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In a Model of Neuroinflammation Designed to Mimic Delirium, Quetiapine Reduces Cortisol Secretion and Preserves Reversal Learning in the Attentional Set Shifting Task

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Abstract

Quetiapine, an atypical antipsychotic medication has lacked pre-clinical validation for its purported benefits in the treatment of delirium. This laboratory investigation examined the effects of quetiapine on the attentional set shifting task (ASST), a measure of cognitive flexibility and executive functioning, in a rodent model of lipopolysaccharide (LPS) mediated neuroinflammation. 19 Sprague Dawley female rats were randomly selected to receive intraperitoneal placebo (N = 5), LPS and placebo (N = 7) or LPS and quetiapine (n = 7) and performed the ASST. We measured trials to criterion, errors, non-locomotion episodes and latency to criterion, serum cortisol and tumor necrosis factor alpha (TNF-α) levels. TNF-α levels were not different between groups at 24 h. Cortisol levels in the LPS + Quetiapine group were reduced compared to LPS + Placebo (P < 0.001) and did not differ from the placebo group (P = 0.15). Analysis between LPS + Quetiapine and LPS + Placebo treated rats demonstrated improvement in the compound discrimination reversal (CD Rev1) (P = 0.016) and the intra-dimensional reversal (ID Rev2) (P = 0.007) discriminations on trials to criterion. LPS + Quetiapine treated rats had fewer errors than LPS + Placebo treated animals in the compound discrimination (CD) (P = 0.007), CD Rev1 (P = 0.005), ID Rev2 (P < 0.001) discriminations. There was no difference in non-locomotion frequency or latency to criterion between the three groups in all discriminations (P > 0.0167). We demonstrated preserved reversal learning, no effect on attentional set shifting and normalized cortisol levels in quetiapine-treated rats in this neuroinflammatory model of delirium. This suggests that quetiapine’s beneficial effects in delirium may be related to the preservation of reversal learning and potential downstream effects related to reduction in cortisol production.

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Data Availability

All data that was generated or analyzed for this series of experiments are included in the published article.

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Funding

This work was supported by internal funding from the Penn State Health Milton S. Hershey Medical Center Department of Anesthesiology & Perioperative Medicine (Study #47992).

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Authors and Affiliations

  1. Department of Anesthesiology & Perioperative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, 17033, USA

    Zyad J. Carr, Lauren Miller, Victor Ruiz-Velasco & Kunal Karamchandani

  2. Department of Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, 17033, USA

    Zyad J. Carr

  3. Department of Anesthesiology & Perioperative Medicine, H187, 500 University Dr., Hershey, PA, 17078, USA

    Zyad J. Carr

  4. Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA

    Victor Ruiz-Velasco

  5. Department of Public Health Sciences, Penn State College of Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, 17033, USA

    Allen R. Kunselman

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  1. Zyad J. Carr
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Contributions

Conceived and designed experiments: ZJC, LM, VRV.

Analysis and interpretation of the data: ZJC, ARK, VRV, KK.

Wrote the manuscript: ZJC, ARK, VRV, KK.

Data acquisition: ZJC, LM.

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Correspondence to Zyad J. Carr.

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The experimental design was approved by the Penn State College of Medicine IACUC. All procedures adhered to the guidelines in the Principles of Laboratory Animal Care (National Institutes of Health, Eighth Ed., National Academies Press, 2011).

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Carr, Z.J., Miller, L., Ruiz-Velasco, V. et al. In a Model of Neuroinflammation Designed to Mimic Delirium, Quetiapine Reduces Cortisol Secretion and Preserves Reversal Learning in the Attentional Set Shifting Task. J Neuroimmune Pharmacol 14, 383–390 (2019). https://doi.org/10.1007/s11481-019-09857-y

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