Insulin enhances presynaptic glutamate release via opioid receptor-mediated disinhibition

Abstract

Insulin influences learning and cognition and activity in brain centers that mediate reward and motivation in humans. However, very little is known about how insulin influences excitatory transmission within brain reward centers such as the nucleus accumbens (NAc). Further, insulin dysregulation that accompanies obesity is linked to cognitive decline, depression, anxiety, and aberrant motivation that also rely on excitatory transmission in the NAc, but potential mechanisms are poorly understood. Here we show 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 in the NAc. Furthermore, obesity results in a loss of the insulin receptor-mediated increases and a reduction in NAc insulin receptor surface expression, while preserving reductions in excitatory transmission mediated by IGF receptors. 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.

Insulin restores the neurochemical effects of nicotine in the mesolimbic pathway of diabetic rats

“…With regard to ACh, it was hypothesized that ACh release would be reduced in the NAc and VTA of STZtreated rats following nicotine administration, an effect that we expected to also be restored by insulin supplementation. The rationale for Aim 2 was based on previous work showing intra-NAc administration of insulin enhances local dopamine and glutamate release (Labouèbe et al, 2013;Oginsky et al, 2019). Another report revealed that systemic administration of insulin increased dopamine release in NAc via activation of insulin receptors on striatal ACh interneurons (Stouffer et al, 2015).…”