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.
"Similarly, addiction is characterized in part by excessive emotional and motivational responses to drug-related cues, i.e. cue-induced craving . 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  . 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. "
[Show abstract][Hide abstract] 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
"These findings may reflect impaired communication across parallel corticostriatal circuits in the dopamine-deprived striatum in Parkinson's disease. A recent body of neuroanatomical data has revealed the existence of striato-nigro-striatal circuitry, comprised of spiraling neuronal connections between the striatum and the dopaminergic midbrain (substantia nigra/ ventral tegmental area) (Haber, 2003; Haber et al., 2000), which have been shown to enable transfer of information across functional subdivisions of the striatum (Belin and Everitt, 2008; Everitt and Robbins, 2005; Porrino et al., 2007; Volkow et al., 2006). Although fMRI is unable to disentangle the underlying cellular mechanisms by which dopaminergic pathology compromises connectivity across striatal subdivisions in Parkinson's disease, impaired dopaminergic neurotransmission throughout striato-nigro-striatal circuitry represents an important candidate mechanism. "
[Show abstract][Hide abstract] ABSTRACT: The pathological hallmark of Parkinson’s disease is the degeneration of dopaminergic nigrostriatal neurons, leading to depletion of striatal dopamine. Recent neuroanatomical work has identified pathways for communication across striatal subdivisions, suggesting that the striatum provides a platform for integration of information across parallel corticostriatal circuits. The aim of this study was to investigate whether dopaminergic dysfunction in Parkinson’s disease was associated with impairments in functional connectivity across striatal subdivisions, which could potentially reflect reduced integration across corticostriatal circuits. Utilizing resting-state functional magnetic resonance imaging (fMRI), we analyzed functional connectivity in 39 patients with Parkinson’s disease, both “on” and “off” their regular dopaminergic medications, along with 40 age-matched healthy controls. Our results demonstrate widespread impairments in connectivity across subdivisions of the striatum in patients with Parkinson’s disease in the “off” state. The administration of dopaminergic medication significantly improved connectivity across striatal subdivisions in Parkinson’s disease, implicating dopaminergic deficits in the pathogenesis of impaired striatal interconnectivity. In addition, impaired striatal interconnectivity in the Parkinson’s disease “off” state was associated with pathological decoupling of the striatum from the thalamic and sensorimotor (SM) networks. Specifically, we found that although the strength of striatal interconnectivity was positively correlated with both (i) the strength of internal thalamic connectivity, and (ii) the strength of internal SM connectivity, in both healthy controls and the Parkinson’s disease “on” state, these relationships were absent in Parkinson’s disease when in the “off” state. Taken together our findings emphasize the central role of dopamine in integrated striatal function and the pathological consequences of striatal dopamine denervation in Parkinson’s disease.
Human Brain Mapping 04/2015; 36(4). DOI:10.1002/hbm.22701 · 5.97 Impact Factor
"Drug-conditioned stimuli, which can be discrete (ie, a syringe) and/or environmental (ie, a room), acquire the ability to activate drugoriented behaviors because they are repeatedly perceived in conjunction with the unconditioned effects of drugs of abuse (Stewart et al., 1984). Hence, through Pavlovian conditioning , drug-conditioned stimuli become " wanted " (Robinson and Berridge, 1993) and preferred (Moeller et al., 2009), " grab " attention (Field and Cox, 2008), and produce various physiological and psychological responses (Carter and Tiffany, 1999; Volkow et al., 2006), including increased self-reports of drug craving. Therefore, if DD act as drug-conditioned stimuli, they should be followed by various conditioned responses including elevation in cravings. "
[Show abstract][Hide abstract] ABSTRACT: To explore the relationship between occurrence of drug dreams (DDs) and daytime negative affect and drug craving during the course of a 5-week treatment program for substance dependence.
Using the dream journal methodology, 86 participants reported occurrence of dreams, dream content, and ratings of affect and drug craving. The relationships between the experience of DD, dream content ("active" vs "passive"), and affect and craving were analyzed using mixed model methods.
The experience of DD was associated with higher levels of negative affect (P < 0.001) and craving (P < 0.001). The occurrence of DD did not decrease significantly over the 5 weeks of the study. Cocaine/crack users reported a higher occurrence of DD (P < 0.05) than the other drug groups (opiates and alcohol), and DD involving "active" drug use was associated with larger (P < 0.05) changes in negative affect.
These results are consistent with the hypothesis that DD can act as drug-conditioned stimuli to elevate negative affect and craving in abstaining individuals. Although correlational, such findings support the implementation of psychological and pharmacological interventions aimed at minimizing the impact of DD on individuals in recovery from drug addiction.
Journal of Addiction Medicine 02/2015; 9(2). DOI:10.1097/ADM.0000000000000105 · 1.76 Impact Factor
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