Impact of insulin and insulin resistance on brain dopamine signalling and reward processing – An underexplored mechanism in the pathophysiology of depression?

Diabetes alters neuroeconomically dissociable forms of mental accounting

“…Thus, the absence of central insulin in Type 1 diabetes may have profound consequences on dopaminergic function, either acutely by altering transient activity or also across longer timescales affecting plasticity and reward circuit remodeling. Such changes could influence not only reward-related behavior during meals but also impact decision-making information processing more broadly, giving rise to complex psychiatric disease vulnerabilities 35,47 . Given the more complex and multifactorial changes in dissociable decision-making behaviors observed on the Restaurant Row task in diabetic mice, we can begin to point to multiple, parallel circuit-computation-specific valuation algorithms that may be uniquely disrupted in diabetes.…”

“…Insulin is actively transported across the blood-brain barrier and has been shown to alter the function of the mesolimbic dopamine system 14 . Insulin receptors are present on both ventral tegmental area dopaminergic neurons, as well as on neurons in the nucleus accumbens, where activation of the receptor by insulin is thought to suppress hedonic feeding 35,[47][48][49] . The observation that STZ-mice are biased for most-preferred flavors is consistent with a role for insulin in hedonic feeding.…”

Frailty, Mental Disorders, and Metabolic Syndrome: A Genetic Association and Mediation Mendelian Randomization Study

“…Supporting this exploration, a meta-analysis of 70 studies and over 240 million participants elucidated a noteworthy positive association between the insulin resistance index and acute depression, and this index remained unaltered even when depression symptoms were alleviated(37). Delving deeper into the molecular mechanisms, insulin resistance was identified as a key player in altering central dopaminergic signaling, particularly in the ventral tegmental area associated with reward behavior(38), contributing to the development of anhedonia and depression. Specifically, insulin resistance was found to diminish the synthesis and reuptake of dopamine through attenuated AKT signaling pathways, while the dysregulation of dopamine intensively promotes the pathophysiologic development of depression(39).…”

Consolidating evidence on the role of insulin resistance in major depressive disorder

“…In an animal study, Martin et al discovered that insulin (i) directly inhibits the activity of serotoninergic neurons in the dorsal raphe nucleus (DRN) via 5-HT1A autoreceptor dependent mechanism, (ii) exerts its anxiolytic-like effects due to modulation of serotoninergic transmission, (iii) in animal models of T2D-related depression serotoninergic neurons in DRN are no longer sensitive to insulin, (iv) in animal models of depression addition of insulin to fluoxetine potentiated the antidepressant action of the drug [ 23 ▪▪ ]. On the other hand, Gruber et al [ 24 ▪▪ ] summarized data coming from animal and human trials exploring the impact of insulin and IR on dopaminergic transmission. Based on the animal studies they have concluded that (a) insulin differently modulates dopamine release, increasing it if applied in the striatum and inhibiting it if applied in the ventral tegmental area (VTA), (b) insulin deficiency and resistance limits the synthesis and reuptake of dopamine as well as the excitatory stimulation and firing frequency of dopaminergic neurons in VTA, (c) restricted insulin signaling/IR in the nucleus accumbens reduces dopamine release and reuptake, (d) IR is linked to increased food intake, motivation to work for food, dampens reward sensitivity, impairs learning and preference formation as well as promotes behavioral despair resulting in anhedonic/anxious phenotype.…”