Nestler EJ. Is there a common molecular pathway for addiction? Nat Neurosci 8: 1445-1449

Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9070, USA.
Nature Neuroscience (Impact Factor: 14.98). 12/2005; 8(11):1445-9. DOI: 10.1038/nn1578
Source: PubMed

ABSTRACT Drugs of abuse have very different acute mechanisms of action but converge on the brain's reward pathways by producing a series of common functional effects after both acute and chronic administration. Some similar actions occur for natural rewards as well. Researchers are making progress in understanding the molecular and cellular basis of these common effects. A major goal for future research is to determine whether such common underpinnings of addiction can be exploited for the development of more effective treatments for a wide range of addictive disorders.

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    • "Improvements in brain function have also been indicated in abstinent methamphetamine- and cocaine-dependent individuals (Volkow et al., 2001; Brewer et al., 2008), and in abstinent cocaine-dependent rats (Hollander and Carelli, 2005). Although studies of abstinent substance users are useful for the investigation of addictive behavior in general, there remains a question as to whether recovery of brain abnormalities is due to withdrawal from repeated exposure to toxic substances (e.g., substance-specific neuronal damage) or to discontinuation of addictive behavior per se (e.g., dopamine-mediated neuroadaptation) (Nestler, 2005). Studying brain abnormalities in abstinent behavioral addiction including PG enables us to exclude possible effects of exposure to toxic substances, which should provide important insight that can lead to a better understanding of addiction. "
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    ABSTRACT: Pathological gambling (PG) is a chronic mental disorder characterized by difficulty inhibiting gambling behavior despite negative consequences. Accumulating evidence suggests that PG has many similarities with substance use disorders. Although brain abnormalities in patients of substance use disorders are facilitated by repetitive drug use and recover partly with drug abstinence, the relationship between brain activity and duration of illness or abstinence of gambling behavior in PG patients remains unclear. Here, using functional magnetic resonance imaging, we compared the brain activity of 23 PG patients recruited from a treatment facility with 27 demographically-matched healthy control subjects during reward anticipation, and examined the correlation between brain activity and duration of illness or abstinence in PG subjects. During reward anticipation, PG patients showed decreased activity compared to healthy controls in a broad range of the reward system regions, including insula and cingulate cortex. In PG patients, activation in left insula was negatively correlated with duration of illness, and showed a modest positive correlation with duration of abstinence. Our findings suggest that insular activation during reward anticipation may serve as a marker of progression and recovery of PG.
    Alcohol and alcoholism (Oxford, Oxfordshire). Supplement 09/2014; 49 Suppl 1(suppl 1):i45. DOI:10.1093/alcalc/agu053.35
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    • "In addition to regulating satiety, leptin controls the incentive value of food and other rewards and suppresses depression and anxiety-like behavior (Fulton et al., 2000; DiLeone et al., 2003; Figlewicz et al., 2006; Lu et al., 2006; Liu et al., 2010). For instance, the mesolimbic dopamine (DA) system that arises from dopaminergic neurons in the ventral tegmental area (VTA), mediates important aspects of incentive salience for food but also contributes to aspects of emotion and behavior (DiLeone et al., 2003; Kelley et al., 2005; Nestler, 2005). Furthermore, the centrally-projecting Edinger–Westphal nucleus (EWcp) urocortin 1 (Ucn1) system is involved in the stress response and anxiety-and depression-like behavior. "
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    ABSTRACT: The midbrain is a heterogeneous brain structure that serves important roles in feeding regulation, motivation and reward, movement and stress adaptation. One common feature of different midbrain regions is that they all express the long form of leptin receptor (LepRb). Leptin is mainly produced and secreted by white adipose tissue, informing the brain centers via LepRb about the amount of fat storage in the body. In this way, leptin exerts its action in the midbrain to regulate different functions. First, this review deals with the basic information of leptin and its signaling. Then, attention is given to various interactions of leptin with the midbrain regions, including ventral tegmental area (VTA), substantia nigra pars compacta (SNc), rostral linear raphe (RLi) and centrally-projecting Edinger-Westphal nucleus (EWcp). Also, the projection areas of these midbrain regions are discussed. Finally, the possible function of leptin in the midbrain is suggested.
    Journal of Chemical Neuroanatomy 07/2014; 61-62. DOI:10.1016/j.jchemneu.2014.06.007 · 2.52 Impact Factor
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    • "Notably, relaxin-3 expressing neurons are strongly regulated by neurogenic stressors (Banerjee et al., 2010; Lenglos et al., 2013; Ryan et al., 2011), arousal-related stimuli (Smith et al., 2012) and associated transmitters, including CRF (Blasiak et al., 2013; Ma et al., 2013) and orexin (Blasiak et al., 2010). Furthermore, relaxin-3 neurons project widely throughout the rat forebrain (Ma et al., 2007; Tanaka et al., 2005), with relaxin- 3 immunoreactive axons/terminals in several regions known to mediate and/or modulate the central effects of alcohol and other drugs of abuse in this species, including the amygdala, bed nucleus of the stria terminalis, thalamic and hypothalamic paraventricular nuclei and lateral hypothalamus (Koob, 2008; Lawrence, 2010; Martin-Fardon and Boutrel, 2012; Nestler, 2005; Smith et al., 2011), which largely coincides with the distribution of RXFP3 expressing neurons (Ma et al., 2007; Sutton et al., 2004). Together these data suggest that examining the response of the relaxin-3/RXFP3 system to chronic alcohol exposure will increase our understanding of the complex neurochemical changes that occur in stress and arousal networks in substance abuse disorders. "
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    ABSTRACT: Background Chronic alcohol intake produces multiple neuroadaptive changes, including up- and down-regulation of neuropeptides and receptors. There are widespread projections of relaxin-3 containing neurons to, and abundant relaxin family peptide 3 receptor (RXFP3) expression within, brain regions involved in modulating alcohol intake. Recently we demonstrated the involvement of relaxin-3/RXFP3 signalling in alcohol-seeking in rats, therefore in this study we examined whether relaxin-3 and/or RXFP3 expression were altered by chronic alcohol intake in alcohol-preferring iP rats. Methods Expression of relaxin-3 mRNA in the hindbrain nucleus incertus and RXFP3 radioligand binding levels in discrete forebrain regions were investigated following voluntary intake of alcohol or sucrose for 12 weeks, with a 2 day washout, using quantitative in situ hybridisation histochemistry and in vitro receptor autoradiography, respectively, in cohorts of adult, male iP rats. Results Levels of relaxin-3 mRNA in the hindbrain nucleus incertus were positively correlated with the level of intake of both alcohol (r(12) = 0.59, p = 0.03) and sucrose (r(7) = 0.70, p = 0.04) in iP rats. Dense binding of the RXFP3-selective radioligand, [125]-R3/I5, was detected in hypothalamic and extrahypothalamic sites, but no significant changes in the density of RXFP3 were observed in the brain regions quantified following chronic sucrose or ethanol intake. Conclusions Our findings suggest high endogenous relaxin-3 expression may be associated with higher intake of rewarding substances, rather than its expression being regulated in response to their intake; consistent with an active role for the relaxin-3/RXFP3 system in modulating ingestive and alcohol-related behaviours.
    Drug and Alcohol Dependence 07/2014; DOI:10.1016/j.drugalcdep.2014.04.017 · 3.28 Impact Factor
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