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Olanzapine sensitization and clozapine tolerance: from adolescence to adulthood in the conditioned avoidance response model.

ABSTRACT: 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 (?P) 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 (?P 50) or after they matured into adults (?P 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 (?P 76 and 92), whereas the CLZ tolerance was only detectable on ?P 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.

SUBMITTER: Qiao J

PROVIDER: S-EPMC3547203 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Olanzapine sensitization and clozapine tolerance: from adolescence to adulthood in the conditioned avoidance response model.

Qiao Jing J Li Hong H Li Ming M

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20121107 3

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 ind ...[more]

PMID: 23132270

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Project description:BackgroundSecond generation antipsychotics (SGAs) induce glucometabolic side-effects, such as hyperglycemia and insulin resistance, which pose a therapeutic challenge for mental illness. Sphingolipids play a role in glycaemic balance and insulin resistance. Endoplasmic reticulum (ER) stress contributes to impaired insulin signalling and whole-body glucose intolerance. Diabetogenic SGA effects on ER stress and sphingolipids, such as ceramide and sphingomyelin, in peripheral metabolic tissues are unknown. This study aimed to investigate the acute effects of clozapine and olanzapine on ceramide and sphingomyelin levels, and protein expression of key enzymes involved in lipid and glucose metabolism, in the liver and skeletal muscle.MethodsFemale rats were administered olanzapine (1 mg/kg), clozapine (12 mg/kg), or vehicle (control) and euthanized 1-h later. Ceramide and sphingomyelin levels were examined using electrospray ionization (ESI) mass spectrometry. Expression of lipid enzymes (ceramide synthase 2 (CerS2), elongation of very long-chain fatty acid 1 (ELOVL1), fatty acid synthase (FAS) and acetyl CoA carboxylase 1 (ACC1)), ER stress markers (inositol-requiring enzyme 1 (IRE1) and eukaryotic initiation factor (eIF2α) were also examined.ResultsClozapine caused robust reductions in hepatic ceramide and sphingolipid levels (p < 0.0001), upregulated CerS2 (p < 0.05) and ELOVL1 (+ 37%) and induced significant hyperglycemia (vs controls). In contrast, olanzapine increased hepatic sphingomyelin levels (p < 0.05 vs controls). SGAs did not alter sphingolipid levels in the muscle. Clozapine increased (+ 52.5%) hepatic eIF2α phosphorylation, demonstrating evidence of activation of the PERK/eIF2α ER stress axis. Hepatic IRE1, FAS and ACC1 were unaltered.ConclusionsThis study provides the first evidence that diabetogenic SGAs disrupt hepatic sphingolipid homeostasis within 1-h of administration. Sphingolipids may be key candidates in the mechanisms underlying the diabetes side-effects of SGAs; however, further research is required.

Project description:Calcyon regulates activity-dependent internalization of ?-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors and long-term depression of excitatory synapses. Elevated levels of calcyon are consistently observed in brains from schizophrenic patients, and the calcyon gene is associated with attention-deficit hyperactivity disorder. Executive function deficits are common to both disorders, and at least for schizophrenia, the etiology appears to involve both heritable and neurodevelopmental factors. Here, we show with calcyon-overexpressing Cal(OE) transgenic mice that lifelong calcyon upregulation impairs executive functions including response inhibition and working memory, without producing learning and memory deficits in general. As response inhibition and working memory, as well as the underlying neural circuitry, continue to mature into early adulthood, we functionally silenced the transgene during postnatal days 28-49, a period corresponding to adolescence. Remarkably, the response inhibition and working memory deficits including perseverative behavior were absent in adult Cal(OE) mice with the transgene silenced in adolescence. Suppressing the calcyon transgene in adulthood only partially rescued the deficits, suggesting calcyon upregulation in adolescence irreversibly alters development of neural circuits supporting mature response inhibition and working memory. Brain regional immunoblots revealed a prominent downregulation of AMPA GluR1 subunits in hippocampus and GluR2/3 subunits in hippocampus and prefrontal cortex of the Cal(OE) mice. Silencing the transgene in adolescence prevented the decrease in hippocampal GluR1, further implicating altered fronto-hippocampal connectivity in the executive function deficits observed in the Cal(OE) mice. Treatments that mitigate the effects of high levels of calcyon during adolescence could preempt adult deficits in executive functions in individuals at risk for serious mental illness.

Dataset Information

Olanzapine sensitization and clozapine tolerance: from adolescence to adulthood in the conditioned avoidance response model.

Publications

Olanzapine sensitization and clozapine tolerance: from adolescence to adulthood in the conditioned avoidance response model.

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