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Boulogne-Billancourt, France

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

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. Source

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

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. Source

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

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. Source

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