IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates

Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9070, USA.
Nature Neuroscience (Impact Factor: 16.1). 02/2007; 10(1):93-9. DOI: 10.1038/nn1812
Source: PubMed


Chronic morphine administration (via subcutaneous pellet) decreases the size of dopamine neurons in the ventral tegmental area (VTA), a key reward region in the brain, yet the molecular basis and functional consequences of this effect are unknown. In this study, we used viral-mediated gene transfer in rat to show that chronic morphine-induced downregulation of the insulin receptor substrate 2 (IRS2)-thymoma viral proto-oncogene (Akt) signaling pathway in the VTA mediates the decrease in dopamine cell size seen after morphine exposure and that this downregulation diminishes morphine reward, as measured by conditioned place preference. We further show that the reduction in size of VTA dopamine neurons persists up to 2 weeks after morphine withdrawal, which parallels the tolerance to morphine's rewarding effects caused by previous chronic morphine exposure. These findings directly implicate the IRS2-Akt signaling pathway as a critical regulator of dopamine cell morphology and opiate reward.

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Available from: David W Self, Jun 18, 2014
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    • "PI3K activity is increased under direct administration of insulin and leptin into the VTA (Figlewicz et al., 2007). Moreover, IRS2/Akt pathway in VTA has been shown to modulate rewarding and psychomotor activating effects of cocaine and opiates (Russo et al., 2007; Iñiguez et al., 2008). Direct leptin administration into the VTA increased JAK-STAT signaling and this is essential for the effect of leptin in the VTA to decrease food intake (Morton et al., 2009). "
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    ABSTRACT: The central actions of leptin and insulin are essential for the regulation of energy and glucose homeostasis. In addition to the crucial effects on the hypothalamus, emerging evidence suggests that the leptin and insulin signaling can act on other brain regions to mediate the reward value of nutrients. Recent studies have indicated the midbrain dopaminergic neurons as a potential site for leptin' and insulin's actions on mediating the feeding behaviors and therefore affecting the energy balance. Although molecular details about the integrative roles of leptin and insulin in this subset of neurons remain to be investigated, substantial body of evidence by far imply that the signaling pathways regulated by leptin and insulin may play an essential role in the regulation of energy balance through the control of food-associated reward. This review therefore describes the convergence of energy regulation and reward system, particularly focusing on leptin and insulin signaling in the midbrain dopaminergic neurons.
    Full-text · Article · Aug 2014 · Frontiers in Psychology
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    • "Chronic opiate administration, including self-administration, decreases the soma size of VTA DA neurons in rodents and humans [1], [2], [3], [4]. This decrease is dependent on AKT signaling and increased neuronal activity, and mediates reward tolerance [2], [3]. In spite of the increase in VTA DA firing rate, DA output to the nucleus accumbens (NAc) is decreased, suggesting that the structural changes alter mesolimbic DA circuit function, contributing to the change in reward behavior [3]. "
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    ABSTRACT: Our previous observations show that chronic opiate administration, including self-administration, decrease the soma size of dopamine (DA) neurons in the ventral tegmental area (VTA) of rodents and humans, a morphological change correlated with increased firing rate and reward tolerance. Given that a general hallmark of drugs of abuse is to increase activity of the mesolimbic DA circuit, we sought to determine whether additional drug classes produced a similar morphological change. Sections containing VTA were obtained from rats that self-administered cocaine or ethanol and from mice that consumed nicotine. In contrast to opiates, we found no change in VTA DA soma size induced by any of these other drugs. These data suggest that VTA morphological changes are induced in a drug-specific manner and reinforce recent findings that some changes in mesolimbic signaling and neuroplasticity are drug-class dependent.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "One intracellular signaling pathway that has received attention recently for its ability to regulate neuroplasticity and its role in neuropsychiatric disorders is the Akt (protein kinase B) - glycogen synthase kinase-3 (GSK3) pathway. Of direct relevance to drug addiction, Akt and its downstream kinase, GSK3, have been shown to mediate dopaminergic neurotransmission and regulate behaviors including those produced by psychostimulants [1]–[4], as well as modulating behavioral and cellular responses to opiates [5]. "
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    ABSTRACT: The Akt - GSK3 signaling pathway has been recently implicated in psychostimulant-induced behavioral and cellular effects. Here, the ability of cocaine to regulate the activity of Akt and GSK3 was investigated by measuring the phosphorylation states of the two kinases. The anatomical specificity of the response was determined, as was the contributions of dopamine and NMDA receptors to the actions of cocaine. As GSK3 activity was found to be increased by cocaine, subsequent experiments investigated the importance of GSK3 activation in cocaine conditioned reward. Adult male CD-1 mice were injected with cocaine or saline, and levels of phosphorylated Akt and GSK3α/β were measured 30 minutes later. Acute administration of cocaine significantly decreased the phosphorylation of Akt-Thr308 (pAkt-Thr308) and GSK3β in the caudate putamen and nucleus accumbens core, without altering pAkt-Ser473 and pGSK3α. To investigate the role of dopamine and NMDA receptors in the regulation of Akt and GSK3 by cocaine, specific receptor antagonists were administered prior to cocaine. Blockade of dopamine D2 receptors with eticlopride prevented the reduction of pAkt-Thr308 produced by cocaine, whereas antagonists at dopamine D1, dopamine D2 or glutamatergic NMDA receptors each blocked cocaine-induced reductions in pGSK3β. The potential importance of GSK3 activity in the rewarding actions of cocaine was determined using a cocaine conditioned place preference procedure. Administration of the selective GSK3 inhibitor, SB 216763, prior to cocaine conditioning sessions blocked the development of cocaine place preference. In contrast, SB 216763 did not alter the acquisition of a contextual fear conditioning response, demonstrating that SB 216763 did not globally inhibit contextual learning processes. The results of this study indicate that phosphorylation of GSK3β is reduced, hence GSK3β activity is increased following acute cocaine, an effect that is contingent upon both dopaminergic and glutamatergic receptors. Further, GSK3 activity is required for the development of cocaine conditioned reward.
    Full-text · Article · Feb 2014 · PLoS ONE
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