Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications

Goldstein, Rita Z.; Volkow, Nora D.

doi:10.1038/nrn3119

Cited by 2,205 publications

(1,895 citation statements)

References 218 publications

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“…This region exerts an inhibitory effect on drug seeking (Goldstein and Volkow, 2011;Tang et al, 2015). Importantly, craving suppression was inversely correlated with the activity of this prefrontal area (Volkow et al, 2010).…”

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confidence: 92%

The cerebellum in drug craving

Moreno-Rius

Miquel

2017

Drug and Alcohol Dependence

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Craving has been considered one of the core features of addiction. It can be defined as the urge or conscious desire to use a drug elicited by the drug itself, drug-associated cues or stressors. Craving plays a major role in relapse, even after prolonged periods of abstinence, as well as in the maintenance of drug seeking in non-abstinent addicts. The circuitry of craving includes medial parts of the prefrontal cortex, ventral striatal zones, ventral tegmental area, ventral pallidum, and limbic regions. Interestingly, the cerebellum shows reciprocal loops with many of these areas. The cerebellum has been linked traditionally to motor functions but increasing evidence indicates that this part of the brain is also involved in functions related to cognition, prediction, learning, and memory. Moreover, the functional neuroimaging studies that have addressed the study of craving in humans repeatedly demonstrate cerebellar activation when craving is elicited by the presentation of drug-related cues. However, the role of cerebellar activity in these craving episodes remains unknown. Therefore, the main goal of this review is to provide a brief update on craving studies and the traditional neural basis of this phenomenon, and then discuss and propose a hypothesis for the function of the cerebellum in craving episodes.

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confidence: 92%

The cerebellum in drug craving

Moreno-Rius

Miquel

2017

Drug and Alcohol Dependence

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“…We have shown that small alterations to mPFC dopamine connectivity lead to sizeable changes in the pyramidal neuron morphology and excitability and, consequently, to changes in cognitive processing and responses to drugs of abuse (Grant et al, 2007;Manitt et al, 2011Manitt et al, , 2013Pokinko et al, 2014). Similarly, dopamine function in the human prefrontal cortex has been shown to play a critical role in higherorder cognitive processing, including behavioral inhibition and salience attribution, as well as in the regulation of subcortical reward circuitry (Robbins et al, 1994;Rogers et al, 1999;Tomasi et al, 2007;Goldstein and Volkow, 2011). Thus, by disrupting prefrontal cortex dopamine maturation, drug use in adolescence likely induces deficits in these processes, increasing vulnerability to develop addiction.…”

Section: Dcc-mediated Effects Of Amphetamine On the Sculpting Of Mpfcmentioning

confidence: 99%

“…Thus, by disrupting prefrontal cortex dopamine maturation, drug use in adolescence likely induces deficits in these processes, increasing vulnerability to develop addiction. Indeed, compelling evidence shows prefrontal cortex dysfunction and associated cognitive deficits in stimulant drug abusers (Verdejo-García et al, 2006;Tomasi et al, 2007;Woicik et al, 2011;Ersche et al, 2011;Goldstein and Volkow, 2011;Kohno et al, 2014;). Furthermore, prefrontal cortex activation in adolescent subjects appears to predict levels of future substance use and dependence symptoms, particularly in individuals who are already high-frequency drug users (Mahmood et al, 2013).…”

Section: Dcc-mediated Effects Of Amphetamine On the Sculpting Of Mpfcmentioning

confidence: 99%

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

Reynolds

Makowski

Yogendran

et al. 2014

Neuropsychopharmacol

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Initiation of drug use during adolescence is a strong predictor of both the incidence and severity of addiction throughout the lifetime. Intriguingly, adolescence is a period of dynamic refinement in the organization of neuronal connectivity, in particular medial prefrontal cortex (mPFC) dopamine circuitry. The guidance cue receptor, DCC (deleted in colorectal cancer), is highly expressed by dopamine neurons and orchestrates their innervation to the mPFC during adolescence. Furthermore, we have shown that amphetamine in adolescence regulates DCC expression in dopamine neurons. Drugs in adolescence may therefore induce their enduring behavioral effects via DCC-mediated disruption in mPFC dopamine development. In this study, we investigated the impact of repeated exposure to amphetamine during adolescence on both the development of mPFC dopamine connectivity and on salience attribution to drug context in adulthood. We compare these effects to those induced by adult exposure to an identical amphetamine regimen. Finally, we determine whether DCC signaling within dopamine neurons is necessary for these events. Exposure to amphetamine in adolescence, but not in adulthood, leads to an increase in the span of dopamine innervation to the mPFC, but a reduction of presynaptic sites present on these axons. Amphetamine treatment in adolescence, but not in adulthood, also produces an increase in salience attribution to a previously drug-paired context in adulthood. Remarkably, DCC signaling within dopamine neurons is required for both of these effects. Drugs of abuse in adolescence may therefore induce their detrimental behavioral consequences by disrupting mesocortical dopamine development through alterations in the DCC signaling cascade.

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“…The later is associated with decreased blood oxygen level dependent (BOLD) activity in the orbitofrontal (OFC) and anterior cingulate cortex (ACC) (Voon et al, 2011b). These areas are also hypoactive in substance addiction, associated with decreased striatal D2 receptor availability measured with [11C] Raclopride and PET (Goldstein and Volkow, 2011;Volkow et al, 2011Volkow et al, , 2012.…”

Section: Introductionmentioning

confidence: 99%

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

Ray

Miyasaki

Zurowski

et al. 2012

Neurobiology of Disease

120

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Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson's disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait.

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Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications

Cited by 2,205 publications

References 218 publications

The cerebellum in drug craving

The cerebellum in drug craving

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

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