The PAW test: An animal model for neuroleptic drugs which fulfils the criteria for pharmacological isomorphism

doi:10.1016/0024-3205(88)90551-6

Life Sciences

Volume 42, Issue 12, 1988, Pages 1205-1213

https://doi.org/10.1016/0024-3205(88)90551-6 Get rights and content

Abstract

Recently we have developed an animal model which could discriminate between classical and atypical neuroleptic drugs: the PAW TEST. This test measures the ability of rats to spontaneously withdraw its fore- and hindlimbs. It was found that the ability of drugs to affect the rat's forelimb retraction time was associated with the liability of the drug to induce so-called extra-pyramidal side-effects in man. Likewise the ability of drugs to affect the rat's hindlimb retraction time was associated with the antipsychotic efficacy of the drug. These data open the perspective that the forelimb retraction time (FRT) is an animal analogue of parkinsonian side-effects, and that the hindlimb retraction time (HRT) is an animal analogue of antipsychotic effects. In the present series of experiments we further evaluated the validity of these notions by applying the criteria of “pharmacological isomorphism” as proposed by Matthysse (1). Thus HRT had to fulfil the criteria of pharmacological isomorphism for the therapeutic effects of neuroleptics, whereas FRT had to fulfil these criteria for the parkinsonian side-effects. The results of the present study show that both FRT and HRT met these criteria. Thus both classical and atypical neuroleptics were effective in prolonging HRT, whereas only the classical neuroleptics prolonged FRT (criterion 1); the non-neuroleptic phenothiazine promethazine (as well as the narcotic morphine, the muscle relaxant diazepam and the antidepressant desipramine) were ineffective in this respect (criterion 2); the acetylcholinergic antagonist scopolamine blocked the FRT, but not the HRT (criterion 3); chronic neuroleptic treatment reduced the FRT, but not the HRT (criterion 4). In conclusion the paw test, an animal model for testing antipsychotic drugs, was found to fulfil the criteria for “pharmacological isomorphism”. Although the exact mechanism underlying the paw test is as yet unknown, the present data improve its validity as an animal model.

References (24)

J. Arnt
Europ. J. Pharmacol.
(1983)
M. Schwarz et al.
Europ. J. Pharmacol.
(1983)
P. Wand et al.
Europ. J. Pharmacol.
(1973)
E. Richelson et al.
Europ. J. Pharmacol.
(1984)
A. Dimascio et al.
Psychosomatics
(1970)
B. Ellenbroek et al.
Brain Res.
(1985)
S. Matthysse
W. McKinney et al.
Arch. Gen. Psychiatry
(1969)
B. Ellenbroek et al.
Psychopharmacol.
(1987)
M. Vrijmoed-De Vries et al.
Psychopharmacol.
(1987)

S. Siegel

Nonparametric statistics for the behavioral sciences

(1956)

A. Sayers et al.

Cited by (47)

Nose-to-brain delivery of paliperidone palmitate poloxamer-guar gum nanogel: Formulation, optimization and pharmacological studies in rats
2023, Annales Pharmaceutiques Francaises
Citation Excerpt :
Thus, demonstrating the absence of EPSs of the PPD nanoformulations. Previous studies have reported [60] the association of latency in FRT as side effects of treatment of Parkinson's disease, whereas latency in HRT can be corroborated with antipsychotic effects. Thus, a prolonged HRT in the treated groups indicates the antipsychotic potential of the PPD intranasal nanoformulations.
Oral delivery of paliperidone palmitate (PPD), a potent antipsychotic agent, has been reported with a potential risk of very serious drug-induced adverse events such as tachycardia, hyperprolactinemia, sexual dysfunction, and neutropenia. Alternatively, the potential of nasal delivery has also been explored to treat CNS complications by delivering the medicines directly to the brain bypassing the blood-brain barrier. Hence, the objectives of current work were to formulate, design, optimize, and investigate the therapeutic potency of PPD-loaded intranasal in-situ gel (PPGISG) in the treatment of schizophrenia. PPD-nanoemulsion (PNE) was fabricated using water titration technique, was further optimized via Box-Behnken design. Furthermore, the optimized PNE was evaluated for parameters such as globule size, polydispersity index, zeta potential, and % entrapment efficiency were found to be 21.44 ± 1.58 nm, 0.268 ± 0.02, -25.56 ± 1.6 mV, and 99.89 ± 0.25%, respectively. PNE was further converted to PPGISG utilizing two polymers, poloxamer, and guar gum. Simultaneously, ex-vivo permeation for PNE, PPGISG, and PPD-suspension was found to be 211.40 ± 4.8, 297.89 ± 3.9 and 98.66 ± 1.6 μg/cm², respectively. While PPGISG nanoparticles showed 1.58 and 5.65-folds more J_ss than PNE and PPD-suspension. Behavioral studies confirmed that no extrapyramidal symptoms were observed in experimental animals post intranasal administration. Finally, the outcomes of the in-vivo hemato-compatibility study proved that intranasal formulation did not cause any alteration in leukocytes, RBCs, and neutrophils count. Therefore, intranasal delivery of PPGISG can be considered a novel tool for the safe delivery of PPD in schizophrenic patients.
L’administration par voie orale du palmitate de palipéridone (PPD), un puissant agent antipsychotique, a été signalée avec un risque potentiel d’effets indésirables très graves induits par le médicament, tels que tachycardie, hyperprolactinémie, dysfonctionnement sexuel et neutropénie. Par ailleurs, le potentiel de l’administration nasale a également été exploré pour traiter les complications du SNC en délivrant les médicaments directement au cerveau en contournant la barrière hémato-encéphalique. Les objectifs du présent travail étaient donc de formuler, concevoir, optimiser et étudier le pouvoir thérapeutique du gel intranasal in situ chargé de PPD (PPGISG) dans le traitement de la schizophrénie. La nano-émulsion de PPD (PNE) a été fabriquée à l’aide de la technique de titrage de l’eau, puis optimisée par la méthode de Box-Behnken. En outre, la PNE optimisée a été évaluée pour des paramètres tels que la taille des globules, l’indice de polydispersité, le potentiel zêta et le pourcentage d’efficacité de piégeage, qui se sont révélés être respectivement de 21,44 ± 1,58 nm, 0,268 ± 0,02, −25,56 ± 1,6 mV et 99,89 ± 0,25 %. Le PNE a ensuite été converti en PPGISG en utilisant deux polymères, le poloxamer et la gomme de guar. Simultanément, la perméation ex-vivo de la suspension de PNE, PPGISG et PPD s’est avérée être de 211,40 ± 4,8, 297,89 ± 3,9 et 98,66 ± 1,6 μg/cm², respectivement. Alors que les nanoparticules de PPGISG ont montré une Jss 1,58 et 5,65 fois supérieure à celle de la PNE et de la suspension de PPD. Des études comportementales ont confirmé qu’aucun symptôme extrapyramidal n’a été observé chez les animaux de laboratoire après l’administration intranasale. Enfin, les résultats de l’étude d’hémato-compatibilité in-vivo ont prouvé que la formulation intranasale ne provoquait aucune altération du nombre de leucocytes, de GR et de neutrophiles. Par conséquent, l’administration intranasale de PPGISG peut être considérée comme un nouvel outil pour l’administration sûre de PPD chez les patients schizophrènes.
A window into the brain: Tools to assess pre-clinical efficacy of biomaterials-based therapies on central nervous system disorders
2019, Advanced Drug Delivery Reviews
Therapeutic conveyance into the brain is a cardinal requirement for treatment of diverse central nervous system (CNS) disorders and associated pathophysiology. Effectual shielding of the brain by the blood-brain barrier (BBB) sieves out major proportion of therapeutics with the exception of small lipophilic molecules. Various nano-delivery systems (NDS) provide an effective solution around this obstacle owing to their small size and targeting properties. To date, these systems have been used for several pre-clinical disease models including glioma, neurodegenerative diseases and psychotic disorders. An efficacy screen for these systems involves a test battery designed to probe into the multiple facets of therapeutic delivery. Despite their wide application in redressing various disease targets, the efficacy evaluation strategies for all can be broadly grouped into four modalities, namely: histological, bio-imaging, molecular and behavioural. This review presents a comprehensive insight into all of these modalities along with their strengths and weaknesses as well as perspectives on an ideal design for a panel of tests to screen brain nano-delivery systems.
Lurasidone-β-cyclodextrin complexes: Physicochemical characterization and comparison of their antidepressant, antipsychotic activities against that of self microemulsifying formulation
2018, Journal of Molecular Structure
Citation Excerpt :
The Paw test (PT) measures increase in forelimbs and hind limbs retraction time (FRT and HRT respectively) in rats. The increase in HRT is related with antipsychotic potential whereas increase in FRT is linked with its potential to induce extrapyramidal side effects [22,23]. Self microemulsifying drug delivery system (SMEDDS) and complexation with β-cyclodextrin (BCD) are commonly used techniques for solubility enhancement.
Lurasidone hydrochloride (LHD) is an atypical antipsychotic drug has poor aqueous solubility and low bioavailability (9–19%). This study describes effect of different methods of complex formation with β-cyclodextrin (BCD) on enhancement of dissolution and on antidepressant, antipsychotic effects of LHD. Other purpose of this study is to compare pharmacodynamic effects of complexes with that of self microemulsifying drug delivery system of LHD (SMEDDS).
Inclusion complexes (IC) of LHD and BCD were prepared by physical mixing (PM), kneading (KN) and spray drying (SD) in a 1:1 M ratio. These complexes were characterized by different techniques. KN and SD showing enhancement in dissolution, were compared with SMEDDS using Forced swim test (FST) and Tail suspension test (TST) for antidepressant action and Paw test for antipsychotic activity.
Characterization of complexes confirmed interaction between LHD and BCD. Enhancement in dissolution is seen in following order SD > KN > PM > LHD. In all three animal models, SD, KN and SMEDDS showed statistically significant effect (p < .05) than drug alone showing enhancement in bioavailability.
Complexation of LHD with BCD enhances dissolution which reflected in improvement of antidepressant and antipsychotic activity of drug. Solubility enhancement methods like complexation and self microemulsion improves pharmacodynamic activities of drug. Improvement of pharmacodynamic effect is seen in order, SD ≥ SMEDDS ≥ KN > LHD.
Evaluation of the behavioral and pharmacokinetic profile of SYA013, a homopiperazine analog of haloperidol in rats
2012, Pharmacology Biochemistry and Behavior
SYA013, a homopiperazine analog of haloperidol, was further evaluated for antipsychotic potential using additional animal models. Previously, SYA013 was tested in mice with an antipsychotic screening model in which it inhibited apomorphine induced climbing behavior, indicating antagonism of the dopaminergic system and the potential for use in the treatment of schizophrenia. In this study, SYA013 was shown to inhibit both d-amphetamine-induced locomotor activity in rats and conditioned avoidance response (CAR) in rats in a dose dependent manner and in the case of CAR, without producing any escape failure responses (EFRs), two tests predictive of antipsychotic action. The selective 5HT_1A antagonist WAY100,635 was used to determine if binding of SYA013 to the 5HT_1A receptor contributed to suppression of CAR. The results indicated that 0.63 mg/kg WAY100,635 did not have a significant effect on the inhibition of CAR by SYA013. Pharmacokinetic parameters in brain and plasma were determined for SYA013. A log brain/plasma concentration ratio at a t_max of 1.48 suggests that SYA013 readily crosses the blood brain barrier (BBB).
The hypothesis that binding of SYA013 to the 5HT_1A receptor contributed to the lack of significant catalepsy was investigated using the 5HT_1A antagonist WAY100,635. The results of acute and semi-chronic tests suggest that binding to the 5HT_1A receptor alone did not significantly account for the lack of catalepsy. Lack of catalepsy was preserved after the semi-chronic challenge with SYA013. These tests further indicate that SYA013 has a pharmacological profile with the potential for use in the treatment of neuropsychiatric diseases. In addition, the 5HT_1A receptor does not appear to play a significant role in the pharmacological profile of SYA013.
T-type calcium channel antagonism produces antipsychotic-like effects and reduces stimulant-induced glutamate release in the nucleus accumbens of rats
2012, Neuropharmacology
Citation Excerpt :
TTA-A2 and olanzapine were given 60 and 30 min prior to CAR testing, respectively. In order to examine the cataleptic potential of T-type antagonism, Wistar Hannover rats were given TTT-A2 (1–40 mg/kg) or haloperidol (0.15–2.4 mg/kg) 60 min before being evaluated on the paw test (Ellenbroek and Cools, 1988; Ellenbroek et al., 1987). The paw test apparatus consisted of a rectangular platform with four holes in which the hindlimbs and forelimbs of the rat could be gently placed through.
T-type calcium channels are important in burst firing and expressed in brain regions implicated in schizophrenia. Therefore, we examined the effects of novel selective T-type calcium channel antagonists in preclinical assays predictive of antipsychotic-like activity. TTA-A2 blocked the psychostimulant effects of amphetamine and MK-801 and decreased conditioned avoidance responding. These effects appeared mechanism based, rather than compound specific, as two structurally dissimilar T-type antagonists also reduced amphetamine-induced psychomotor activity. Importantly, the ability to reduce amphetamine’s effects was maintained following 20 days pre-treatment with TTA-A2. To explore the neural substrates mediating the observed behavioral effects, we examined the influence of TTA-A2 on amphetamine-induced c-fos expression as well as basal and stimulant-evoked dopamine and glutamate release in the nucleus accumbens. TTA-A2 decreased amphetamine-induced c-fos expression as well as MK-801-induced, but not basal, glutamate levels in the nucleus accumbens. Basal, amphetamine- and MK-801-induced dopamine efflux was altered. These findings suggest that T-type calcium channel antagonism could represent a novel mechanism for treating schizophrenia.
This article is part of a Special Issue entitled ‘Schizophrenia’.
Characterization of motor, depressive-like and neurochemical alterations induced by a short-term rotenone administration
2012, Pharmacological Reports
Rotenone exposure in rodents provides an interesting model for studying mechanisms of toxin-induced dopaminergic neuronal injury. However, several aspects remain unclear regarding the effects and the accuracy of rotenone as an animal model of Parkinson’s disease (PD). In this study, we investigated the motor and depressive-like behaviors associated to neurochemical alterations induced by a novel protocol of rotenone administration.
In the first experiment, we adopted the paw test to characterize an effective dose of rotenone able to promote nigrostriatal toxicity. In the second experiment, control and rotenone 2.5 mg/kg groups were injected (ip) for 10 consecutive days.
This test indicated that intraperitonial (ip) rotenone at 2.5 and 5.0 mg/kg promoted a significant neurotoxicity to striatum and nucleus accumbens. However, only 2.5 mg/kg of rotenone was associated to a negligible mortality rate. Open-field tests were conducted on 1, 7, 14 and 21 day after the last day of treatment and showed an important locomotor impairment, confined to 1 and 7 day. Besides, rotenone affected dopamine levels and increased its turnover in the striatum. Modified forced swim test (performed on 22 day) and sucrose preference test (performed on 14 and 21 day) demonstrated that rotenone produced impairments in the swimming and immobility. In parallel, increments in the serotonin and noradrenaline turnovers were observed in the striatum and hippocampus of the rotenone group.
These data suggest important participations of serotonin and noradrenaline in depressive-like behaviors induced by rotenone. Thus, it is proposed that the current rotenone protocol provides an improvement regarding the existing rotenone models of PD.

View all citing articles on Scopus

View full text

The PAW test: An animal model for neuroleptic drugs which fulfils the criteria for pharmacological isomorphism

Abstract

Europ. J. Pharmacol.

Europ. J. Pharmacol.

Europ. J. Pharmacol.

Europ. J. Pharmacol.

Psychosomatics

Brain Res.

Arch. Gen. Psychiatry

Psychopharmacol.

Psychopharmacol.

Nonparametric statistics for the behavioral sciences