Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: Contrast with haloperidol and chlordiazepoxide

Mead, Alexa; Li, Ming; Kapur, Shitij

doi:10.1016/j.pbb.2008.04.014

Cited by 47 publications

(47 citation statements)

References 72 publications

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“…To confirm our hypothesis that the increased levels of DFosB in PFC seen in medicated patients are a result of drug exposure, we examined whether repeated administration of the standard antipsychotic drug, haloperidol, altered DFosB expression in a homologous region of PFC of rats. Following 7 daily injections of haloperidol (0.1 mg/kg s.c.), using a dose that is behaviorally active in rodents (Mead et al, 2008), we found increased levels of DFosB in haloperidol-treated rats compared with vehicletreated controls (Figure 1b: t ¼ 1.996, df ¼ 8; po0.05; n ¼ 5 per group). We next asked whether the expression of DFosB in the PFC was a key factor in regulating the clinical efficacy of haloperidol or, conversely, perhaps some of its negative side effects.…”

Section: Resultsmentioning

confidence: 85%

ΔFosB Induction in Prefrontal Cortex by Antipsychotic Drugs is Associated with Negative Behavioral Outcomes

Dietz

Kennedy

Sun

et al. 2013

Neuropsychopharmacol

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DFosB, a FosB gene product, is induced in the prefrontal cortex (PFC) by repeated exposure to several stimuli including antipsychotic drugs such as haloperidol. However, the functional consequences of increased DFosB expression following antipsychotic treatment have not been explored. Here, we assessed whether DFosB induction by haloperidol mediates the positive or negative consequences or clinical-related actions of antipsychotic treatment. We show that individuals with schizophrenia who were medicated with antipsychotic drugs at their time of death display increased DFosB levels in the PFC, an effect that is replicated in rats treated chronically with haloperidol. In contrast, individuals with schizophrenia who were medication-free did not exhibit this effect. Viral-mediated overexpression of DFosB in the PFC of rodents induced cognitive deficits as measured by inhibitory avoidance, increased startle responses in prepulse inhibition tasks, and increased MK-801-induced anxiety-like behaviors. Together, these results suggest that DFosB induction in the PFC by antipsychotic treatment contributes to the deleterious effects of these drugs and not to their therapeutic actions.

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Section: Resultsmentioning

confidence: 85%

ΔFosB Induction in Prefrontal Cortex by Antipsychotic Drugs is Associated with Negative Behavioral Outcomes

Dietz

Kennedy

Sun

et al. 2013

Neuropsychopharmacol

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“…In our previous rat CAR studies (Mead et al, 2008;Sun et al, 2010), we have shown that OLZ and CLZ as atypical antipsychotics also possess an intrinsic anxiolytic property as revealed by their ability to decrease various behavioral and physiological measures of anxiety/fear (eg, stressinduced hyperthermia, 22 kHz USV, startle reactivity, defecation, and urination), in addition to their antipsychotic property as indexed by their anti-avoidance effect. These two properties seem dissociable and might be mediated by their different molecular actions.…”

Section: Discussionmentioning

confidence: 98%

“…Similar results have been found in the PCP-induced hyperlocomotion model (unpublished observations). As sensitization and tolerance often develop to a particular effect of a drug, but not to a drug itself, in order to assess the behavioral specificity of OLZ sensitization and CLZ tolerance, we also examined their effects on 22 kHz ultrasonic vocalization (USV, a measure of fear/anxiety; Mead et al, 2008;Sun et al, 2010) and on intertrial crossing in the CAR task (a putative measure of motor function/ sedation). In addition, we examined the prepulse inhibition (PPI) of acoustic startle response of the rats periodically throughout their developmental period (approximate postnatal days, (BP) 43-47) as a way to assess how adolescence antipsychotic treatment affects the brain and behavioral functions and development of adolescent rats.…”

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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“…During these 10 days of the training/testing period, the rat's body temperature was also measured, using a probe (lubricated with mineral oil) inserted in the rectum (Thermalert TH-5, Physitemp, Clifton, NJ, USA) before and after each session. Because these data were not relevant to the question addressed here, they were not reported here but were reported in a separate paper (Mead, et al, 2008). After 3 days of resting, all rats were retrained (drug free) to reacquire avoidance responding in 10 sessions (30 trials/ session) over 15 days.…”

Section: Methodsmentioning

confidence: 99%

Avoidance-suppressing effect of antipsychotic drugs is progressively potentiated after repeated administration: an interoceptive drug state mechanism

Mead

2009

J Psychopharmacol

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Antipsychotic drugs selectively suppress conditioned avoidance response. Using a two-way active avoidance response paradigm, we examined the role of drug-induced interoceptive state in the mediation of avoidance-suppressive effect. In Experiment 1, we found that rats intermittently treated with olanzapine (OLZ) (1.0 mg/kg, s.c.) or haloperidol (0.03 mg/kg, s.c.) on the 1st day of a 3-day cycle for seven cycles exhibited a progressive across-session decline in avoidance responding, despite the fact that they exhibited a comparable high level of avoidance responding on the 3rd day of each cycle during the drug-free retraining session. In Experiments 2 and 3, rats that were previously treated with OLZ (0.5—2.0 mg/kg, s.c.) or risperidone (0.2—1.0 mg/kg) during the acquisition phase of avoidance conditioning exhibited significantly fewer avoidance responses when they were retested 3 weeks later to the same drug in comparison to rats that were previously treated with nonantipsychotic drugs (chlordiazepoxide, 10 mg/kg, citalopram 10 mg/kg, or sterile water). Overall, these findings indicate a ‘drug memory’-like mechanism that maintains the avoidance-suppressing effect of antipsychotics over time. This mechanism is likely driven by the interoceptive state caused by the antipsychotics, which may also be an important behavioral mechanism mediating the clinical effects of antipsychotic treatments.

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Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: Contrast with haloperidol and chlordiazepoxide

Cited by 47 publications

References 72 publications

ΔFosB Induction in Prefrontal Cortex by Antipsychotic Drugs is Associated with Negative Behavioral Outcomes

ΔFosB Induction in Prefrontal Cortex by Antipsychotic Drugs is Associated with Negative Behavioral Outcomes

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

Avoidance-suppressing effect of antipsychotic drugs is progressively potentiated after repeated administration: an interoceptive drug state mechanism

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