Addiction: A Disease of Learning and Memory

Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
American Journal of Psychiatry (Impact Factor: 12.3). 09/2005; 162(8):1414-22. DOI: 10.1176/appi.ajp.162.8.1414
Source: PubMed


If neurobiology is ultimately to contribute to the development of successful treatments for drug addiction, researchers must discover the molecular mechanisms by which drug-seeking behaviors are consolidated into compulsive use, the mechanisms that underlie the long persistence of relapse risk, and the mechanisms by which drug-associated cues come to control behavior. Evidence at the molecular, cellular, systems, behavioral, and computational levels of analysis is converging to suggest the view that addiction represents a pathological usurpation of the neural mechanisms of learning and memory that under normal circumstances serve to shape survival behaviors related to the pursuit of rewards and the cues that predict them. The author summarizes the converging evidence in this area and highlights key questions that remain.

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    • "Research, using diverse methods, has converged on the point that the dopamine (DA) system is fundamentally important to reward related behaviors (Berridge and Robinson, 1998; Hyman, 2005; Palmiter, 2008). It has been well established that drugs producing rewarding effects are dependent on their ability to elevate extracellular DA levels in the mesolimbic DA system (Koob and Volkow, 2010). "
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    ABSTRACT: It is well known that dopamine (DA) is critical for reward, but the precise role of DA in reward remains uncertain. The aim of this study was to determine what percentage of dopaminergic neurons in the primate brain is required for the expression of conditioned reward by measuring the performance of DA-deficient rhesus monkeys in a morphine-induced conditioned place preference (CPP) paradigm. Animals with mild Parkinsonian symptoms successfully developed and retained a morphine preference that was equivalent to control monkeys. However, these monkeys could not maintain the preference as well as controls when they retained severe Parkinsonian symptoms. On the other hand, monkeys initially in a severe Parkinsonian state developed a preference for morphine, but this preference was weaker than that of the controls. Histological results showed that the loss of dopaminergic neurons in monkeys that had severe Parkinsonian symptoms was about 80% in comparison to the control monkeys. All these data suggest that a severely impaired DA system alters rewarding-seeking behavior in non-human primates.
    Frontiers in Behavioral Neuroscience 11/2015; 9:273. DOI:10.3389/fnbeh.2015.00273 · 3.27 Impact Factor
    • "Drug addiction can be characterized as a disorder of maladaptive learning and memory (Everitt, Dickinson, & Robbins, 2001). Addictive drugs have the ability to hijack the natural reward system and influence the strength of memories that predict reward (Everitt et al., 2001; Hyman, 2005; Hyman, Malenka, & Nestler, 2006; Torregrossa, Corlett, & Taylor, 2011). These memories can be linked to external cues in the environment that have previously been accompanied by drug use (Crombag & Shaham, 2002). "
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    ABSTRACT: Over the past decade, a growing body of research has sought to investigate how the pharmacological disruption of memory reconsolidation can degrade or erase memories. Much of this research has focused specifically on disrupting memories that are considered bad or maladaptive for the ultimate purpose of translation to a human population. While most of the research was pioneered in fear memory, recent studies have focused on degrading drug-cued memories in the context of addiction. Essentially, this research seeks to disrupt cues as predictors of reward or drug availability. A core component of this reconsolidation process is glutamate signaling. An overall review of the literature suggests that disruption of glutamate signaling under reconsolidation parameters is sufficient to erase drug-related memories. This review will focus on specific studies that examine the glutamatergic mechanisms of reconsolidation disruption in the context of drug addiction.
    Journal of Applied Biobehavioral Research 09/2015; 20(3). DOI:10.1111/jabr.12031
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    • "Forexample,Simonyietal.(2010)reviewednumerousani- malstudieswhichemployedmGluR5receptorantagonistsin knockoutmicetodeterminetheroleofmGluR5inlearning andmemory.Inhibitorylearning,suchaspassiveavoidance learning,isawell-establishedtaskinanimalmodelsthatisused tostudyhippocampallearningprocesses,andhasbeenshown innumerousstudiestobedependentonthemGluR5receptor (Simonyietal.,2010).Forinstance,researchdemonstrated hyperexpressionofmGluR5proteininCA3duringshort- andCA1long-termpotentiationinrats(Riedeletal.,2000). Hyman(2005)presentedabiologicalmodelofaddictionthat incorporatesabnormalneuralprocessesoflearningandmemory formingthebasicelementsofaddiction.Theauthorsproposed thatlong-termpotentiation,whichincludes,alterationsinthe availabilityofglutamatereceptors,andregulationofgeneexpres- sionaspotentiallyimportantmechanismsforthedrug-induced alterationsfoundintheabnormalcircuitsassociatedwithdrug addiction.Finally,thestudiesonmGluR5andsleephomeostasis (Heftietal.,2013;Ahnaouetal.,2015)suggestanimportant roleofmGluR5inRDoC'sarousalandmodulatorysystems domain. "
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    ABSTRACT: In the present review, we deliver an overview of the involvement of metabotropic glutamate receptor 5 (mGluR5) activity and density in pathological anxiety, mood disorders and addiction. Specifically, we will describe mGluR5 studies in humans that employed Positron Emission Tomography (PET) and combined the findings with preclinical animal research. This combined view of different methodological approaches-from basic neurobiological approaches to human studies-might give a more comprehensive and clinically relevant view of mGluR5 function in mental health than the view on preclinical data alone. We will also review the current research data on mGluR5 along the Research Domain Criteria (RDoC). Firstly, we found evidence of abnormal glutamate activity related to the positive and negative valence systems, which would suggest that antagonistic mGluR5 intervention has prominent anti-addictive, anti-depressive and anxiolytic effects. Secondly, there is evidence that mGluR5 plays an important role in systems for social functioning and the response to social stress. Finally, mGluR5's important role in sleep homeostasis suggests that this glutamate receptor may play an important role in RDoC's arousal and modulatory systems domain. Glutamate was previously mostly investigated in non-human studies, however initial human clinical PET research now also supports the hypothesis that, by mediating brain excitability, neuroplasticity and social cognition, abnormal metabotropic glutamate activity might predispose individuals to a broad range of psychiatric problems.
    Frontiers in Neuroscience 03/2015; 9:86. DOI:10.3389/fnins.2015.00086 · 3.66 Impact Factor
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