Is There a Common Molecular Pathway for Addiction?

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: 16.1). 12/2005; 8(11):1445-9. DOI: 10.1038/nn1578
Source: PubMed


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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    • "It is assumed that opioids reduce alcohol consumption by blocking the rewarding effects associated with an alcohol-stimulated increase in endogenous opioid activity (Gianoulakis, 2001; Modesto-Lowe and Fritz, 2005). One reason for such interaction may be because opioids, alcohol and other drugs of abuse share a common pathway (Nestler, 2005). The specific opioid receptor subtype that mediates the effects of ethanol and the ability of opioid antagonists to reduce ethanol consumption continue to be explored. "
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    ABSTRACT: Opioidergic system plays an important role in controlling alcohol seeking behaviour. We have previously shown that a quinoline compound, S4 (2-(2-methylquinolin-4-ylamino)-N-phenyl acetamide), having dual affinity for µ- and κ-opioid receptors, could successfully inhibit withdrawal symptoms in mice rendered dependent on morphine. Accordingly, in the present study, we sought to determine the potential of S4 in attenuating voluntary alcohol intake in alcohol-preferring (AP) mice and the mechanism thereof. The study was conducted in different mice strains initially screened for AP and alcohol-avoiding (AA) behavior. S4 was injected subcutaneously (20 mg/kg) to evaluate its efficacy in reducing voluntary alcohol consumption along with prevention of body weight loss during withdrawal from alcohol after discontinuation of the drug. The results showed that S4 significantly reduced the alcohol intake in AP mice and also in a dose dependent manner. Mechanistic studies on the post translational histone H3 modifications in brain of AP mice compared to the AA mice were determined. Compared to AA mice, histone H3 trimethylation at lys9 and its regulators, jumonji domain containing 2A and phosphorylated histones H3 at thr11 as well as the expression of 14-3-3 protein and phosphorylated histones H3 at ser28, were altered in the AP animals, most of which were restored post S4 treatment in the AP mice. Together, the present results suggest that S4 effectively blocked alcohol drinking behavior by restoring the altered epigenetic signature in the AP mice. The study provides a novel compound which could lead to developing effective drugs against alcoholism/alcohol abuse. Copyright © 2015. Published by Elsevier Ltd.
    Neurochemistry International 06/2015; 87. DOI:10.1016/j.neuint.2015.06.007 · 3.09 Impact Factor
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    • "Their analgesic and addictive properties, however, depend on distinct neural systems. Analgesia is mediated by actions at various spinal, brain stem and forebrain sites (Millan, 2002) whereas their abuse liability depends instead on the indirect activation of the mesolimbic dopamine system (Koob and Volkow, 2010; Nestler, 2005). Thus, it may be possible to counteract opioid abuse without interfering with analgesia. "
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    ABSTRACT: Many drugs abused by humans acutely facilitate, either directly or indirectly, dopamine neurotransmission in the mesolimbic pathway. As a consequence dopamine receptor agonists and antagonists have been widely investigated as putative pharmacological therapies for addiction. This general strategy, however, has had only limited success due in part to poor treatment adherence and efficacy and the significant adverse effects of dopaminergic medications. In this perspective, we discuss the potential therapeutic use of dopamine receptor partial agonists in addiction, developed initially as antipsychotic agents. Recent research indicates that the dopamine D2 receptor partial agonists, such as aripiprazole, also shows useful ancillary efficacy in several animal models of psychostimulant and opioid addiction. Notably, these findings suggest that unlike full dopamine receptor agonists and antagonists these compounds have low abuse liability and are generally well tolerated. Indeed, partial dopamine agonists attenuate the rewarding properties of opioids without interfering with their analgesic effects. Herein we discuss the utility and potential of dopamine receptor partial agonists as treatments for both stimulant and non-stimulant drug addiction. Copyright © 2015. Published by Elsevier B.V.
    European Journal of Pharmacology 02/2015; 752. DOI:10.1016/j.ejphar.2015.02.025 · 2.53 Impact Factor
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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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