Elsevier

Neuropharmacology

Volume 61, Issue 7, December 2011, Pages 1123-1128
Neuropharmacology

Invited review
Insulin signaling and addiction

https://doi.org/10.1016/j.neuropharm.2011.02.028Get rights and content

Abstract

Across species, the brain evolved to respond to natural rewards such as food and sex. These physiological responses are important for survival, reproduction and evolutionary processes. It is no surprise, therefore, that many of the neural circuits and signaling pathways supporting reward processes are conserved from Caenorhabditis elegans to Drosophilae, to rats, monkeys and humans. The central role of dopamine (DA) in encoding reward and in attaching salience to external environmental cues is well recognized. Less widely recognized is the role of reporters of the “internal environment”, particularly insulin, in the modulation of reward. Insulin has traditionally been considered an important signaling molecule in regulating energy homeostasis and feeding behavior rather than a major component of neural reward circuits. However, research over recent decades has revealed that DA and insulin systems do not operate in isolation from each other, but instead, work together to orchestrate both the motivation to engage in consummatory behavior and to calibrate the associated level of reward. Insulin signaling has been found to regulate DA neurotransmission and to affect the ability of drugs that target the DA system to exert their neurochemical and behavioral effects. Given that many abused drugs target the DA system, the elucidation of how dopaminergic, as well as other brain reward systems, are regulated by insulin will create opportunities to develop therapies for drug and potentially food addiction. Moreover, a more complete understanding of the relationship between DA neurotransmission and insulin may help to uncover etiological bases for “food addiction” and the growing epidemic of obesity. This review focuses on the role of insulin signaling in regulating DA homeostasis and DA signaling, and the potential impact of impaired insulin signaling in obesity and psychostimulant abuse.

This article is part of a Special Issue entitled ‘Synaptic Plasticity and Addiction’.

Section snippets

Insulin signaling in brain

In the periphery, insulin signaling plays a central role in the control of plasma glucose levels, and as a signal relaying the status of body energy stores to central (hypothalamic) regulators of energy homeostasis. Less well recognized is the important role insulin plays in regulating a broad spectrum of cellular and molecular functions within the central nervous system (CNS), including neurodevelopment, cell survival, neurogenesis, receptor trafficking, neurotransmitter release, and

Insulin and DA homeostasis

Very few studies have investigated the relationship between physiological or pathological changes in insulin levels and DA homeostasis. A major regulator of DA homeostasis is the dopamine transporter (DAT). The DAT controls the strength and duration of DA neurotransmission by the high-affinity uptake of DA released into the extracellular space. Patterson and co-workers (Patterson et al., 1998), using food deprivation as a model to decrease levels of plasma insulin in rats, measured uptake of DA

Insulin signaling regulates psychostimulant actions

Amphetamine (AMPH)-like stimulants are actively transported by catecholamine carriers such as DAT (Sulzer et al., 2005). As substrates, AMPHs not only competitively inhibit DA reuptake and thereby increase synaptic DA, but also promote reversal of transport, resulting in efflux of DA via the DAT (Sulzer et al., 2005). This efflux results in an increase in extracellular DA and is of major importance for the psychomotor stimulant properties of AMPHs (Sulzer et al., 2005). However, studies of the

Brain insulin resistance and impaired DA neurotransmission: A pathway to obesity

DA is important in modulating several behaviors, ranging from movement to cognition to motivation and pleasure, including our motivation to eat and the pleasure we receive from it (Palmiter, 2007, Palmiter, 2008). A role for DA in feeding behavior is demonstrated by studies showing improper DA signaling in obesity. For example, in humans, upon eating a palatable meal, dopamine rich regions in the brain, such as the striatum, increase in activity (Stice et al., 2008). In subjects with a BMI in

Summarizing remarks

The exploding obesity epidemic provides compelling support for the idea that feeding behaviors depend heavily - often negatively – on factors beyond the simple need to maintain energy homeostasis. Indeed, emotions provide positive (or negative) feedback toward certain behaviors, and reward has increasingly become a large part of human consummatory behavior. Thus, there is growing recognition that this epidemic is fueled in large part by a transformational shift in the mechanisms – molecular,

Acknowledgements

Work supported by NIH grants DA14684 (AG & LCD), DK085712 (KN & AG), partially by resources of the Tennessee Valley Healthcare System.

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