Dataset Information

Imaging Cortical Dopamine Transmission in Cocaine Dependence: A [¹¹C]FLB 457-Amphetamine Positron Emission Tomography Study.

ABSTRACT:

Background

Positron emission tomography studies have demonstrated less dopamine D_2/3 receptor availability and blunted psychostimulant-induced dopamine release in cocaine-dependent subjects (CDSs). No studies in CDSs have reported the in vivo status of D_2/3 and dopamine release in the cortex. Basic and functional imaging studies suggest a role for prefrontal cortical dopaminergic abnormalities in impaired executive function and relapse in cocaine dependence. We used [¹¹C]FLB 457 positron emission tomography and amphetamine to measure cortical D_2/3 receptors and dopamine release in CDSs.

Methods

[¹¹C]FLB 457 and positron emission tomography were used to measure D_2/3 receptor binding potential in cortical regions of interest in recently abstinent CDSs (n = 24) and healthy control subjects (n = 36) both before and after 0.5 mg kg^-1 of oral d-amphetamine. Binding potential relative to nondisplaceable uptake (BP_ND) and binding potential relative to total plasma concentration (BP_P) were derived using an arterial input function-based kinetic analysis. Cortical dopamine release in regions of interest was measured as the change in BP_ND and BP_P after amphetamine.

Results

Baseline D_2/3 receptor availability (BP_P and BP_ND) and amphetamine-induced dopamine release (ΔBP_ND and ΔBP_P) were significantly lower in the cortical regions in CDSs compared with healthy control subjects. Fewer D_2/3 receptors and less dopamine release in CDSs were not associated with performance on working memory and attention tasks.

Conclusions

The results of this study suggest that deficits in dopamine D_2/3 transmission involve the cortex in cocaine dependence. Further studies to understand the clinical relevance of these findings are warranted.

SUBMITTER: Narendran R

PROVIDER: S-EPMC7554061 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Recent functional magnetic resonance imaging (fMRI) studies have provided compelling evidence that corticolimbic brain regions are integrally involved in human decision-making. Although much less is known about molecular mechanisms, there is growing evidence that the mesolimbic dopamine (DA) neurotransmitter system may be an important neural substrate. Thus far, direct examination of DA signaling in human risk-taking has centered on gambling disorder. Findings from several positron emission tomography (PET) studies suggest that dysfunctions in mesolimbic DA circuits may play an important role in gambling behavior. Nevertheless, interpretation of these findings is currently hampered by a need for better understanding of how individual differences in regional DA function influence normative decision-making in humans. To further our understanding of these processes, we used [(11)C]raclopride PET to examine associations between ventral striatal (VS) DA responses to amphetamine (AMPH) and risky decision-making in a sample of healthy young adults with no history of psychiatric disorder, Forty-five male and female subjects, ages 18-29 years, completed a computerized version of the Iowa Gambling Task. Participants then underwent two 90-minute PET studies with high specific activity [(11)C]raclopride. The first scan was preceded by intravenous saline; the second, by intravenous AMPH (0.3mg/kg). Findings of primary analyses showed that less advantageous decision-making was associated with greater right VS DA release; the relationship did not differ as a function of gender. No associations were observed between risk-taking and left VS DA release or baseline D2/D3 receptor availability in either hemisphere. Overall, the results support notions that variability in striatal DA function may mediate inter-individual differences in risky decision-making in healthy adults, further suggesting that hypersensitive DA circuits may represent a risk pathway in this population.

Project description:BackgroundMesolimbic dopamine system dysfunction is believed to contribute to major depressive disorder (MDD), but molecular neuroimaging of striatal dopamine neurotransmission has yielded mixed results, possibly owing to limited sensitivity of antagonist radioligands used with positron emission tomography to assess dopamine release capacity. This study used an agonist radioligand with agonist challenge to assess dopamine release capacity and D2/D3 receptor availability in MDD.MethodsTwenty-six treatment-naive adults with MDD and 26 healthy comparison participants underwent functional magnetic resonance imaging during a probabilistic reinforcement task, and positron emission tomography with the D3-preferring ligand [11C]-(+)-PHNO, before and after oral dextroamphetamine. MDD participants then received pramipexole treatment for 6 weeks.ResultsMDD participants had trend-level greater dopamine release capacity in the ventral striatum, as measured by percent change in baseline binding potential relative to nondisplaceable compartment (ΔBPND) (-34% vs. -30%; p = .072, d = 0.58) but no difference in D2/D3 receptor availability (BPND). Striatal and extrastriatal BPND and percent change in baseline BPND were not significantly associated with blood oxygen level-dependent response to reward prediction error in the ventral striatum, severity of depression and anhedonia, or antidepressant response to pramipexole (response rate = 72.7%).Conclusions[11C]-(+)-PHNO demonstrated high sensitivity to displacement by amphetamine-induced dopamine release, but dopamine release capacity and D2/D3 availability were not associated with ventral striatal activation to reward prediction error or clinical features, in this study powered to detect large effects. While a preponderance of indirect evidence implicates dopaminergic dysfunction in MDD, these findings suggest that presynaptic dopamine dysregulation may not be a feature of MDD or a prerequisite for treatment response to dopamine agonists.

Dataset Information

Imaging Cortical Dopamine Transmission in Cocaine Dependence: A [¹¹C]FLB 457-Amphetamine Positron Emission Tomography Study.

Background

Methods

Results

Conclusions

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Dataset Information

Imaging Cortical Dopamine Transmission in Cocaine Dependence: A [11C]FLB 457-Amphetamine Positron Emission Tomography Study.

Background

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Imaging Cortical Dopamine Transmission in Cocaine Dependence: A [¹¹C]FLB 457-Amphetamine Positron Emission Tomography Study.