Cocaine Cues and Dopamine in Dorsal Striatum: Mechanism of Craving in Cocaine Addiction

National Institute on Alcohol Abuse and Alcoholism, Bethesda Maryland 20892, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2006; 26(24):6583-8. DOI: 10.1523/JNEUROSCI.1544-06.2006
Source: PubMed


The ability of drugs of abuse to increase dopamine in nucleus accumbens underlies their reinforcing effects. However, preclinical studies have shown that with repeated drug exposure neutral stimuli paired with the drug (conditioned stimuli) start to increase dopamine by themselves, which is an effect that could underlie drug-seeking behavior. Here we test whether dopamine increases occur to conditioned stimuli in human subjects addicted to cocaine and whether this is associated with drug craving. We tested eighteen cocaine-addicted subjects using positron emission tomography and [11C]raclopride (dopamine D2 receptor radioligand sensitive to competition with endogenous dopamine). We measured changes in dopamine by comparing the specific binding of [11C]raclopride when subjects watched a neutral video (nature scenes) versus when they watched a cocaine-cue video (scenes of subjects smoking cocaine). The specific binding of [11C]raclopride in dorsal (caudate and putamen) but not in ventral striatum (in which nucleus accumbens is located) was significantly reduced in the cocaine-cue condition and the magnitude of this reduction correlated with self-reports of craving. Moreover, subjects with the highest scores on measures of withdrawal symptoms and of addiction severity that have been shown to predict treatment outcomes, had the largest dopamine changes in dorsal striatum. This provides evidence that dopamine in the dorsal striatum (region implicated in habit learning and in action initiation) is involved with craving and is a fundamental component of addiction. Because craving is a key contributor to relapse, strategies aimed at inhibiting dopamine increases from conditioned responses are likely to be therapeutically beneficial in cocaine addiction.

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    • "l . , 1998 ) . One of the most common functional abnormalities exhibited by cocaine users is and over - reactivity to cocaine - related stimuli and under - reactivity to stimuli with any other contant ( Aguilar de Arcos et al . , 2005 ; Volkow et al . , 2010 ) , and this differential reactivity is generally associated with aberrant vSTR activity ( Volkow et al . , 2006 ; Childress et al . , 2008 ; Asensio et al . , 2010 ; Dunning et al . , 2011 ; Holroyd et al . , 2014 ) . Our findings suggest that , in addition to being under - reactive to non - drug rewards , cocaine users may also be under - reactive to aversive stimuli which are unrelated to cocaine use , such as depictions of immoral acts . As par"
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    ABSTRACT: Investigations into the neurobiology of moral cognition are often done by examining clinical populations characterized by diminished moral emotions and a proclivity toward immoral behavior. Psychopathy is the most common disorder studied for this purpose. Although cocaine abuse is highly co-morbid with psychopathy and cocaine-dependent individuals exhibit many of the same abnormalities in socio-affective processing as psychopaths, this population has received relatively little attention in moral psychology. To address this issue, the authors used functional magnetic resonance imaging (fMRI) to record hemodynamic activity in 306 incarcerated male adults, stratified into regular cocaine users (n = 87) and a matched sample of non-cocaine users (n = 87), while viewing pictures that did or did not depict immoral actions and determining whether each depicted scenario occurred indoors or outdoors. Consistent with expectations, cocaine users showed abnormal neural activity in several frontostriatial regions during implicit moral picture processing compared to their non-cocaine using peers. This included reduced moral/non-moral picture discrimination in the vACC, vmPFC, lOFC, and left vSTR. Additionally, psychopathy was negatively correlated with activity in an overlapping region of the ACC and right lateralized vSTR. These results suggest that regular cocaine abuse may be associated with affective deficits which can impact relatively high-level processes like moral cognition.
    Frontiers in Human Neuroscience 11/2015; 9. DOI:10.3389/fnhum.2015.00565 · 3.63 Impact Factor
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    • "al tegmental area , anterior and prefrontal cortex ( PFC ) , hippocampus , and nucleus accumbens ( NAc ) ( Garavan et al. , 2000 ; Grusser et al. , 2004 ; Jasinska et al. , 2014 ; Lukas et al. , 2013 ; Maas et al. , 1998 ) . With re - peated and uncontrollable drug use , dorsal striatal responses to drug cues are elevated ( Dalley et al . , 2011 ; Volkow et al . , 2006 ) . Functional MRI ( fMRI ) responses in adult rodents exposed to drug - associated cues following chronic cocaine intake show remarkable anatomical faithfulness to these human fMRI changes ( Johnson et al . , 2013 ; Liu et al . , 2013a ) . Because these responses are both reliable and robust , ge - netically modified animals could prov"
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    ABSTRACT: Adolescents are highly vulnerable to addiction and are four times more likely to become addicted at first exposure than at any other age. The dopamine D1 receptor, which is typically overexpressed in the normal adolescent prefrontal cortex, is involved in drug cue responses and is associated with relapse in animal models. In human drug addicts, imaging methods have detected increased activation in response to drug cues in reward- and habit-associated brain regions. These same methods can be applied more quantitatively to rodent models. Here, changes in neuronal activation in response to cocaine-conditioned cues were observed using functional magnetic resonance imaging in juvenile rats that were made to over-express either D1 receptors or green fluorescent protein by viral-mediated transduction. Reduced activation was observed in the amygdala and dopamine cell body regions in the low cue-preferring/control juvenile rats in response to cocaine cues. In contrast, increased activation was observed in the dorsal striatum, nucleus accumbens, prefrontal cortex, and dopamine cell bodies in high cue-preferring/D1 juveniles. The increase in cue salience that is mediated by increased D1 receptor density, rather than excessive cocaine experience, appears to underlie the transition from aversion to reward in cue-induced neural response and may form the basis for habit-forming vulnerability.
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    • "Similarly, addiction is characterized in part by excessive emotional and motivational responses to drug-related cues, i.e. cue-induced craving [17]. The extent to which drug-related cues induce such motivational responses in an individual is positively correlated with a number of clinically relevant variables, such as addiction severity, risk of relapse, and poor treatment outcomes [18] [19]. Thus, a general tendency to attribute excessive motivational salience to conditioned cues, regardless of the emotional valence of those cues, would likely predispose an individual to developing both addiction and PTSD. "
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    ABSTRACT: Although post-traumatic stress disorder (PTSD) and addiction are very different disorders, both are characterized by hyperreactivity to trauma- or drug-related cues, respectively. We investigated whether an appetitive conditioning task, Pavlovian conditioned approach, which predicts vulnerability to reinstatement of cocaine-seeking, also predicts fear incubation, which may be a marker for vulnerability to PTSD. We classified rats based on whether they learned to approach and interact with a food predictive cue (sign-trackers), or, whether upon cue presentation they went to the location of impending food delivery (goal-trackers). Rats were then exposed to extensive Pavlovian tone-shock pairings, which causes the fear response to increase or "incubate" over time. We found that the fear incubation effect was only present in sign-trackers. The behavior of goal-trackers was more consistent with a normal fear response-it was most robust immediately after training and decayed slowly over time. Sign-trackers also had lower levels of brain-derived neurotrophic factor (BDNF) protein in the prefrontal cortex than goal-trackers. These results indicate that, while many factors likely contribute to the disproportionate co-occurrence of PTSD and substance abuse, one such factor may be a core psychological trait that biases some individuals to attribute excessive motivational significance to predictive cues, regardless of the emotional valence of those cues. High levels of BDNF in the prefrontal cortex may be protective against developing excessive emotional and motivational responses to salient cues.
    Behavioural brain research 04/2015; 276:59-66. DOI:10.1016/j.bbr.2014.04.002 · 3.03 Impact Factor
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