Insulin Regulation of Monoamine Signaling: Pathway to Obesity

Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 01/2011; 36(1):359-60. DOI: 10.1038/npp.2010.167
Source: PubMed


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Available from: Aurelio Galli, Dec 31, 2013
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    • "Cocaine increases extracellular dopamine (DA) by blocking DA uptake via the high-affinity DA transporter (DAT) (Kalivas and Duffy, 1990; Weiss et al., 1992; Giros et al., 1996; Amara et al., 1998). Converging lines of evidence suggest that insulin signaling is an important regulator of DAT, the primary target of cocaine (Figlewicz et al., 1994; Patterson et al., 1998; Owens et al., 2005; Sevak et al., 2007; Williams et al., 2007; Daws et al., 2011; Niswender et al., 2011; Speed, et al., 2011; Owens et al., 2012). Insulin receptors are coexpressed extensively with tyrosine hydroxylase (a marker for DA neurons; Hill et al., 1986; Figlewicz et al., 2003), and several studies have shown that insulin, via the phosphoinositide 3-kinase/Akt signaling pathway (Williams et al., 2007; Speed et al., 2011), regulates the expression and activity of DAT. "
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    ABSTRACT: Feeding conditions can influence dopamine (DA) neurotransmission and impact behavioral and neurochemical effects of drugs acting on DA systems. This study examined whether eating high fat chow alters the locomotor effects of cocaine and DA transporter (DAT) activity in adolescent (PND 25) and adult (PND 75) male Sprague-Dawley rats. Dose-response curves for cocaine-induced locomotor activity were generated in rats with free access to either standard or high fat chow or restricted access to high fat chow (body weight matched to rats eating standard chow). Compared with eating standard chow, eating high fat chow increased the sensitivity of Sensitivity increased to the acute effects of cocaine in adolescent, but not adult, rats to the acute effects of cocaineeating high fat chow, compared with rats eating standard chow. When tested once per week, sensitization to the locomotor effects of cocaine was enhanced in adolescent rats eating high fat chow, compared with adolescent rats eating standard chow. Sensitization to cocaine was not different among feeding conditions in adults. When adolescent rats that previously ate high fat chow ate standard chow, sensitivity to cocaine returned to normal. As measured by chronoamperometry, DA clearance rate in striatum was decreased in both adolescent and adult rats eating high fat chow, compared with age-matched rats eating standard chow. These results suggest that high fat diet-induced reductions in DA clearance rate do not always correspond to increased sensitivity to the locomotor effects of cocaine, suggesting that mechanisms other than DAT might play a role. Moreover, in adolescent but not adult rats, eating high fat chow increases sensitivity to cocaine and enhances the sensitization that develops to cocaine. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    Full-text · Article · Mar 2015 · The International Journal of Neuropsychopharmacology
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    • "Values are expressed as mean ± S.E.M, One-way ANOVA with Newman–Keuls post test was performed to determine the statistical difference ***p < 0.001, **p < 0.01, *p < 0.05 vs VHFD. decrease and altered corresponding reuptake [40] [41] [50]. In this work, rimonabant markedly influenced the expression of the three monoamine transporters in all the investigated area of DIO mice brain, with possible negative effects on animal behavior. "
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    ABSTRACT: The present work aims to study the effects induced by a chronic treatment with a novel CB1 antagonist (NESS038C6) in C57BL/6N diet-induced obesity (DIO) mice. Mice treated with NESS038C6 and fed with a fat diet (NESS038C6 FD) were compared with the following three reference experimental groups: DIO mice fed with the same fat diet used for NESS038C6 and treated with vehicle or the reference CB1 antagonist/inverse agonist rimonabant, "VH FD" and "SR141716 FD", respectively; DIO mice treated with vehicle and switched to a normal diet (VH ND). NESS038C6 chronic treatment (30 mg/kg/day for 31 days) determined a significant reduction in DIO mice weight relative to that of VH FD. The entity of the effect was comparable to that detected in both SR141716 FD and VH ND groups. Moreover, if compared to VH FD, NESS038C6 FD evidenced: (i) improvement of cardiovascular risk factors; (ii) significant decrease in adipose tissue leptin expression; (iii) increase in mRNA expression of hypothalamic orexigenic peptides and a decrease of anorexigenic peptides; (iv) expression increase of metabolic enzymes and peroxisome proliferator-activated receptor-α in the liver; (v) normalization of monoaminergic transporters and neurotrophic expression in mesolimbic area. However, in contrast to the case of rimonabant, the novel CB1 antagonist improved the disrupted expression profile of genes linked to the hunger-satiety circuit, without altering monoaminergic transmission. In conclusion, the novel CB1 antagonist compound NESS038C6 may represent a useful candidate agent for the treatment of obesity and its metabolic complications, without or with reduced side effects relative to those instead observed with rimonabant.
    Full-text · Article · Jul 2012 · Behavioural brain research
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    • "While insulin is well known for its important role in regulating energy homeostasis, it is now recognized to be an important regulator of monoaminergic neurotransmission (e.g. Figure 8; Figlewicz and Benoit, 2009; Daws et al., 2011; Niswender et al., 2011). We and others have shown that conditions that dampen insulin signaling, such as diabetes, food restriction or fasting, dramatically impair the ability of DAT to clear DA from extracellular fluid in brain areas subserving reward, as well as motivated and learned behaviors including drug and food seeking activities (Figlewicz et al., 2007; Palmiter 2007; 2008 "
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    ABSTRACT: The dopamine (DA) transporter (DAT) is a major target for abused drugs and a key regulator of extracellular DA. A rapidly growing literature implicates insulin as an important regulator of DAT function. We showed previously that amphetamine (AMPH)-evoked DA release is markedly impaired in rats depleted of insulin with the diabetogenic agent streptozotocin (STZ). Similarly, functional magnetic resonance imaging experiments revealed that the blood oxygenation level-dependent signal following acute AMPH administration in STZ-treated rats is reduced. Here, we report that these deficits are restored by repeated, systemic administration of AMPH (1.78 mg/kg, every other day for 8 d). AMPH stimulates DA D(2) receptors indirectly by increasing extracellular DA. Supporting a role for D(2) receptors in mediating this "rescue," the effect was completely blocked by pre-treatment of STZ-treated rats with the D(2) receptor antagonist raclopride before systemic AMPH. D(2) receptors regulate DAT cell surface expression through ERK1/2 signaling. In ex vivo striatal preparations, repeated AMPH injections increased immunoreactivity of phosphorylated ERK1/2 (p-ERK1/2) in STZ-treated but not control rats. These data suggest that repeated exposure to AMPH can rescue, by activating D(2) receptors and p-ERK signaling, deficits in DAT function that result from hypoinsulinemia. Our data confirm the idea that disorders influencing insulin levels and/or signaling, such as diabetes and anorexia, can degrade DAT function and that insulin-independent pathways are present that may be exploited as potential therapeutic targets to restore normal DAT function.
    Full-text · Article · Feb 2012 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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