Conditioned Avoidance Response in the Development of New Antipsychotics

Wadenberg, Marie-Louise

doi:10.2174/138161210790170085

Cited by 72 publications

(70 citation statements)

References 106 publications

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“…10,36 Antipsychotics block the CAR in doses that do not interfere with escape after stimulus onset and correlate well with clinically used doses. 35 Interestingly, the percentage of striatal D2 receptor occupation required to inhibit the CAR is around 70%, similar to the threshold required for the therapeutic effect of antipsychotics in humans. 35,[37][38][39][40] In addition, this paradigm does not tend to yield false-positive results with sedative drugs (e.g., benzodiazepines), since these normally impair both the avoidance and the escape responses.…”

Section: Conditioned Avoidance Responsementioning

confidence: 89%

“…35 Interestingly, the percentage of striatal D2 receptor occupation required to inhibit the CAR is around 70%, similar to the threshold required for the therapeutic effect of antipsychotics in humans. 35,[37][38][39][40] In addition, this paradigm does not tend to yield false-positive results with sedative drugs (e.g., benzodiazepines), since these normally impair both the avoidance and the escape responses. Regarding its predictive validity, this model is reliable for identifying new drugs, in addition to being simple, quick, and low-cost.…”

Section: Conditioned Avoidance Responsementioning

confidence: 89%

“…35 In the CAR, animals are trained to avoid the occurrence of an aversive stimulation, usually an electric shock, by making a specific behavioral response in a shuttle box, such as moving to the other side of the box. 10,36 Antipsychotics block the CAR in doses that do not interfere with escape after stimulus onset and correlate well with clinically used doses.…”

Section: Conditioned Avoidance Responsementioning

confidence: 99%

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Animal models for predicting the efficacy and side effects of antipsychotic drugs

Gobira

Röpke

Aguiar

et al. 2013

Rev. Bras. Psiquiatr.

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The use of antipsychotic drugs represents an important approach for the treatment of schizophrenia. However, their efficacy is limited to certain symptoms of this disorder, and they induce serious side effects. As a result, there is a strong demand for the development of new drugs, which depends on reliable animal models for pharmacological characterization. The present review discusses the face, construct, and predictive validity of classical animal models for studying the efficacy and side effects of compounds for the treatment of schizophrenia. These models are based on the properties of antipsychotics to impair the conditioned avoidance response and reverse certain behavioral changes induced by psychotomimetic drugs, such as stereotypies, hyperlocomotion, and deficit in prepulse inhibition of the startle response. Other tests, which are not specific to schizophrenia, may predict drug effects on negative and cognitive symptoms, such as deficits in social interaction and memory impairment. Regarding motor side effects, the catalepsy test predicts the liability of a drug to induce Parkinson-like syndrome, whereas vacuous chewing movements predict the liability to induce dyskinesia after chronic treatment. Despite certain limitations, these models may contribute to the development of more safe and efficacious antipsychotic drugs.

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Section: Conditioned Avoidance Responsementioning

confidence: 89%

Section: Conditioned Avoidance Responsementioning

confidence: 89%

Section: Conditioned Avoidance Responsementioning

confidence: 99%

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Animal models for predicting the efficacy and side effects of antipsychotic drugs

Gobira

Röpke

Aguiar

et al. 2013

Rev. Bras. Psiquiatr.

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“…We evaluated the effects of HDAC inhibitors on HAL efficacy in mice using CAR. CAR paradigm is a wellestablished test for assessing the potential for antipsychotic drug efficacy in preclinical studies (Wadenberg, 2010). Both typical and atypical antipsychotics selectively suppress the avoidance response.…”

Section: Discussionmentioning

confidence: 99%

HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation

Montalvo-Ortiz

Keegan

Gallardo

et al. 2013

Neuropsychopharmacol

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Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psychopathological conditions, including psychosis and the behavioral disturbances associated with dementia. However, clinical experience suggests that these drugs may be less efficacious in the elderly individuals than in the young. Recent studies suggest that aging may be associated with epigenetic changes and that valproic acid (VPA), a histone deacetylase inhibitor, may reverse such changes. However, it is not yet known whether HDAC inhibitors can modulate age-related epigenetic changes that may impact antipsychotic drug action. In this study, we analyzed conditioned avoidance response (CAR) and c-Fos expression patterns to elucidate the effect of HDAC inhibitors VPA and entinostat (MS-275) on behavioral and molecular markers of the effects of haloperidol (HAL) in aged mice. Our results showed that HAL administration failed to suppress the avoidance response during the CAR test, suggesting an age-related decrease in drug efficacy. In addition, HAL-induced c-Fos expression in the nucleus accumbens shell and prefrontal cortex was significantly lower in aged mice as compared with young mice. Pretreatment with VPA and MS-275 significantly improved HAL effects on the CAR test in aged mice. Also, VPA and MS-275 pretreatment restored HAL-induced increases in c-Fos expression in the nucleus accumbens shell and prefrontal cortex of aged mice to levels comparable with those observed in young mice. Lastly, but most importantly, increases in c-Fos expression and HAL efficacy in the CAR test of the HAL þ VPA and HAL þ MS-275 groups were correlated with elevated histone acetylation at the c-fos promoter region in aged mice. These findings suggest that pretreatment with VPA or MS-275 increases the behavioral and molecular effects of HAL in aged mice and that these effects occur via modulation of age-related histone hypoacetylation in the nucleus accumbens shell and prefrontal cortex.

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“…In recent years, we have used the conditioned avoidance response (CAR) and phencyclidine (PCP)-induced hyperlocomotion, two models with high predictive validity for antipsychotic efficacy (Gleason and Shannon, 1997;Natesan et al, 2005;Wadenberg, 2010), to examine the long-term treatment effects of antipsychotic drugs. We employed a behavioral paradigm similar to those used for the study of psychomotor sensitization (Stewart and Badiani, 1993;Robinson et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Olanzapine Sensitization and Clozapine Tolerance: From Adolescence to Adulthood in the Conditioned Avoidance Response Model

Qiao

2012

Neuropsychopharmacol

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Disruption of conditioned avoidance response (CAR) in rodents is one trademark feature of many antipsychotic drugs. In adult rats, repeated olanzapine (OLZ) treatment causes an enhanced disruption of avoidance response (sensitization), whereas repeated clozapine (CLZ) treatment causes a decreased disruption (tolerance). The present study addressed (1) whether OLZ sensitization and CLZ tolerance can be induced in adolescent rats, and (2) the extent to which OLZ sensitization and CLZ tolerance induced in adolescence persists into adulthood. Male adolescent Sprague-Dawley rats (approximate postnatal days (BP) 43-47) were first treated with OLZ (1.0 or 2.0 mg/kg, subcutaneously (sc)) or CLZ (10 or 20 mg/kg, sc) daily for 5 consecutive days in the CAR model. They were then tested for the expression of OLZ sensitization or CLZ tolerance either in adolescence (BP 50) or after they matured into adults (BP 76 and 92) in a challenge test during which all rats were injected with either a lower dose of OLZ (0.5 mg/kg) or CLZ (5.0 mg/kg). When tested in adolescence, rats previously treated with OLZ showed a stronger inhibition of CAR than those previously treated with vehicle (ie, sensitization). In contrast, rats previously treated with CLZ showed a weaker inhibition of CAR than those previously treated with vehicle (ie, tolerance). When tested in adulthood, the OLZ sensitization was still detectable at both time points (BP 76 and 92), whereas the CLZ tolerance was only detectable on BP 76, and only manifested in the intertrial crossing. Performance in the prepulse inhibition and fear-induced 22 kHz ultrasonic vocalizations in adulthood were not altered by adolescence drug treatment. Collectively, these findings suggest that atypical antipsychotic treatment during adolescence can induce a long-term specific alteration in antipsychotic effect that persists into adulthood despite the brain maturation. As antipsychotic drugs are being increasingly used in children and adolescents in the past two decades, findings from this study are important for understanding the impacts of adolescent antipsychotic treatment on the brain and behavioral developments. This work also has implications for clinical practice involving adolescence antipsychotic treatments in terms of drug choice, drug dose, and schedule.

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Conditioned Avoidance Response in the Development of New Antipsychotics

Cited by 72 publications

References 106 publications

Animal models for predicting the efficacy and side effects of antipsychotic drugs

Animal models for predicting the efficacy and side effects of antipsychotic drugs

HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation

Olanzapine Sensitization and Clozapine Tolerance: From Adolescence to Adulthood in the Conditioned Avoidance Response Model

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