- Email: [email protected]
P4.a.003 Involvement of CYP2C19 in stress-induced despair
P.4.a. Anxiety disorders, OCD, stress related disorders and treatment − Anxiety disorders (basic) They concluded that it was because of the higher frequency of sexual, religious and agressive obsessions of OCD patients with tic disorders than without tic disorders [3]. Hasler et al. found spesific relationship between aggresive, sexual, religious and somatic obsessions and checking compulsions among other OCD symptoms [4]. The results of our study was consistent with this study that; OCD patients with these obsessions had higher impulsivity scores than others. Mataix et al. also suggested that the provacation of checking-related anxiety is associated with dysfunction in a circuit that is important for attentional and motor functions as well as the inhibiton of unanted impulses rather than emotion processing [5]. Higher scores of attentional impulsivity, particulary in patients suffering from sexual, aggresive or religious obsessions suggest a common dysfunction in attentional circuits/ processes of those people. The results of our study may promote further studies conducted with more advanced and objective neuropsychometric tests evaluating features of the neurobiology, clinical course and the response to treatment of OCD. References [1] Kashyap H, Fontenelle LF, Miguel EC, Ferrao YA, Torres AR, Shavitt RG, 2012. ‘Impulsive compulsivity’ in obsessive-compulsive disorder: a phenotype marker of patients with poor clinical outcome. J Psychiatry Res. 46,1146–1152. [2] Potenza MN, Koran LM, Pallanti S, 2009. The relationship between impulse-control disorders and obsessive-compulsive disorder:A current understanding and future research directions. Psychiatry Research 170, 22−31. [3] Summerfeldt LJ, Hood K, Antony MM, Richter MA, Swinson RP, 2004. Impulsivity in obsessive-compulsive disorder: comparisons with other anxiety disorders and within tic-related subgroups. Personality and Individual Differences 36, 539–553. [4] Hasler G, LaSalle-Ricci H, Ronquillo J, Crawley S, Cochran L, Kazuba D. et al.,2005. Obsessive-compulsive symptom dimensions show spesific relationships to psychiatric comorbidity. Psychiatry Research 135,121–132. [5] Mataix-Cols D, Wooderson S, Lawrence N, Branner M, Speckens A, Mary L, 2004. Distinct neural correlates of washing, checking and hoarding symptom dimensions in obsessive-compulsive disorder. Arch Gen Pschiatry 61, 564–576.
P.4.a.002 Anxiolytic effects of an orally available novel TSPO antagonist in rodents Katsumata1 ° ,
Kishi1 ,
Niwa1 ,
S553
day, rats were again placed in the apparatus 2 hours after oral administration of vehicle (0.5% methylcellulose) or ONO-2952 (0.1, 0.3, 1, 3 mg/kg), or 1 hour after oral administration of vehicle or diazepam (3 mg/kg) and were testsed for 30 minutes without exposure to foot shock. The length of time during which rats ceased physical movements other than respiration and appeared frozen were recorded. 2. CCK-4-induced freezing behavior in rats: Male LEW/CrlCrlj rats were used. Vehicle, ONO-2952 (0.1, 0.3, 1, 3 mg/kg) or alprazolam (3 mg/kg) were orally administered to rats 2 hours before subcutaneous adminstration of CCK-4 (3 mg/kg). Two minutes following CCK-4 administration, rats were placed with their forepaws on a 7 cm high wooden block and the time remaining in a frozen position, i.e. until moving down from the wooden block, was recorded for five times with 2 minuites intervals. 3. CCK-4-induced anxiety-like behavior in mice EPM test: Male Slc:ICR mice were used. Vehicle, ONO-2952 (1, 10 mg/kg) or diazepam (3 mg/kg) were orally administered 2 hours before, and saline or CCK-4 (1 mg/kg) was intraperitoneally administered 15 minutes before EPM test. Summary of the results: ONO-2952, at the doses of 1 and 3 mg/kg, and diazepam significantly inhibited CFS-induced increase in freezing time compared with vehicle group (p < 0.001, Dunnett test, p < 0.05, t test). ONO-2952, at the doses of 1 and 3 mg/kg, and alprazolam significantly inhibited CCK-4-induced increase in freezing time compared with vehicle group (p < 0.05, Steel test, p < 0.001, Wilcoxon rank sum test). In EPM test, CCK-4 significantly decreased time spent on the open arms compared with saline group (p < 0.01, t test). ONO-2952 at the doses of 1 and 10 mg/kg and diazepam significantly increased time spent on the open arms compared with vehicle group (p < 0.05, Dunnett test, p < 0.001, t test), but about 30% mice in diazepam group fell from the open arms. Conclusion: ONO-2952 inihibited CFS- or CCK-4-induced freezing hehavior and CCK-4-induced anxiety-like behavior in EPM test. These results show that ONO-2952 produces anxiolytic effects in rodents and suggest that ONO-2952 would be an efficacious treatment for anxiety disorders such as panic disorder. Disclosure statement: This abstract is financially supported by ONO Pharmaceutical Co., Ltd.
Nakanishi2 ,
S. T. N. A. Y. Kawahara3 , K. Mitsui4 1 ONO Pharmaceutical − Co. − Ltd., Discovery Research Laboratories I, Osaka, Japan; 2 ONO Pharmaceutical − Co. − Ltd., Exploratory Research Laboratories II, Osaka, Japan; 3 ONO Pharmaceutical − Co. − Ltd., Exploratory Research Laboratories IV, Ibaragi, Japan; 4 ONO Pharmaceutical − Co. − Ltd., Discovery Research Alliance, Osaka, Japan nbk-3pt Purpose: TSPO regulates cholesterol transport into the mitochondria which is a rate limiting step in steroid production. We have previously shown that ONO-2952, an orally available novel TSPO antagonist, inhibited restraint stress-induced neurosteroid accumulation in the rat brain. In this study, effects of ONO-2952 on conditioned fear stress (CFS) and CCK-4-induced freezing behavior in rats and CCK-4 induced anxiety-like behavior on elevated plus maze (EPM) in mice were examined. Methods: 1. CFS-induced freezing behavior in rats: Male Crl:CD(SD) rats were used. Rats were conditioned 15 times at 1 minutes intervals by a 3 second warning beep followed by a 5 second 2 mA foot shock and a flash of light. On the following
P.4.a.003 Involvement of CYP2C19 in stress-induced despair M.M. Juki´c1 ° , E. Pe˜nas-Lled´o2 , P. Courtet3 , A. Llerena2 , M. Ingelman-Sundberg1 1 Karolinska Institute, Physiology and Pharmacology Department, Stockholm, Sweden; 2 Extremadura University, CICAB Clinical Research Center, Badajoz, Spain; 3 University Hospital Center of Montpellier, Psychiatric Emergency and Post Emergency Department, Montpellier, France Background: Cytochrome P450 2C19 (CYP2C19) is a liver enzyme known to metabolize many endogenous and synthetic psychoactive compounds [1]. CYP2C19 expression was recently found in the fetal human brain, indicating a potential role of this enzyme in brain development [2]. CYP2C19 enzymatic capacity is genotype-dependent and human subjects homozygous for defective variant of CYP2C19 gene (CYP2C19*2) show lower levels of depressive symptoms than controls [3], suggesting an involvement of CYP2C19 polymorphism in the etiology of major depression
S554
P.4.a. Anxiety disorders, OCD, stress related disorders and treatment − Anxiety disorders (basic)
(MDD). Transgenic mice containing human CYP2C19 gene show CYP2C19 expression in developing brain, decreased hippocampal (HC) volume, more anxiety, depletion in adult HC neurogenesis, decrease in parvalbumin positive GABAergic neuronal density in the HC, and increased HC activation after acute stress [2]. CYP2C19 gene does not have a homolog in mice making this mutant a unique tool in the research of the CYP2C19 role in the brain in vivo. Methods: We exposed CYP2C19 humanized mice to various stressors including the acute restrain stress, repetitive forced swim test, and chronic restrain stress with the aim to study their stressinduced phenotype in detail. Next, we used antidepressant drugs, citalopram and ketamine, with the aim to reverse stress-induced alterations in mutant mice. In order to translate preclinical findings to human MDD patients, we analyzed the effect of common CYP2C19 allelic variants on suicide severity in suicide attempters suffering from MDD, derived from the larger clinical study [4]. Results: Chronic restrain stress caused a body weight decrease in both CYP2C19 humanized and control mice (Time F4,75 =8.068, p = 0.007); however, this decrease was more pronounced in the mutants compared to controls (Genotype F4,75 =10.660, p < 0.001) during the first (Fisher’s LSD post hoc test p = 0.048) and the second week (Fisher’s LSD post hoc test p = 0.031) of stress exposure. Immobility time in the first exposure to the forced swim test was increased in the CYP2C19 humanized mice compared to controls (t46 =2.557, p = 0.010). In daily repetitive forced swim test, acute 10 mg/kg citalopram treatment 30 minutes prior to the fifth consecutive day of testing specifically reversed immobility time in mutants (Genotype∗Treatment F4,75 =6.886, p = 0.013; Fisher’s LSD post hoc test p = 0.009). Treatment with sub-anesthetic dose of ketamine (10 mg/kg) 30 minutes prior to the forced swim test on the fifth consecutive day of testing reduced the immobility time in both mutant and control mice (Treatment F4,75 =4.575, p = 0.042). Bdnf expression was lower in mutant HC compared to controls after thirty minutes of the acute restrain stress exposure (t10 =2.558, p = 0.027); this difference was no longer observed after thirty minutes of recovery from the stress. We found a significant positive association between suicide severity and CYP2C19 enzymatic capacity in MDD patients, measured by objective circumstances score on Beck’s suicide intent scale (X22,206 =8.655; p = 0.012). Conclusions: Transgenic mice with CYP2C19 expression in developing brain are more sensitive to stress and they show antidepressant-sensitive stress-induced despair-like behavior. In addition, MDD patients carrying genotypes connected with increased CYP2C19 enzymatic capacity show more severe suicide attempts. References [1] Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: Pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 2007 Dec;116(3):496–526. [2] Sim SC, Nordin L, Andersson TM, Virding S, Olsson M, Pedersen NL, Ingelman-Sundberg M. Association between CYP2C19 polymorphism and depressive symptoms. Am J Med Genet B Neuropsychiatr Genet 2010 Sep;153B(6):1160−6. [3] Persson A, Sim SC, Virding S, Onishchenko N, Schulte G, IngelmanSundberg M. Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene. Mol Psychiatry 2014 Jun;19(6):733−41. [4] Pe˜nas-Lled´o E, Guillaume S, Naranjo ME, Delgado A, Jaussent I, Blasco-Fontecilla H, Courtet P, Llerena A. A combined high CYP2D6CYP2C19 metabolic capacity is associated with the severity of suicide attempt as measured by objective circumstances. Pharmacogenomics J. 2015 Apr;15(2):172−6.
P.4.a.004 Fear extinction deficits and BDNF dysregulation in mice with full 5-HT2C receptor editing: a model for post-traumatic stress disorders? M. Regue1 ° , C. Poilbout1 , L. Lanfumey1 , R. Mongeau2 1 INSERM U894, CPN, Paris, France; 2 Universit´ e Paris Descartes − EA4475, Pharmacology department, Paris, France Purpose of the study: Post-traumatic stress disorder (PTSD) is a major anxiety disorder caused by exposure to a strong psychological trauma, and for which, until now, no pharmacological treatment has demonstrated a wide efficacy. PTSD appears to involve, at least in part, fear memory extinction deficits and fear generalization [1]. We recently demonstrated that a dysregulation in serotonin 2C receptor (5-HT2CR) editing induced anxiety-like disorders, and mice expressing only the fully edited VGV isoform of the 5-HT2CR (VGV mice) displayed increased fear behaviors [2]. Moreover, it has been reported that 5-HT2CR blockade or deletion can alter BDNF expression [3],a neurotrophic factor known to regulate cortical, hippocampal and amygdala-dependent memory, and which has also been proposed to play a central role in the mechanisms underlying PTSD [4]. In this context, we studied VGV mice to further analyze the pathophysiology of PTSD and to determine whether these mice could be used as a model to design new pharmacological strategies. Methods used: Wild-type (WT) or VGV adult (10−13 weekold) male C57Bl/6 mice were used to assess locomotor activity (rotarod, running wheel), anxiety-like (openfield, elevated plus maze) and fear-related behaviors (fear conditioning). In addition, WT and VGV mice received either paroxetine (delivered in drinking water; ~7 mg/kg/day x28 days) or tap water. At the end of the treatment, fear conditioning (6 sounds (30 s, 85 dB) paired with 6 footshocks (2 s, 0.5 mA)) was conducted to evaluate fear extinction (induced by 40 exposures to the same sound). Finally, brains from both na¨ıve and treated mice were dissected for qRTPCR analyses of Bdnf and neuroplasticity gene-related expression. Data were analyzed using Student’s t-test, one-way or two-way ANOVAs and Bonferroni multiple comparisons post-hoc test. Results: Behavioral data showed that VGV mice displayed locomotor activity deficit together with an anxiogenic phenotype. In addition, they exhibited greater fear expression during training, extensive fear extinction deficits and context generalization in the fear conditioning paradigm (% of time spent freezing during fear extinction: WT: 26.44±4.61% and VGV: 84.8±2.97%). In VGV mice, a deficit in Bdnf exon IV mRNA expression in both the hippocampus (−0.43±0.07) and the prefrontal cortex (−0.33±0.06) was observed in VGV compared to WT mice (p < 0.0001). After the 24 h wash-out period, chronic paroxetine induced a withdrawal effect that unfortunately impaired fear extinction process in WT mice. Nevertheless, it partially reversed the context generalization occurring in VGV mice (quantified by the % of time spent freezing during the baseline period of the test, VGV Vehicle: 39±7.89%, Paroxetine-treated VGV: 16±3.30%, VGV Vehicle vs VGV Paroxetine p < 0.001). Conclusion: Our data suggest that VGV mice displayed behavioral modifications in fear conditioning that are consistent with PTSD symptoms. Bdnf mRNA expression dysregulation in fearrelated structures could, at least partially, reflect an alteration in the activation of the fear circuitry in VGV mice. These results provides further evidence that BDNF may be a factor underlying PTSD pathogenesis and indicates that VGV mice could be a
P.4.a.002 Anxiolytic effects of an orally available novel TSPO antagonist in rodents Katsumata1 ° ,
Kishi1 ,
Niwa1 ,
S553
day, rats were again placed in the apparatus 2 hours after oral administration of vehicle (0.5% methylcellulose) or ONO-2952 (0.1, 0.3, 1, 3 mg/kg), or 1 hour after oral administration of vehicle or diazepam (3 mg/kg) and were testsed for 30 minutes without exposure to foot shock. The length of time during which rats ceased physical movements other than respiration and appeared frozen were recorded. 2. CCK-4-induced freezing behavior in rats: Male LEW/CrlCrlj rats were used. Vehicle, ONO-2952 (0.1, 0.3, 1, 3 mg/kg) or alprazolam (3 mg/kg) were orally administered to rats 2 hours before subcutaneous adminstration of CCK-4 (3 mg/kg). Two minutes following CCK-4 administration, rats were placed with their forepaws on a 7 cm high wooden block and the time remaining in a frozen position, i.e. until moving down from the wooden block, was recorded for five times with 2 minuites intervals. 3. CCK-4-induced anxiety-like behavior in mice EPM test: Male Slc:ICR mice were used. Vehicle, ONO-2952 (1, 10 mg/kg) or diazepam (3 mg/kg) were orally administered 2 hours before, and saline or CCK-4 (1 mg/kg) was intraperitoneally administered 15 minutes before EPM test. Summary of the results: ONO-2952, at the doses of 1 and 3 mg/kg, and diazepam significantly inhibited CFS-induced increase in freezing time compared with vehicle group (p < 0.001, Dunnett test, p < 0.05, t test). ONO-2952, at the doses of 1 and 3 mg/kg, and alprazolam significantly inhibited CCK-4-induced increase in freezing time compared with vehicle group (p < 0.05, Steel test, p < 0.001, Wilcoxon rank sum test). In EPM test, CCK-4 significantly decreased time spent on the open arms compared with saline group (p < 0.01, t test). ONO-2952 at the doses of 1 and 10 mg/kg and diazepam significantly increased time spent on the open arms compared with vehicle group (p < 0.05, Dunnett test, p < 0.001, t test), but about 30% mice in diazepam group fell from the open arms. Conclusion: ONO-2952 inihibited CFS- or CCK-4-induced freezing hehavior and CCK-4-induced anxiety-like behavior in EPM test. These results show that ONO-2952 produces anxiolytic effects in rodents and suggest that ONO-2952 would be an efficacious treatment for anxiety disorders such as panic disorder. Disclosure statement: This abstract is financially supported by ONO Pharmaceutical Co., Ltd.
Nakanishi2 ,
S. T. N. A. Y. Kawahara3 , K. Mitsui4 1 ONO Pharmaceutical − Co. − Ltd., Discovery Research Laboratories I, Osaka, Japan; 2 ONO Pharmaceutical − Co. − Ltd., Exploratory Research Laboratories II, Osaka, Japan; 3 ONO Pharmaceutical − Co. − Ltd., Exploratory Research Laboratories IV, Ibaragi, Japan; 4 ONO Pharmaceutical − Co. − Ltd., Discovery Research Alliance, Osaka, Japan nbk-3pt Purpose: TSPO regulates cholesterol transport into the mitochondria which is a rate limiting step in steroid production. We have previously shown that ONO-2952, an orally available novel TSPO antagonist, inhibited restraint stress-induced neurosteroid accumulation in the rat brain. In this study, effects of ONO-2952 on conditioned fear stress (CFS) and CCK-4-induced freezing behavior in rats and CCK-4 induced anxiety-like behavior on elevated plus maze (EPM) in mice were examined. Methods: 1. CFS-induced freezing behavior in rats: Male Crl:CD(SD) rats were used. Rats were conditioned 15 times at 1 minutes intervals by a 3 second warning beep followed by a 5 second 2 mA foot shock and a flash of light. On the following
P.4.a.003 Involvement of CYP2C19 in stress-induced despair M.M. Juki´c1 ° , E. Pe˜nas-Lled´o2 , P. Courtet3 , A. Llerena2 , M. Ingelman-Sundberg1 1 Karolinska Institute, Physiology and Pharmacology Department, Stockholm, Sweden; 2 Extremadura University, CICAB Clinical Research Center, Badajoz, Spain; 3 University Hospital Center of Montpellier, Psychiatric Emergency and Post Emergency Department, Montpellier, France Background: Cytochrome P450 2C19 (CYP2C19) is a liver enzyme known to metabolize many endogenous and synthetic psychoactive compounds [1]. CYP2C19 expression was recently found in the fetal human brain, indicating a potential role of this enzyme in brain development [2]. CYP2C19 enzymatic capacity is genotype-dependent and human subjects homozygous for defective variant of CYP2C19 gene (CYP2C19*2) show lower levels of depressive symptoms than controls [3], suggesting an involvement of CYP2C19 polymorphism in the etiology of major depression
S554
P.4.a. Anxiety disorders, OCD, stress related disorders and treatment − Anxiety disorders (basic)
(MDD). Transgenic mice containing human CYP2C19 gene show CYP2C19 expression in developing brain, decreased hippocampal (HC) volume, more anxiety, depletion in adult HC neurogenesis, decrease in parvalbumin positive GABAergic neuronal density in the HC, and increased HC activation after acute stress [2]. CYP2C19 gene does not have a homolog in mice making this mutant a unique tool in the research of the CYP2C19 role in the brain in vivo. Methods: We exposed CYP2C19 humanized mice to various stressors including the acute restrain stress, repetitive forced swim test, and chronic restrain stress with the aim to study their stressinduced phenotype in detail. Next, we used antidepressant drugs, citalopram and ketamine, with the aim to reverse stress-induced alterations in mutant mice. In order to translate preclinical findings to human MDD patients, we analyzed the effect of common CYP2C19 allelic variants on suicide severity in suicide attempters suffering from MDD, derived from the larger clinical study [4]. Results: Chronic restrain stress caused a body weight decrease in both CYP2C19 humanized and control mice (Time F4,75 =8.068, p = 0.007); however, this decrease was more pronounced in the mutants compared to controls (Genotype F4,75 =10.660, p < 0.001) during the first (Fisher’s LSD post hoc test p = 0.048) and the second week (Fisher’s LSD post hoc test p = 0.031) of stress exposure. Immobility time in the first exposure to the forced swim test was increased in the CYP2C19 humanized mice compared to controls (t46 =2.557, p = 0.010). In daily repetitive forced swim test, acute 10 mg/kg citalopram treatment 30 minutes prior to the fifth consecutive day of testing specifically reversed immobility time in mutants (Genotype∗Treatment F4,75 =6.886, p = 0.013; Fisher’s LSD post hoc test p = 0.009). Treatment with sub-anesthetic dose of ketamine (10 mg/kg) 30 minutes prior to the forced swim test on the fifth consecutive day of testing reduced the immobility time in both mutant and control mice (Treatment F4,75 =4.575, p = 0.042). Bdnf expression was lower in mutant HC compared to controls after thirty minutes of the acute restrain stress exposure (t10 =2.558, p = 0.027); this difference was no longer observed after thirty minutes of recovery from the stress. We found a significant positive association between suicide severity and CYP2C19 enzymatic capacity in MDD patients, measured by objective circumstances score on Beck’s suicide intent scale (X22,206 =8.655; p = 0.012). Conclusions: Transgenic mice with CYP2C19 expression in developing brain are more sensitive to stress and they show antidepressant-sensitive stress-induced despair-like behavior. In addition, MDD patients carrying genotypes connected with increased CYP2C19 enzymatic capacity show more severe suicide attempts. References [1] Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: Pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 2007 Dec;116(3):496–526. [2] Sim SC, Nordin L, Andersson TM, Virding S, Olsson M, Pedersen NL, Ingelman-Sundberg M. Association between CYP2C19 polymorphism and depressive symptoms. Am J Med Genet B Neuropsychiatr Genet 2010 Sep;153B(6):1160−6. [3] Persson A, Sim SC, Virding S, Onishchenko N, Schulte G, IngelmanSundberg M. Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene. Mol Psychiatry 2014 Jun;19(6):733−41. [4] Pe˜nas-Lled´o E, Guillaume S, Naranjo ME, Delgado A, Jaussent I, Blasco-Fontecilla H, Courtet P, Llerena A. A combined high CYP2D6CYP2C19 metabolic capacity is associated with the severity of suicide attempt as measured by objective circumstances. Pharmacogenomics J. 2015 Apr;15(2):172−6.
P.4.a.004 Fear extinction deficits and BDNF dysregulation in mice with full 5-HT2C receptor editing: a model for post-traumatic stress disorders? M. Regue1 ° , C. Poilbout1 , L. Lanfumey1 , R. Mongeau2 1 INSERM U894, CPN, Paris, France; 2 Universit´ e Paris Descartes − EA4475, Pharmacology department, Paris, France Purpose of the study: Post-traumatic stress disorder (PTSD) is a major anxiety disorder caused by exposure to a strong psychological trauma, and for which, until now, no pharmacological treatment has demonstrated a wide efficacy. PTSD appears to involve, at least in part, fear memory extinction deficits and fear generalization [1]. We recently demonstrated that a dysregulation in serotonin 2C receptor (5-HT2CR) editing induced anxiety-like disorders, and mice expressing only the fully edited VGV isoform of the 5-HT2CR (VGV mice) displayed increased fear behaviors [2]. Moreover, it has been reported that 5-HT2CR blockade or deletion can alter BDNF expression [3],a neurotrophic factor known to regulate cortical, hippocampal and amygdala-dependent memory, and which has also been proposed to play a central role in the mechanisms underlying PTSD [4]. In this context, we studied VGV mice to further analyze the pathophysiology of PTSD and to determine whether these mice could be used as a model to design new pharmacological strategies. Methods used: Wild-type (WT) or VGV adult (10−13 weekold) male C57Bl/6 mice were used to assess locomotor activity (rotarod, running wheel), anxiety-like (openfield, elevated plus maze) and fear-related behaviors (fear conditioning). In addition, WT and VGV mice received either paroxetine (delivered in drinking water; ~7 mg/kg/day x28 days) or tap water. At the end of the treatment, fear conditioning (6 sounds (30 s, 85 dB) paired with 6 footshocks (2 s, 0.5 mA)) was conducted to evaluate fear extinction (induced by 40 exposures to the same sound). Finally, brains from both na¨ıve and treated mice were dissected for qRTPCR analyses of Bdnf and neuroplasticity gene-related expression. Data were analyzed using Student’s t-test, one-way or two-way ANOVAs and Bonferroni multiple comparisons post-hoc test. Results: Behavioral data showed that VGV mice displayed locomotor activity deficit together with an anxiogenic phenotype. In addition, they exhibited greater fear expression during training, extensive fear extinction deficits and context generalization in the fear conditioning paradigm (% of time spent freezing during fear extinction: WT: 26.44±4.61% and VGV: 84.8±2.97%). In VGV mice, a deficit in Bdnf exon IV mRNA expression in both the hippocampus (−0.43±0.07) and the prefrontal cortex (−0.33±0.06) was observed in VGV compared to WT mice (p < 0.0001). After the 24 h wash-out period, chronic paroxetine induced a withdrawal effect that unfortunately impaired fear extinction process in WT mice. Nevertheless, it partially reversed the context generalization occurring in VGV mice (quantified by the % of time spent freezing during the baseline period of the test, VGV Vehicle: 39±7.89%, Paroxetine-treated VGV: 16±3.30%, VGV Vehicle vs VGV Paroxetine p < 0.001). Conclusion: Our data suggest that VGV mice displayed behavioral modifications in fear conditioning that are consistent with PTSD symptoms. Bdnf mRNA expression dysregulation in fearrelated structures could, at least partially, reflect an alteration in the activation of the fear circuitry in VGV mice. These results provides further evidence that BDNF may be a factor underlying PTSD pathogenesis and indicates that VGV mice could be a