Investigation of the Effects of Antipsychotics on CNS Insulin-mediated Brain Glucose Uptake using 2DG Autoradiography

Antipsychotics (APs) drugs are associated with adverse metabolic side effect. Recent studies have shifted focus onto the central nervous system (CNS) suggesting that APs can induce central insulin resistance and disrupt glucose regulation. Attenuated central insulin action has also been shown to be a critical factor in the development of age-related cognitive decline and Alzheimer’s disease (AD). As such, aberrant brain insulin signaling has been posited to lie at the crossroads of metabolic and cognitive disorders. In recent years, a greater focus has been placed on using insulin delivered to the brain as a potential treatment intervention. Thus, we conducted a systematic review and meta-analysis to examine the cognitive outcomes and clinical implications of patients and healthy individuals treated with intranasal insulin. We discovered that intranasal insulin failed to improve cognition in AP-treated chronic patients with schizophrenia in comparison to the pro-cognitive benefits observed for patients with AD/mild cognitive impairment. Next, we sought to determine if APs impaired central insulin action by measuring insulin-mediated cerebral glucose uptake using 2-Deoxy-D-glucose autoradiography. We discovered that olanzapine attenuated central insulin-mediated cerebral glucose uptake across various regions of the brain. We also investigated whether this was a class or dopamine 2 receptor (D2R) antagonism driven effect by using four additional APs (haloperidol, raclopride, risperidone, and aripiprazole) with varying receptor affinities. We determined that all APs, regardless of class, also induced central insulin resistance in regions responsible for reward processing, motivation, metabolism, as well as cognition. Taken together, our findings suggest that an acute dose of AP can induce brain insulin resistance in a rodent model which may explain the lack of efficacy of intranasal insulin for patients taking APs due to pre-existing insulin resistance in the brain.

Department dc:contributor.department

Medical Science

Year dc:date.issued

2025

Author dc:creator

• Wu, Sally

Advisors dc:contributor.advisor

• Agarwal, Sri Mahavir
• Hahn, Margaret

• 2DG autoradiography
• antipsychotics
• brain glucose metabolism
• central insulin resistance
• metabolic side effects

Handle dc:identifier.uri

https://hdl.handle.net/1807/144885

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/144885