Clozapine Administration in Adolescence Prevents Postpubertal Emergence of Brain Structural Pathology in an Animal Model of Schizophrenia

Piontkewitz, Yael; Assaf, Yaniv; Weiner, Ina

doi:10.1016/j.biopsych.2009.07.005

Cited by 134 publications

(127 citation statements)

References 64 publications

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“…The second issue of interest is the long-term behavioral and brain consequences of antipsychotic treatment in adolescence (Llorente-Berzal et al, 2012). One focal area is the potential preventive or treatment effects of adolescence antipsychotic exposure on behavioral and brain abnormalities in animal models of schizophrenia (Piontkewitz et al, 2009;Piontkewitz et al, 2011). The present study differed from those studies in that it focused on how antipsychotic treatment during adolescence alters antipsychotic response in adolescence and beyond (eg, adulthood).…”

Section: Discussionmentioning

confidence: 96%

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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Section: Discussionmentioning

confidence: 96%

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

Qiao

2012

Neuropsychopharmacol

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“…enlarged lateral ventricles and reduced prefrontal cortex volumes) (Piontkewitz et al, 2009). It was this progressive nature of brain abnormalities that led clinicians and scientists to administer atypical antipsychotic drugs prior to the full manifestation of symptoms in an attempt to halt disease progression (McGlashan et al, 2006;Piontkewitz et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Using a maternal immune stimulation model of schizophrenia to study behavioral and neurobiological alterations over the developmental course

Hadar

Soto-Montenegro

Götz

et al. 2015

Schizophrenia Research

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A growing body of evidence sheds light on the neurodevelopmental nature of schizophrenia with symptoms typically emerging during late adolescence or young adulthood. We compared the presymptomatic adolescence period with the full symptomatic period of adulthood at the behavioral and neurobiological level in the poly I:C maternal immune stimulation (MIS) rat model of schizophrenia. We found that in MIS-rats impaired sensorimotor gating, as reflected in disrupted prepusle inhibition (PPI), emerged post-pubertally, with behavioral deficits being only recorded in adulthood but not during adolescence. Using post mortem HPLC we found that MIS-rats show distinct dopamine and serotonin changes in the medial prefrontal cortex (mPFC), nucleus CIHR Author ManuscriptCIHR Author Manuscript CIHR Author Manuscript accumbens (Nacc), caudate putamen, globus pallidus, and hippocampus. Further, FDG-PET has shown that these animals had lower glucose uptake in the ventral hippocampus and PFC and a higher metabolism in the amygdala and Nacc when compared to controls. Changes in neurotransmission and metabolic activity varied across brain structures with respect to first appearance and further development. In the mPFC and Hipp, MIS-rats showed abnormal neurochemical and metabolic activity prior to and with the development of behavioral deficits in both adolescent and adult states, reflecting an early impairment of these regions. In contrast, biochemical alteration in the Nacc and globus pallidus developed as a matter of age. Our findings suggest that MIS-induced neurochemical and metabolic changes are neurodevelopmental in nature and either progressive or non-progressive and that the behavioral deficits manifest as these abnormalities increase.

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“…While administration of poly I:C to pregnant rodents can result in increased levels of cytokines in fetal brain, it only generates a non-specific immune response, without particular anti-viral antibodies (for references, see Markham & Koenig, 2011). With respect to PPI, treatment of p r e g n a n t m i c e o r r a t s w i t h p o l y I : C g e n e rates offspring that shows an impaired PPI response from post pubertal age (Ozawa et al, 2006;Li et al, 2009b;Piontkewitz et al, 2009;Vuillermot et al, 2010), which is presumably mediated by dopaminergic maldevelopment (Ozawa et al, 2006;Vuillermot et al, 2010). Thus, animal models of prenatal maternal infection show altered fetal brain development and disrupted PPI in adult offspring, probably mediated by the maternal immune response.…”

Section: Prenatal Maternal Immune Activationmentioning

confidence: 99%

Linking Stress and Schizophrenia: A Focus on Prepulse Inhibition

Douma¹,

Millan²,

Olivier³

et al. 2011

Psychiatric Disorders - Trends and Developments

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Clozapine Administration in Adolescence Prevents Postpubertal Emergence of Brain Structural Pathology in an Animal Model of Schizophrenia

Cited by 134 publications

References 64 publications

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

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

Using a maternal immune stimulation model of schizophrenia to study behavioral and neurobiological alterations over the developmental course

Linking Stress and Schizophrenia: A Focus on Prepulse Inhibition

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