Porsolt

Saint-Martin-Vésubie, France
Saint-Martin-Vésubie, France

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Castagne V.,Porsolt | Wolinsky T.,Porsolt | Quinn L.,Porsolt | Virley D.,Porsolt
Pharmacology Biochemistry and Behavior | Year: 2012

Preclinical testing requires rapid and reliable evaluation of the main in vivo effects of novel test substances usually in rodents. Nevertheless, the techniques primarily used up to now involve either automated measurement of motor activity or direct observation of behavioral effects by extensively trained investigators. The advantages of these approaches are respectively high-throughput and comprehensive behavioral assessment. Nevertheless, motor activity is only one aspect of animal behavior and it cannot predict the full neurobehavioral profile of a substance, whereas direct observation is time-consuming. There is thus a need for novel approaches that combine the advantages of both automatic detection and comprehensive behavioral analysis. In the present study, we used the LABORAS™ system to analyze motor and non-motor behavior in rats administered various stimulant substances with or without known psychotomimetic properties or abuse liability (amphetamine, cocaine dizocilpine (MK-801), ketamine, modafinil and nicotine). The data show that LABORAS™ clearly detects the stimulating effects on motor behaviors of amphetamine, cocaine, dizocilpine and ketamine in a dose- and time-dependent manner. Differential effects of these test substances on non-motor behaviors, such as grooming, eating and drinking could also be detected. Nicotine displayed only slight stimulating effects on locomotion, whereas modafinil was virtually without effect on the behaviors evaluated by the system. These data with different stimulant substances suggest that LABORAS™ presents an advantage over classical methods performing automated measurements restricted to locomotion. Furthermore, the procedure is considerably more rapid than behavioral observation procedures. Characterization of the behavioral profile of test substances using LABORAS™ should therefore accelerate preclinical studies. In addition, the multi-faceted parameters measured by LABORAS™ permit a more detailed comparison of the behavioral profiles of novel substances with standard reference substances, thereby providing important indicators for orienting further substance evaluation and supporting drug development. © 2012 Elsevier Inc.


Hernier A.M.,Porsolt | Froger-Colleaux C.,Porsolt | Castagne V.,Porsolt
Journal of Pharmacological and Toxicological Methods | Year: 2016

Introduction: The guidelines from different agencies do not include studies on cognitive functions as part of safety pharmacology. This is unfortunate as it seems important to verify that drugs entering into the central nervous system (CNS) are devoid of detrimental effects on cognition. Our aim is to show examples on how an evaluation of unwanted effects of drugs on cognitive functions may be included in preclinical studies. Rather than a review of the scientific context, the present text is an appeal for a wider consideration of cognition as a safety pharmacology endpoint. Methods: The following procedures provide an index of the ability of substances to induce cognitive deficits in rodents. In the passive avoidance (PA) test, rats receiving an electric shock show on a later occasion an avoidance of the shock-associated environment. In the social recognition (SR) test, rats recognize familiar congeners. In the Morris water maze (MWM) test, rats placed into a tank containing water learn to find an invisible escape platform using extra-maze visual cues. In the delayed alternation (DA) test, rats placed in a Skinner box learn to alternate their pressing behavior between two levers in order to obtain food rewards. In the operant reversal (OR) test, rats adapt their behavior following a change of the reinforcement rule. Results: Standard reference agents were used to confirm that the different assays were able to detect pharmacologically induced cognitive impairments. Diazepam decreased associative memory performances in the PA test. MK-801-induced memory deficits in SR. Haloperidol increased escape latencies in the MWM test. Scopolamine decreased the number of correct responses in the DA test, and nicotine decreased the number of correct responses in the OR test. The relationship between the doses administered and the effects observed was also evaluated. Discussion: Cognitive assays may provide utility in determining potential undesirable effects or discharging perceived risks with novel CNS drugs under development. © 2015 Elsevier Inc.


Froger-Colleaux C.,Porsolt | Rompion S.,Porsolt | Guillaume P.,Porsolt | Porsolt R.D.,Porsolt | And 2 more authors.
Journal of Pharmacological and Toxicological Methods | Year: 2011

Introduction: The procedures used to assess withdrawal must be sensitive and widely applicable, i.e. not specific to any particular drug class. Furthermore, the measurements should not be affected by repeat testing. Methods: We have used implanted telemetry devices to continuously follow body temperature, locomotor activity (LMA), heart rate (HR) and mean arterial blood pressure (mean ABP) in addition to food intake and body weight gain over 20. days of treatment and 8. days of withdrawal. The effects of morphine (32 and 64. mg/kg p.o., b.i.d.) and chlordiazepoxide (16, 32 and 64. mg/kg p.o., b.i.d.) were studied in rats. Results: The results show that during the treatment phase chronic morphine reduced food intake and body weight gain, increased body temperature, HR, mean ABP and LMA. These effects continued over the 20. days of treatment. In contrast, chlordiazepoxide slightly increased food intake and body weight gain throughout the treatment period. It also decreased body temperature and LMA but increased HR and mean ABP after the first few administrations but these effects disappeared over the 20. days of treatment. Following discontinuation, both morphine- and chlordiazepoxide-treated rats showed a dose-related decrease in food intake and loss of weight on days 2 and 3 of discontinuation. Morphine discontinuation also induced a nocturnal hypothermia and a diurnal hypertension (i.e. during the light phase) which lasted for 4-5. days and also moderate diurnal increases in locomotor activity and heart rate over the first 3. days of discontinuation. Chlordiazepoxide discontinuation induced small increases in telemetry parameters some of which, such as the effect on locomotor activity, lasted for more than 5. days. The intensity and duration of effects for both substances were broadly dose-related. Discussion: These data show that telemetry can increase the sensitivity of withdrawal experiments to changes that might otherwise be missed and allows a better definition of the time-course of withdrawal effects. This technique is therefore useful as part of safety pharmacology abuse liability evaluation of novel test substances across a broad range of pharmacological and therapeutic classes. © 2011 Elsevier Inc.


PubMed | Porsolt
Type: Journal Article | Journal: Journal of pharmacological and toxicological methods | Year: 2011

The procedures used to assess withdrawal must be sensitive and widely applicable, i.e. not specific to any particular drug class. Furthermore, the measurements should not be affected by repeat testing.We have used implanted telemetry devices to continuously follow body temperature, locomotor activity (LMA), heart rate (HR) and mean arterial blood pressure (mean ABP) in addition to food intake and body weight gain over 20days of treatment and 8days of withdrawal. The effects of morphine (32 and 64mg/kg p.o., b.i.d.) and chlordiazepoxide (16, 32 and 64mg/kg p.o., b.i.d.) were studied in rats.The results show that during the treatment phase chronic morphine reduced food intake and body weight gain, increased body temperature, HR, mean ABP and LMA. These effects continued over the 20days of treatment. In contrast, chlordiazepoxide slightly increased food intake and body weight gain throughout the treatment period. It also decreased body temperature and LMA but increased HR and mean ABP after the first few administrations but these effects disappeared over the 20days of treatment. Following discontinuation, both morphine- and chlordiazepoxide-treated rats showed a dose-related decrease in food intake and loss of weight on days 2 and 3 of discontinuation. Morphine discontinuation also induced a nocturnal hypothermia and a diurnal hypertension (i.e. during the light phase) which lasted for 4-5days and also moderate diurnal increases in locomotor activity and heart rate over the first 3days of discontinuation. Chlordiazepoxide discontinuation induced small increases in telemetry parameters some of which, such as the effect on locomotor activity, lasted for more than 5days. The intensity and duration of effects for both substances were broadly dose-related.These data show that telemetry can increase the sensitivity of withdrawal experiments to changes that might otherwise be missed and allows a better definition of the time-course of withdrawal effects. This technique is therefore useful as part of safety pharmacology abuse liability evaluation of novel test substances across a broad range of pharmacological and therapeutic classes.


PubMed | Porsolt
Type: Journal Article | Journal: Pharmacology, biochemistry, and behavior | Year: 2012

Preclinical testing requires rapid and reliable evaluation of the main in vivo effects of novel test substances usually in rodents. Nevertheless, the techniques primarily used up to now involve either automated measurement of motor activity or direct observation of behavioral effects by extensively trained investigators. The advantages of these approaches are respectively high-throughput and comprehensive behavioral assessment. Nevertheless, motor activity is only one aspect of animal behavior and it cannot predict the full neurobehavioral profile of a substance, whereas direct observation is time-consuming. There is thus a need for novel approaches that combine the advantages of both automatic detection and comprehensive behavioral analysis. In the present study, we used the LABORAS system to analyze motor and non-motor behavior in rats administered various stimulant substances with or without known psychotomimetic properties or abuse liability (amphetamine, cocaine dizocilpine (MK-801), ketamine, modafinil and nicotine). The data show that LABORAS clearly detects the stimulating effects on motor behaviors of amphetamine, cocaine, dizocilpine and ketamine in a dose- and time-dependent manner. Differential effects of these test substances on non-motor behaviors, such as grooming, eating and drinking could also be detected. Nicotine displayed only slight stimulating effects on locomotion, whereas modafinil was virtually without effect on the behaviors evaluated by the system. These data with different stimulant substances suggest that LABORAS presents an advantage over classical methods performing automated measurements restricted to locomotion. Furthermore, the procedure is considerably more rapid than behavioral observation procedures. Characterization of the behavioral profile of test substances using LABORAS should therefore accelerate preclinical studies. In addition, the multi-faceted parameters measured by LABORAS permit a more detailed comparison of the behavioral profiles of novel substances with standard reference substances, thereby providing important indicators for orienting further substance evaluation and supporting drug development.


PubMed | Porsolt
Type: | Journal: Journal of pharmacological and toxicological methods | Year: 2016

The guidelines from different agencies do not include studies on cognitive functions as part of safety pharmacology. This is unfortunate as it seems important to verify that drugs entering into the central nervous system (CNS) are devoid of detrimental effects on cognition. Our aim is to show examples on how an evaluation of unwanted effects of drugs on cognitive functions may be included in preclinical studies. Rather than a review of the scientific context, the present text is an appeal for a wider consideration of cognition as a safety pharmacology endpoint.The following procedures provide an index of the ability of substances to induce cognitive deficits in rodents. In the passive avoidance (PA) test, rats receiving an electric shock show on a later occasion an avoidance of the shock-associated environment. In the social recognition (SR) test, rats recognize familiar congeners. In the Morris water maze (MWM) test, rats placed into a tank containing water learn to find an invisible escape platform using extra-maze visual cues. In the delayed alternation (DA) test, rats placed in a Skinner box learn to alternate their pressing behavior between two levers in order to obtain food rewards. In the operant reversal (OR) test, rats adapt their behavior following a change of the reinforcement rule.Standard reference agents were used to confirm that the different assays were able to detect pharmacologically induced cognitive impairments. Diazepam decreased associative memory performances in the PA test. MK-801-induced memory deficits in SR. Haloperidol increased escape latencies in the MWM test. Scopolamine decreased the number of correct responses in the DA test, and nicotine decreased the number of correct responses in the OR test. The relationship between the doses administered and the effects observed was also evaluated.Cognitive assays may provide utility in determining potential undesirable effects or discharging perceived risks with novel CNS drugs under development.


PubMed | Porsolt
Type: Comparative Study | Journal: Journal of pharmacological and toxicological methods | Year: 2012

In the current ICH S7B guideline, in vitro evaluation of proarrhythmic liability is limited to the risk of QT interval prolongation, whilst the effect of new chemical entities on cardiac conductivity is often overlooked. The aim of this work was to compare the effects of the sodium channel blocker, lidocaine in three in vitro safety pharmacology models: hNa(v)1.5 channel test, atrial action potential (AP) and Purkinje fiber AP and to identify the most sensitive model for detecting cardiac conduction slowing.Whole-cell patch-clamp methods were used to record the sodium current (I(Na)) encoded by hNa(v)1.5 in stably transfected HEK293 cells at ambient temperature. Transmembrane APs were recorded in rabbit Purkinje fibers and rabbit and guinea-pig left stimulated atria at physiological temperature. Parameters involved in depolarization or repolarization were reported.Lidocaine (from 10 to 1000 M) decreased the amplitude of I(Na) (IC(50): 25637 M) in a concentration-dependent manner. In the Purkinje fiber assay, lidocaine (10, 30 and 100 M) had no effects on maximal upstroke velocity (Vmax), but shortened AP duration at 90% repolarization (APD(90)). At 30 and 100 M, lidocaine also increased AP triangulation. In guinea-pig atria, lidocaine decreased Vmax starting from 30 M and conduction velocity (CV) at 100 M, but had no effects on other parameters. In rabbit atria, lidocaine decreased Vmax and CV at 100 M without affecting APD(90). The effects of 100 M lidocaine on Vmax and CV were more marked in rabbit than in guinea-pig atria.Rabbit atria are more sensitive than rabbit Purkinje fibers or guinea-pig atria for detecting lidocaine-induced cardiac conduction slowing. These data suggest that isolated rabbit atria in addition to the hNa(v)1.5 channel assay could be relevant models to predict drug-induced conduction slowing.


PubMed | Porsolt
Type: Journal Article | Journal: Regulatory toxicology and pharmacology : RTP | Year: 2013

Collection of formulation samples is required for GLP in vitro studies to check the exposure of the test system and allow reliable determinations of safety margins. In vitro studies conducted in-house were investigated to evaluate problems of solubility, stability and adsorption of the formulations. Terfenadine was used as reference substance to illustrate the purpose. Lowered target concentrations of test substances in in vitro studies can be attributed to the solubility limitation in the superfusion medium, the low stability under frozen conditions (24% of the final solutions stable at -20 C) and/or the adsorption on the superfusion tubing (30% of the studies). Terfenadine also showed a limited solubility (measured concentrations ranging from 0.597 M to 0.833 M instead of 1 M) and a loss of substance through the superfusion tubing from -30.2% to -39.2% with dimethylsulfoxide, ethanol or methanol. Terfenadine solubility was improved with 2-hydroxypropyl--cyclodextrin, no adsorption was observed, but its capacity to block the hERG channel was decreased. It is recommended to determine the substance solubility in appropriate buffers, to evaluate possible adsorption during method validation (formulation samples collected after superfusion), and to prepare fresh formulation each testing day with immediate analysis in absence of stability data. This strategy clearly favors single-site as opposed to multi-site studies.

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