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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    • "Taken together, these findings support the hypothesis that a shift from the ventral to the dorsal striatum may occur in more advanced stages in addiction-like trajectory, after prolonged exposure to cocaine (Everitt and Robbins, 2005;Fagergren et al., 2003;Vanderschuren et al., 2005). Whereas drugs of abuse, including cocaine, initially lead to dopamine release into the ventral striatum, as well as dorsal striatum (Di Chiara and Imperato, 1988a;Goeders and Smith, 1983;Pontieri et al., 1995), it has been postulated that repeated exposure in the context of extended access self-administration lead to compulsive-like habit M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPTValenza M. et al. 26formations, mediated at least in part by the DS (Ito et al., 2002;Veeneman et al., 2012;Volkow et al., 2006;Willuhn et al., 2014). The possibility that gene expression alterations in cocaine-exposed rats were induced by acute withdrawal (24 h) cannot be ruled out. "
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    ABSTRACT: The aim of the present study was to investigate alterations in gene expression of opioid system components induced by extended access (18 h) cocaine self-administration and to determine the impact of genetic background in the vulnerability to escalate cocaine intake. Comparing two inbred rat strains, we previously reported that Lewis rats progressively escalated cocaine consumption compared to Fischer rats, in a new translational model of intravenous cocaine self-administration, which included 14 sessions of 18-h operant sessions in which rats were allowed to select the cocaine unit dose to self-administer. We compare here Fischer and Lewis rats in the gene expression of endogenous opioid peptides (Pomc, Penk, Pdyn) and cognate receptors (Oprm, Oprk and Oprd) in reward-related brain regions, after exposure to either cocaine self-administration or yoked-saline, in the aforementioned translational paradigm. We performed a correlation analysis between the mRNA level, found in the Dorsal Striatum (DS), Nucleus accumbens (NAcc) shell and core respectively, and individual cocaine intake. Our findings show that the gene expression of all the aforementioned opioid genes exhibit strain-dependent differences in the DS, in absence of cocaine exposure. Also, different strain-specific cocaine-induced mRNA expression of Oprm and Oprk was found in DS. Only few differences were found in the ventral parts of the striatum. Moreover, gene expression level of Pdyn, Penk, Oprk, and Oprm in the DS was significantly correlated with cocaine intake only in Fischer rats. Overall, these data shed light on potential genetic differences which may predispose of subjects to initiate and escalate cocaine consumption.
    Full-text · Article · Jan 2016 · Neuropharmacology
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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.
    Full-text · Article · Nov 2015 · Frontiers in Human Neuroscience
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    • "Mounting evidence suggests that dopamine D 2 -like (D 2 , D 3 and D 4 ) receptors mediate, at least in part, a variety of abuserelated behaviors, including those impacting vulnerability to relapse (Newman et al., 2005; Heidbreder et al., 2005; Everitt et al., 2008; Heidbreder and Newman, 2010). Although numerous factors likely contribute to relapse, it is now well established that previously neutral environmental stimuli can take on powerful conditioned properties that might serve to promote relapse-related behaviors in laboratory animals (Davis and Smith, 1976; De Wit and Stewart, 1983; Goldberg et al., 1979) and humans (O'Brien et al., 1977; Childress et al., 1988; Volkow et al., 2006). Over the past 40 years, procedures have been developed to investigate factors important to relapse, with reinstatement procedures used widely to model relapse in laboratory animals (e.g., De Wit and Stewart, 1983; Epstein et al., 2006; Bossert et al., 2013). "
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    ABSTRACT: Environmental stimuli associated with drug use can take on conditioned properties capable of promoting drug-seeking behaviors during abstinence. This study investigated the relative importance of the amount of reinforced responding, number of cocaine-stimulus pairings, total cocaine intake, and reinforcing effectiveness of the self-administered dose of cocaine to the conditioned reinforcing effectiveness of cocaine-associated stimuli (CS). Male rats were trained to self-administer cocaine (0.1 [small] or 1.0mg/kg/inf [large]) under a fixed ratio schedule of reinforcement. A progressive ratio (PR) schedule was used to quantify the reinforcing effectiveness of each dose of cocaine, as well as the conditioned reinforcing effectiveness of the CS following treatment with saline or the dopamine D2-like receptor agonist pramipexole (0.1-3.2mg/kg). The large dose of cocaine maintained larger final ratios and greater levels of cocaine intake, whereas the small dose resulted in more cocaine-CS pairings. The total amount of responding was comparable between groups. During PR tests of conditioned reinforcement, pramipexole increased responding for CS presentations in both groups; however, the final ratio completed was significantly greater in large- as compared to small-dose group. In addition to highlighting a central role for dopamine D2-like receptors in modulating the effectiveness of cocaine-paired stimuli to reinforce behavior, these results suggest that conditioned reinforcing effectiveness is primarily determined by the reinforcing effectiveness of the self-administered dose of cocaine and/or total cocaine intake, and not the total amount of responding or number cocaine-stimulus pairings. These findings have implications for understanding how different patterns of drug-taking might impact vulnerability to relapse.
    Full-text · Article · Nov 2015 · European journal of pharmacology
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