Dopaminergic Network Differences in Human Impulsivity

Buckholtz, Joshua W.; Treadway, Michael T.; Cowan, Ronald L.; Woodward, Neil D.; Li, Rui; Ansari, M. Sib; Baldwin, Ronald M.; Schwartzman, Ashley N.; Shelby, Evan; Smith, Clarence E.; Kessler, Robert; Zald, David H.

doi:10.1126/science.1185778

Cited by 550 publications

(562 citation statements)

References 8 publications

Supporting

Mentioning

477

Contrasting

Unclassified

Order By: Relevance

“…For instance, microinjection of quinpirole into the VTA, but not the SN, of rats dose-dependently decreases cocaine-induced reinstatement (Xue et al, 2011). Furthermore, the availability of midbrain D2/D3 autoreceptors is inversely correlated with drug reward and impulsivity (Bello et al, 2011;Buckholtz et al, 2010). In agreement with the literature, our study clearly demonstrates that 5 days of AMPH self-administration compromises midbrain D2/D3 receptor function and signaling.…”

Section: Discussionsupporting

confidence: 80%

“…Given the role of D2 autoreceptors in the regulation of neuron excitability and DA release, impaired autoreceptor function would lead to aberrant DA activity in the VTA and thereby produce altered DA transmission in the NAcc. Moreover, newly emerging evidence from human studies indicate that functional expression of midbrain D2/D3 autoreceptors is inversely correlated with impulsivity for drugs and the amount of DA release elicited by AMPH (Buckholtz et al, 2010). This notion was also supported by findings from D2 autoreceptor conditional knockout mice, in which knockout mice display supersensitivity to cocaineinduced locomotor activity and conditioned place preference (Bello et al, 2011).…”

Section: Introductionsupporting

confidence: 65%

See 1 more Smart Citation

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

Calipari

Sun

Eldeeb

et al. 2014

Neuropsychopharmacol

View full text Add to dashboard Cite

Dopamine D2 autoreceptors located on the midbrain dopaminergic neurons modulate dopamine (DA) neuron firing, DA release, and DA synthesis through a negative-feedback mechanism. Dysfunctional D2 autoreceptors following repeated drug exposure could lead to aberrant DA activity in the ventral tegmental area (VTA) and projection areas such as nucleus accumbens (NAcc), promoting drugseeking and -taking behavior. Therefore, it is important to understand molecular mechanisms underlying drug-induced changes in D2 autoreceptors. Here, we reported that 5 days of amphetamine (AMPH) self-administration reduced the ability of D2 autoreceptors to inhibit DA release in the NAcc as determined by voltammetry. Using the antibody-capture [ 35 S]GTPgS scintillation proximity assay, we demonstrated for the first time that midbrain D2/D3 receptors were preferentially coupled to Gai2, whereas striatal D2/D3 receptors were coupled equally to Gai2 and Gao for signaling. Importantly, AMPH abolished the interaction between Gai2 and D2/D3 receptors in the midbrain while leaving striatal D2/D3 receptors unchanged. The disruption of the coupling between D2/D3 receptors and Gai2 by AMPH is at least partially explained by the enhanced RGS2 (regulator of G-protein signaling 2) activity resulting from an increased RGS2 trafficking to the membrane. AMPH had no effects on the midbrain expression and trafficking of other RGS proteins such as RGS4 and RGS8. Our data suggest that midbrain D2/D3 receptors are more susceptible to AMPH-induced alterations. Reduced D2 autoreceptor function could lead to enhanced DA signaling and ultimately addiction-related behavior. RGS2 may be a potential non-dopaminergic target for pharmacological intervention of dysfunctional DA transmission and drug addiction.

show abstract

Section: Discussionsupporting

confidence: 80%

Section: Introductionsupporting

confidence: 65%

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

Calipari

Sun

Eldeeb

et al. 2014

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…This downregulation may be a consequence of drug-taking, but it may also predispose to the development of addiction and to relapse (Volkow et al, 2009;Morgan et al, 2002;Thanos et al, 2001;Heinz et al, 2005;Volkow et al, 2002;Buckholtz et al, 2010). Dopamine D 2 receptors are both pre-and postsynaptically located.…”

Section: Phasic Dopaminergic Signals In Addictionmentioning

confidence: 99%

“…Just as in animals, this variation may be related to the dopaminergic system (Buckholtz et al, 2010;Dalley and Roiser, 2012). Leyton et al (2002) showed that even in healthy subjects the variability in dopamine response to amphetamine relates to subjective ratings of "wanting".…”

Section: Individual Variability In Addiction Vulnerabilitymentioning

confidence: 99%

The role of learning-related dopamine signals in addiction vulnerability

Huys

Tobler

Hasler

et al. 2014

Progress in Brain Research

View full text Add to dashboard Cite

Psychostimulants such as methylphenidate (MPH) and antidepressants such as fluoxetine (FLX) are widely used in the treatment of various mental disorders or as cognitive enhancers. These medications are often combined, for example, to treat comorbid disorders. There is a considerable body of evidence from animal models indicating that individually these psychotropic medications can have detrimental effects on the brain and behavior, especially when given during sensitive periods of brain development. However, almost no studies investigate possible interactions between these drugs. This is surprising given that their combined neurochemical effects (enhanced dopamine and serotonin neurotransmission) mimic some effects of illicit drugs such as cocaine and amphetamine. Here, we summarize recent studies in juvenile rats on the molecular effects in the mid-and forebrain and associated behavioral changes, after such combination treatments. Our findings indicate that these combined MPH + FLX treatments can produce similar molecular changes as seen after cocaine exposure while inducing behavioral changes indicative of dysregulated mood and motivation, effects that often endure into adulthood. Tables: 2 References: 254 ABSTRACT Dopaminergic signals play a mathematically precise role in reward-related learning, and variations in dopaminergic signalling have been implicated in vulnerability to addiction. Here, we provide a detailed overview of the relationship between theoretical, mathematical and experimental accounts of phasic dopamine signalling, with implications for the role of learning-related dopamine signalling in addiction and related disorders. We describe the theoretical and behavioural characteristics of model-free learning based on errors in the prediction of reward, including step-by-step explanations of the underlying equations. We then use recent insights from an animal model that highlights individual variation in learning during a Pavlovian conditioning paradigm to describe overlapping aspects of incentive salience attribution and model-free learning. We argue that this provides a computationally coherent account of some features of addiction. CONTENTS

show abstract

“…In the non-PD population, impulsive individuals have greater amphetamine-induced release of DA in the striatum (Buckholtz et al, 2010), an abnormality also seen in PD patients with PG in response to monetary reward (Steeves et al, 2009). Buckholtz et al (2010), using the PET ligand [18F] Fallypride, also found that trait impulsivity was negatively associated with binding to DA D2/3 receptors in the midbrain. DA receptors in this region are dominated by autoreceptors (Khan et al, 1998), which function to limit striatal DA release following reward.…”

Section: Introductionmentioning

confidence: 98%

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

119

View full text Add to dashboard Cite

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.

show abstract

Dopaminergic Network Differences in Human Impulsivity

Cited by 550 publications

References 8 publications

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

The role of learning-related dopamine signals in addiction vulnerability

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

Contact Info

Product

Resources

About