MEET US AT ECNP CONGRESS 2019

Porsolt will be present at the 31th European College of Neuropsychopharmacology congress 

Copenhagen | Denmark

September 7th - 10th, 2019

Our experts will presenting these posters:

> Presentation number: P.065

The dual-hit model of schizophrenia-like behavior in the rat: effects of antipsychotics on locomotor hyperactivity and social recognition deficits

V. Castagné1, A.M. Hernier1, A. Quentel1, A.M. Hamieh1.
1Porsolt SAS, Pharmacology, Le Genest-saint-isle, France.

Background:
Schizophrenia is a severe mental disorder characterized by the presence of symptoms usually grouped into three categories: positive, negative and cognitive signs. Many acute and sub-chronic animal models have been established and used in preclinical studies related to schizophrenia. In particular, phencyclidine (PCP) is used to induce schizophrenia-like deficits in rodents. The construct validity of some models has been criticized because they do not take into consideration the neurodevelopmental origin of schizophrenia given that PCP is administered at adult age [1]. A second criticism is the variable duration of the observed behavioral deficits which complicates the interpretation of the results. In this study, we focused on the neonatal PCP exposure and post-weaning social isolation model, aiming to induce schizophrenia-like symptoms in the rat. This dual-hit model, which combines an adverse early-life challenge followed by stress during adolescence, aims to induce at adulthood enduring behavioral deficits related to some signs of schizophrenia [2].

Objective:
The aim of this study was to firstly characterize the behavioral changes occurring longitudinally in the model at different ages and then to evaluate the effects of chronic treatment with clozapine and aripiprazole on these behaviors.

Methods:
Male Wistar rat pups were treated with PCP (10mg/kg s.c.) on postnatal days (PND) 7, 9 and 11. Control rats were injected with physiological saline. On PND 24 all pups were weaned, neonatal PCP-treated rat pups were placed in individual cages for social isolation for the rest of the study while control rats were group housed. For the behavioral part of the study, rats were assessed at 2, 3 and 6 months old using behavioral tasks evaluating locomotor activity and social recognition. The pharmacological study was performed at the age of 2 months. The performances of the different groups of rats were compared using unpaired Student’s t tests.

Results:
Neonatal PCP-treated and post-weaning social isolated (PCP-PWSI) rats displayed locomotor hyperactivity and social recognition impairment persisting for at least 6 months (P < 0.001 and P < 0.01, respectively). Both acute and chronic treatment with aripiprazole and clozapine at the dose of 3mg/kg normalized locomotor activity (P < 0.05 and P < 0.001, respectively). Likewise, chronic treatment with clozapine was able to attenuate social recognition impairment in PCP-PWSI rats (P < 0.05). Acute treatment with antipsychotics did not affect social recognition deficits.

Conclusion:
Our findings reveal that the dual-hit neonatal PCP and post-weaning social isolation model is associated with the presence of enduring hyperactivity and social recognition that are relevant to positive symptoms and social behavior deficits respectively, affecting schizophrenic patients. This is further confirmed with chronic treatment with clozapine normalizing the behavior of animals. These results confirm the construct and predictive validities of this model. Dual interventions at two crucial early-life neurodevelopmental stages (corresponding to the third trimester of pregnancy and adolescence in humans) lead to the persistence of chronic behavioral deficits which can be reversed by antipsychotic drugs used to treat schizophrenia in humans.

References

[1] Marcotte, E.R., Pearson, D.M., Srivastava, L.K., 2001. Animal models of schizophrenia: a critical review. Journal of Psychiatry & Neuroscience 26(5), 395–410.n

[2] Gaskin, P.L., Alexander, S.P., Fone, K.C., 2014. Neonatal phencyclidine administration and post-weaning social isolation as a dual-hit model of 'schizophrenia-like' behaviour in the rat. Psychopharmacology 231, 2533–2545.

> Presentation number: P.433

Impact of sex in three paradigms evaluating the abuse and dependence potential of New Chemical Entities

C. Froger Colleaux1, E. Sablé1, D. Babin1, Q. Rochais1, V. Castagné1.
1Porsolt SAS, Drug abuse and dependence, Le Genest Saint Isle, France.

Background:

Following the FDA guidelines January, 2017 [1], New Chemical Entities (or an active metabolite) that enters the CNS, irrespective of the therapeutic indication; need to be evaluated for Abuse potential. One of the FDA‘s recommendations for Nonclinical evaluation states that it’s appropriate to use animals of both sexes.

Objective:
The aim of this study was to evaluate the impact of sex of rats on 1) diazepam rewarding properties, 2) withdrawal symptoms following cessation of treatment with diazepam and 3) the subjective effects produced by diazepam. Amphetamine and morphine were used as positive controls in the conditioned place preference (CPP) and non-precipitated withdrawal tests, respectively.

Methods:
For the evaluation of the rewarding properties, groups of male or female Sprague Dawley (SD) rats were submitted to the CPP paradigm using a two-chambered CPP apparatus and a biased procedure. Rats were allowed to explore one side of the apparatus after an i.p. administration of drug (diazepam or amphetamine) or vehicle. Drugs were paired with the least preferred compartment. The rats were evaluated for preference for the drug-paired compartment before and after the conditioning period. For the evaluation of withdrawal signs, food intake and body weight gain of male or female SD rats were observed throughout the 20 days of treatment with diazepam or morphine and then for 8 days following the cessation of treatment. Diazepam was also evaluated for its subjective effects with groups of male or female SD rats trained to discriminate diazepam from its vehicle, using a two choice Drug Discrimination operant task under a FR10 schedule of food reinforcement. Once performances stabilized, several doses of diazepam were substituted for the training dose.

Results:
CPP was well established for male and female rats with amphetamine at 2 mg/kg i.p. (p < 0.001 in both sexes) whereas only male rats developed significant CPP following diazepam 2.5 mg/kg i.p. administration (p < 0.001). Cessation of morphine (64 mg/kg p.o. twice daily) treatment after 20 days of administration induced significant decreases in body weight and in food consumption in both male (p < 0.001 and p < 0.001; respectively) and female rats (p < 0.001 and p < 0.001, respectively). Whereas cessation of diazepam (40 mg/kg p.o.) only induced a decrease in food consumption in male (p < 0.05) and female rats (p < 0.001) without affecting the body weight. In the Drug Discrimination experiment, diazepam over the dose range 0.02 – 4 mg/kg i.p. induced a dose-dependent generalization to the training dose of 2 mg/kg i.p. in both male and female rats.

Conclusion:
Our findings suggest no marked differences related to the sex of rats in the 3 paradigms used. Nevertheless, these data tend to indicate that male Sprague Dawley rats are more prone to develop CPP and display more marked withdrawal symptoms following treatment with diazepam. Taking into account the 3R’s principle in preclinical research, further studies evaluating additional paradigms such as intravenous self-administration would be useful to support the new guidelines.

References

[1] FDA Assessment of Abuse Potential of Drugs, 2017. Guidance for Industry.

 

UP COMING EVENTS

NEWS ARCHIVES

25/06/2019 Visit us at SPS 2019 READ THIS NEWS 25/06/2019 Visit us at Eurotox 2019 READ THIS NEWS 25/06/2019 Meet us at EFIC 2019 READ THIS NEWS 24/06/2019 Meet us at AFSTAL meeting 2019 READ THIS NEWS 13/06/2019 Meet us at CPDD / NIDA meeting READ THIS NEWS 23/05/2019 Visit us at Bio International 2019 READ THIS NEWS 20/05/2019 Meet us at the 4th Annual Advances in Immuno-Oncology Congress READ THIS NEWS 23/04/2019 Meet us at SPIN Congress 2019 ! READ THIS NEWS 23/04/2019 Meet us at EUCAS Congress 2019 ! READ THIS NEWS 23/04/2019 Meet us at Biotrinity Congress 2019 ! READ THIS NEWS 04/03/2019 Meet us at ADPD Congress 2019 READ THIS NEWS 04/03/2019 Meet us at Bio Europe Spring Congress 2019 READ THIS NEWS 15/01/2019 Meet us at 35th Scientific Day of AFERO 2019 READ THIS NEWS 19/12/2018 Porsolt team wishes you a Merry Christmas & a Happy New Year ! READ THIS NEWS 09/08/2018 Meet us at World Congress of Pain 2018 READ THIS NEWS 09/08/2018 Visit us at EuroTox 2018 READ THIS NEWS 09/08/2018 Visit us at BIOFIT 2018 READ THIS NEWS 09/08/2018 Visit us at Society of Neuroscience 2018 READ THIS NEWS 09/08/2018 Visit us at ACTox 2018 READ THIS NEWS 09/08/2018 Visit us at Bio Europe 2018 READ THIS NEWS 09/08/2018 Meet us at ECNP Congress 2018 READ THIS NEWS 09/08/2018 Visit us at NLS Days 2018 READ THIS NEWS 09/08/2018 Meet us at ITTC 2018 - CGO READ THIS NEWS 08/08/2018 Visit us at SAFETY PHARMACOLOGY 2018 READ THIS NEWS 26/03/2018 Meet us at NIDA Forum 2018 READ THIS NEWS 26/03/2018 Meet us at WPC 2018 READ THIS NEWS 26/03/2018 Visit us at Bio International 2018 READ THIS NEWS 26/03/2018 Visit us at BIOMED 2018 READ THIS NEWS 26/03/2018 Meet us at Immuno-Oncology Congress 2018 READ THIS NEWS 26/03/2018 Meet us at Advances in neurodevelopmental & neurodegenerative disorders READ THIS NEWS 06/02/2018 Visit us at SOT 2018 READ THIS NEWS 06/02/2018 Meet us at AD/PD conference 2018 READ THIS NEWS 26/01/2018 Porsolt Catalog 2018 ! READ THIS NEWS 21/12/2017 Happy Holidays from the Porsolt Team ! READ THIS NEWS 08/11/2017 Porsolt Newsletter - November 2017 READ THIS NEWS 01/11/2017 Visit us at BIOFIT 2017 READ THIS NEWS 01/11/2017 Meet us at Genesis 2017 READ THIS NEWS 18/09/2017 Visit us at Neuroscience READ THIS NEWS 18/09/2017 Visit us at ACTox READ THIS NEWS 18/09/2017 Visit us at Bio Europe READ THIS NEWS 30/05/2017 Visit us at Bio International 2017 READ THIS NEWS 30/05/2017 Meet us at On Helix 2017 READ THIS NEWS 30/05/2017 Visit us at ECNP Congress 2017 READ THIS NEWS 30/05/2017 Visit us at EuroTox 2017 READ THIS NEWS 30/05/2017 Meet us at EFIC 2017 READ THIS NEWS 30/05/2017 Visit us at SAFETY PHARMACOLOGY 2017 READ THIS NEWS 30/05/2017 Visit us at NLS Days 2017 READ THIS NEWS 24/02/2017 Meet us at Biotrinity 2017 READ THIS NEWS 24/02/2017 Meet us at Immuno-Oncology Congress READ THIS NEWS 24/02/2017 Visit us at BioMed 2017 READ THIS NEWS 24/02/2017 Meet us at NeuroFrance 2017 READ THIS NEWS 20/01/2017 Visit us at Bio-Europe Spring 2017 READ THIS NEWS 20/01/2017 Visit us at SOT 2017 READ THIS NEWS 20/01/2017 Visit us at AD/PD conference READ THIS NEWS 01/11/2016 Meet us at Genesis 2016 READ THIS NEWS 04/09/2016 Visit us at ACTox 2016 READ THIS NEWS 03/09/2016 Visit us at Neuroscience 2016 READ THIS NEWS 02/09/2016 Visit us at Bio-Europe 2016 READ THIS NEWS 01/09/2016 Meet us at ESTIV READ THIS NEWS 16/08/2016 Visit us at Safety Pharmacology 2016 joint meeting READ THIS NEWS 16/08/2016 Meet us at the Brain Conference 2016 READ THIS NEWS 16/08/2016 Meet us at ECNP Congress READ THIS NEWS 16/08/2016 Visit us at NLS Days READ THIS NEWS 16/08/2016 Visit us at the Innovation Days READ THIS NEWS 22/06/2016 Cardiac risk assessment in human induced pluripotent stem cell derived cardiomyocytes READ THIS NEWS 01/06/2016 Meet us at ESC 2016 READ THIS NEWS 29/03/2016 Meet us at FENS 2016 READ THIS NEWS 02/03/2016 Meet us at CPDD READ THIS NEWS 02/03/2016 Meet us the Alzheimer's Disease Congress READ THIS NEWS 01/03/2016 Meet us at EPHAR 2016 READ THIS NEWS 29/02/2016 Visit us at Bio 2016 READ THIS NEWS 29/02/2016 Visit us at IATI-Biomed 2016 READ THIS NEWS 26/02/2016 Meet us at ISDN 2016 READ THIS NEWS 11/02/2016 Visit us at Bio-Europe Spring 2016 READ THIS NEWS 18/12/2015 Season's Greetings READ THIS NEWS 10/12/2015 Porsolt expands its in vitro drug discovery service capabilities with the acquisition of Fluofarma READ THIS NEWS 02/11/2015 Visit us at SOT 2016 READ THIS NEWS 28/07/2015 Meet us at Prix Galien USA 2015 READ THIS NEWS 04/06/2015 Meet us at EFIC 2015 READ THIS NEWS 02/06/2015 Meet us at ESDR Annual Meeting READ THIS NEWS 02/06/2015 Visit us at Neurosciences READ THIS NEWS 02/06/2015 Visit us at Bio Latin America READ THIS NEWS 30/05/2015 Meet us at EAACI READ THIS NEWS 15/05/2015 Meet us at EAVPT READ THIS NEWS 03/01/2011 New laboratory READ THIS NEWS