment interactions that affects about 1% of the population worldwide [1]. In the 1950’s, the serendipitous discovery of drugs with antipsychotic effects revolutionized the treatment and outcome of
P.2.e. Mood disorders and treatment − Treatment (basic) schizophrenia. However, drug treatment of schizophrenia remains problematic; and the therapeutic effects of antipsychotic drugs in the different behavioral dimensions of schizophrenia are still largely unknown [2]. To address this question, an animal model of schizophrenia with prenatal neurogenesis disruption with methylazoxymethanol (MAM) was used. To induce this model, MAM was administrated in pregnant dams (Wistar rats prenatally treated at gestational day 17, 20 mg/kg) [3]. Schizophrenia-like phenotype was evaluated in the male offspring (3 months old) using the pre-pulse inhibition (PPI) test. These animals were subsequently treated (intraperitoneal injection) with the classic antipsychotic drug haloperidol (0.05 mg/kg/day), and three different atypical antipsychotics clozapine (2.5 mg/kg/day), risperidone (0.25 mg/kg/day) and aripiprazole (1 mg/kg/day) for a period of five weeks. During the last two weeks of treatment a battery of behavior tests to assess mood (forced swimming test (FST)), anxiety (elevated-plus maze test (EPM)), cognition (Morris water maze (MWM) and novel object recognition (NOR) test) and social interaction (three-chamber sociability test) were performed. After confirmation of homogeneity, appropriate statistical tests were applied to the data. Repeated measures ANOVA were used to analyze the MWM. Two-factor ANOVA was used to evaluate the remaining behavioral data. Differences between groups were then determined by Tukey’s honestly significant difference test (Tukey HSD) post hoc analysis. Statistical significance was accepted for P < 0.05. Our data indicates that animals exposed to MAM in utero present no alterations in the FST and EPM and also in the different tasks of the MWM. Regarding social interaction using the three chamber test, MAM animals present a decrease in the time spend interacting (time spent with another rodent). The classical antipsychotic drug haloperidol had no significant effects on sociability. The atypical antipsychotic drugs clozapine, risperidone and aripiprazole were able to revert the impairment on sociability induced by MAM exposure. Regarding cognition, animals exposed to MAM in the prenatal period reveal impairment in the novel object recognition task, spending less time exploring the novel object (revealing impairments in discrimination). The classical antipsychotic drug haloperidol had no significant cognitive effects in these animals. The atypical antipsychotic drugs clozapine and risperidone were able to revert the cognitive impairment induced by mam exposure. The effects of aripiprazole on cognition were not significant. In summary, using a neurodevelopmental animal model of schizophrenia (MAM model) we identify specific cognitive deficits and social interaction impairments that are differentially modulated by different antipsychotic drugs. The classical haloperidol presents no beneficial effects in these behavior dimensions. On the other hand, the atypical clozapine and risperidone have a positive effect on both dimensions with aripiprazole presenting only a significant effect in the social measure References [1] Os, J.V., 2009. Clinical overview “Salience syndrome” replaces schizophrenia in DSM-V and ICD-11 : psychiatrys evidence-based entry into the 21st century ? Acta Psychiatrica Scandinavica 120, 363–372. [2] Miyamoto, S., Miyake, N., Jarskog, L.F., Fleischhacker, W.W., Lieberman, J.A., 2012. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry 17, 1206–1227. [3] Le Pen, G., Gourevitch, R., Hazane, F., Hoareau, C., Jay, T.M., Krebs, M.O., 2006. Peri-pubertal maturation after developmental disturbance: a model for psychosis onset in the rat. Neuroscience 143, 395–405.
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P.2.e.010 Effects of maternal depression and venlafaxine treatment on the neurobehavioural development of the juvenile rat offspring E. Cs´asz´ar1 ° , K. Beloviˇcov´a1 , E. Ujhazy1 , M. Mach1 , M. Dubovick´y1 1 Institute of experimental pharmacology and toxicology, Department of developmental and behavioral toxicology, Bratislava, Slovak Republic Depression during pregnancy and in the post partum period is a growing health issue in modern society. An important question is whether to treat or not to treat depression during gestation and lactation. However previous preclinical and clinical studies have shown that the consequences of not treated depression can be so serious that the benefit from antidepressant therapy may overweight the possible risk for neonatal and/or postnatal development of the offspring. Venlafaxine, a representative of serotonine and noradrenaline reuptake inhibitors, is used to treat a wide spectrum of mood disorders. Thus, the limited number of prenatal and perinatal studies raises the question about the safety of venlafaxine therapy during gestation and lactation. Our previous experimental studies showed that pre- and early postnatal exposure to venlafaxine alone affected anxiety- and depressionlike behavior in adult rat offspring of both sexes, though not necessarily in a negative way. However, we did not evaluated the action of venlafaxine in conditions of maternal depression. Unpredictable chronic mild stress before mating is commonly used in experimental animals to induce maternal adversity manifested by signs similar to depression. In the present study, we investigated the effect of venlafaxine treatment on selected reproductive and neurobehavioral variables of the juvenile offspring using a model of maternal adversity. Stressed and non-stressed Wistar rat dams were treated with either venlafaxine (10 mg/kg/day) or vehicle. Dams were divided into four groups: (1) Control + Vehicle, (2) Control + Venlafaxine, (3) Stress + Vehicle and (4) Stress + Venlafaxine. Venlafaxine was administered to the dams from day 15 of gestation to day 20 post partum via cookies. The results of the present study showed that mild maternal stress and/or administration of venlafaxine during gestation and lactation did not cause any major alterations in reproductive variables of the newborn offspring right after the birth. There were no differences in the duration of the pregnancy, litter weight of the offspring after the birth and also no alterations in the number of the living born pups. Nevertheless, dams previously exposed to stress had higher incidence of spontaneous abortions compare to non-stressed mothers. Moreover offspring of stressed mothers showed higher weight gain in the age of 35 days post partum. Maternal stress and venlafaxine do not affect play behavior of juvenile offspring in their familiar environment. However pups exposed to venlafaxine via their mother showed increased anxiety-like behavior in the new unfamiliar environment. In conclusion, we suggest that exposure to maternal stress and venlafaxine treatment during gestation and lactation may interfere with functional development of the brain and can cause neurobehavioral alterations. However these functional changes may not occur immediately after birth. They can manifest later during adolescence or even in adulthood and senescence as delayed and/or long-term neurobehavioral dysfunctions.