Insulin enhances presynaptic glutamate release via opioid receptor‐mediated disinhibition

Abstract

Recent studies show that insulin modulates the function of brain reward and motivation systems. For example, insulin receptor activation enhances dopamine release in the nucleus accumbens (NAc), reduces excitatory transmission in the VTA, and decreases food intake when infused into the NAc. Excitatory transmission in the NAc plays critical roles in motivation, and diet‐induced obesity alters NAc activity and peripheral sensitivity to insulin. However, insulin's effects on NAc excitatory transmission are unknown. Therefore here, we used whole‐cell patch clamp recordings in adult rat brain slices to determine how insulin affects excitatory transmission onto NAc medium spiny neurons (MSNs) and the mechanisms involved. Importantly, in addition to insulin receptors, insulin‐like growth factor receptors (IGFRs) are also expressed in the NAc and can be activated by moderate to high concentrations of insulin. Thus, a wide range of insulin concentrations were examined here (30–500 nM), and the contribution of insulin receptor activation vs. IGFR activation to insulin's effects was determined using pharmacological approaches. We find that insulin receptor activation increases presynaptic glutamate release via a previously unidentified form of opioid receptor‐mediated disinhibition, whereas activation of IGF receptors by insulin decreases presynaptic glutamate release. Furthermore, diet‐induced obesity (60% high‐fat; Open Source Diets D12492, 8 weeks) resulted in a loss of insulin receptor‐mediated increases and a reduction in NAc insulin receptor surface expression compared to chow fed controls (Lab Diet 5001, 13% fat), while preserving reductions in transmission mediated by IGRFs. These results provide the first insights into how insulin influences excitatory transmission in the adult brain and have broad implications for the regulation of motivation and reward related processes by peripheral hormones.Support or Funding InformationThis work was supported by NIDDK R01DK106188, R01DK115526, and the Brain and Behavior Research Foundation N018940 awards to CRF; MFO was supported by NIDA T32DA007268 and NIDDK FDK112627A. The authors declare no competing financial interests. Studies utilized the Chemistry Core of the Michigan Diabetes Research and Training Center funded by DK020572, and the University of Michigan Animal Phenotyping Core supported by P30 grants DK020572 (MDRC) and DK089503 (MNORC). We thank Drs. Marina Wolf, Larry Reagan, William Birdsong, Travis Brown and Garret Stuber for helpful conversations and Dr. Kenner C. Rice (Drug Design and Synthesis Section, NIDA IRP) for the gift of (+)‐naloxone.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.