Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use

Departments of Psychiatry and Behavioral Sciences and Pharmacology, University of Washington, Seattle, WA 98195.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2012; 109(50). DOI: 10.1073/pnas.1213460109
Source: PubMed

ABSTRACT Drug addiction is a neuropsychiatric disorder that marks the end stage of a progression beginning with recreational drug taking but culminating in habitual and compulsive drug use. This progression is considered to reflect transitions among multiple neural loci. Dopamine neurotransmission in the ventromedial striatum (VMS) is pivotal in the control of initial drug use, but emerging evidence indicates that once drug use is well established, its control is dominated by the dorsolateral striatum (DLS). In the current work, we conducted longitudinal neurochemical recordings to ascertain the spatiotemporal profile of striatal dopamine release and to investigate how it changes during the period from initial to established drug use. Dopamine release was detected using fast-scan cyclic voltammetry simultaneously in the VMS and DLS of rats bearing indwelling i.v. catheters over the course of 3 wk of cocaine self-administration. We found that phasic dopamine release in DLS emerged progressively during drug taking over the course of weeks, a period during which VMS dopamine signaling declined. This emergent dopamine signaling in the DLS mediated discriminated behavior to obtain drug but did not promote escalated or compulsive drug use. We also demonstrate that this recruitment of dopamine signaling in the DLS is dependent on antecedent activity in VMS circuitry. Thus, the current findings identify a striatal hierarchy that is instantiated during the expression of established responses to obtain cocaine.

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Available from: Ingo Willuhn, Sep 28, 2015
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    • "were completely prevented by a specific nucleus accumbens core (NAcbC) lesion (Willuhn et al. 2012). Remarkably, functional coupling between the ventral and the dorsal striatum has also been shown in former heroin addicts, together with decreased functional coupling between the striatum and the PFC (Xie et al. 2014). "
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    ABSTRACT: A decade ago, we hypothesized that drug addiction can be viewed as a transition from voluntary, recreational drug use to compulsive drug-seeking habits, neurally underpinned by a transition from prefrontal cortical to striatal control over drug seeking and taking as well as a progression from the ventral to the dorsal striatum. Here, in the light of burgeoning, supportive evidence, we reconsider and elaborate this hypothesis, in particular the refinements in our understanding of ventral and dorsal striatal mechanisms underlying goal-directed and habitual drug seeking, the influence of drug-associated Pavlovian-conditioned stimuli on drug seeking and relapse, and evidence for impairments in top-down prefrontal cortical inhibitory control over this behavior. We further review animal and human studies that have begun to define etiological factors and individual differences in the propensity to become addicted to drugs, leading to the description of addiction endophenotypes, especially for cocaine addiction. We consider the prospect of novel treatments for addiction that promote abstinence from and relapse to drug use. Expected final online publication date for the Annual Review of Psychology Volume 67 is January 03, 2016. Please see for revised estimates.
    Annual Review of Psychology 08/2015; 67(1). DOI:10.1146/annurev-psych-122414-033457 · 21.81 Impact Factor
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    • "From a more general view, and given the model we have advanced regarding the role of striatal circuits in the conversion of nociception to acute pain, one can further expand our proposed model to chronic pain. Borrowing from the literature on mechanisms underlying addictive behavior for positive reward (Robinson and Kolb, 2004; Schultz, 2000; Volkow et al., 2010; Willuhn et al., 2012), we affirm that long-term shifts in the threshold mechanisms that gate the conversion from nociception to pain also underlie the transition to chronic pain (Figure 2E). We further propose that the threshold shift is dependent on limbic circuitry invoking synaptic learning-based reorganization (Apkarian, 2008; Apkarian et al., 2009). "
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    ABSTRACT: Recent neuroimaging studies suggest that the brain adapts with pain, as well as imparts risk for developing chronic pain. Within this context, we revisit the concepts for nociception, acute and chronic pain, and negative moods relative to behavior selection. We redefine nociception as the mechanism protecting the organism from injury, while acute pain as failure of avoidant behavior, and a mesolimbic threshold process that gates the transformation of nociceptive activity to conscious pain. Adaptations in this threshold process are envisioned to be critical for development of chronic pain. We deconstruct chronic pain into four distinct phases, each with specific mechanisms, and outline current state of knowledge regarding these mechanisms: the limbic brain imparting risk, and the mesolimbic learning processes reorganizing the neocortex into a chronic pain state. Moreover, pain and negative moods are envisioned as a continuum of aversive behavioral learning, which enhance survival by protecting against threats. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 08/2015; 87(3):474-91. DOI:10.1016/j.neuron.2015.06.005 · 15.05 Impact Factor
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    • "As the charging currents resulting from these voltage ramps are stable (Robinson et al., 2003), they are continually background-subtracted in order to examine the changes in current associated with changes in concentration of electroactive species surrounding the carbon fiber (Fig. 1B–D) (Robinson et al., 2003). As such, FSCV data are presented as a delta, and background-subtracted data are the norm for measuring phasic changes in neurotransmission, including DA release (Garris & Wightman, 1994; Phillips et al., 2003b; Willuhn et al., 2012). Current changes are detected at the surface of the carbon-fiber microelectrodes, and changes beyond those caused by the charging current are plotted in false color against time and the applied voltage ramp (Fig. 1B) (Michael et al., 1999). "
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    ABSTRACT: While most drugs of abuse increase dopamine neurotransmission, rapid neurochemical measurements show that different drugs evoke distinct dopamine release patterns within the nucleus accumbens. Rapid changes in dopamine concentration following psy-chostimulant administration have been well studied; however, such changes have never been examined following opioid delivery. Here, we provide novel measures of rapid dopamine release following intravenous infusion of two opioids, morphine and oxyco-done, in drug-na€ ıve rats using fast-scan cyclic voltammetry and rapid (1 min) microdialysis coupled with high-performance liquid chromatography -tandem mass spectrometry (HPLC-MS). In addition to measuring rapid dopamine transmission, microdialysis HPLC-MS measures changes in GABA, glutamate, monoamines, monoamine metabolites and several other neurotransmitters. Although both opioids increased dopamine release in the nucleus accumbens, their patterns of drug-evoked dopamine transmis-sion differed dramatically. Oxycodone evoked a robust and stable increase in dopamine concentration and a robust increase in the frequency and amplitude of phasic dopamine release events. Conversely, morphine evoked a brief (~ 1 min) increase in dopamine that was coincident with a surge in GABA concentration and then both transmitters returned to baseline levels. Thus, by providing rapid measures of neurotransmission, this study reveals previously unknown differences in opioid-induced neuro-transmitter signaling. Investigating these differences may be essential for understanding how these two drugs of abuse could differentially usurp motivational circuitry and powerfully influence behavior.
    European Journal of Neuroscience 11/2014; 40(7):1-14. DOI:10.1111/ejn.12709 · 3.18 Impact Factor
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