Dataset Information

Striatal Dopamine Release in Response to Morphine: A [11C]Raclopride Positron Emission Tomography Study in Healthy Men.

ABSTRACT: BACKGROUND:Preclinical and human positron emission tomography studies have produced inconsistent results regarding the effects of opioids on mesolimbic dopamine (DA). Here, we quantify striatal DA release (measured by [11C]raclopride displacement) in response to an intravenous infusion of morphine, and its relationship with morphine-induced subjective effects, in healthy, nondependent opioid-experienced participants. METHODS:Fifteen healthy male participants were initially included. Sessions were on separate days. On session 1, participants received intravenous morphine (10 mg/70 kg) in the clinic to ensure tolerability. Participants without adverse reactions (n = 10) then received intravenous morphine and placebo (saline) sessions, in counterbalanced order, while undergoing [11C]raclopride positron emission tomography scans. Subjective and physiological responses were assessed. Region-of-interest and voxelwise image analyses were used to assess changes in [11C]raclopride nondisplaceable binding potential. RESULTS:Morphine produced marked subjective and physiological effects and induced a significant decrease in [11C]raclopride nondisplaceable binding potential, particularly in the nucleus accumbens and globus pallidus, where the change in [11C]raclopride nondisplaceable binding potential was approximately 9%. However, the subjective effects of morphine did not show a simple pattern of correlation with DA release. CONCLUSIONS:This is, to our knowledge, the first study providing in vivo human evidence that DA transmission in the ventral striatum is affected by morphine. Further studies are required to fully delineate the DA contribution to the reinforcing effects of opioids.

SUBMITTER: Spagnolo PA

PROVIDER: S-EPMC6699765 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Striatal Dopamine Release in Response to Morphine: A [<sup>11</sup>C]Raclopride Positron Emission Tomography Study in Healthy Men.

Spagnolo Primavera A PA Kimes Alane A Schwandt Melanie L ML Shokri-Kojori Ehsan E Thada Shantalaxmi S Phillips Karran A KA Diazgranados Nancy N Preston Kenzie L KL Herscovitch Peter P Tomasi Dardo D Ramchandani Vijay A VA Heilig Markus M

Biological psychiatry 20190315 5

<h4>Background</h4>Preclinical and human positron emission tomography studies have produced inconsistent results regarding the effects of opioids on mesolimbic dopamine (DA). Here, we quantify striatal DA release (measured by [<sup>11</sup>C]raclopride displacement) in response to an intravenous infusion of morphine, and its relationship with morphine-induced subjective effects, in healthy, nondependent opioid-experienced participants.<h4>Methods</h4>Fifteen healthy male participants were initia ...[more]

PMID: 31097294

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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:BACKGROUND:Mesolimbic 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. METHODS:Twenty-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. RESULTS:MDD 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 (?BPND) (-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

Striatal Dopamine Release in Response to Morphine: A [11C]Raclopride Positron Emission Tomography Study in Healthy Men.

Publications

Striatal Dopamine Release in Response to Morphine: A [<sup>11</sup>C]Raclopride Positron Emission Tomography Study in Healthy Men.

Similar Datasets

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