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Psychopharmacology Aug 2023Dopaminergic dysfunction is implicated in disorders of impulsivity and inattention. The rodent continuous performance test (rCPT) has been used to quantify changes in...
Assessing attention and impulsivity in the variable stimulus duration and variable intertrial interval rodent continuous performance test schedules using dopamine receptor antagonists in female C57BL/6JRj mice.
RATIONALE
Dopaminergic dysfunction is implicated in disorders of impulsivity and inattention. The rodent continuous performance test (rCPT) has been used to quantify changes in attention and impulsivity.
OBJECTIVE
To examine the roles of dopamine receptors in attention and impulsivity behaviours measured in the rCPT variable stimulus duration (vSD) and the variable intertrial interval schedules (vITI) using DA receptor antagonists.
METHODS
Two cohorts of 35 and 36 female C57BL/6JRj mice were examined separately in the rCPT, vSD, and vITI schedules, respectively. Both cohorts received antagonists of the following receptors: D (SCH23390, SCH: 0.01, 0.02, 0.04 mg/kg) and D (raclopride, RAC 0.03, 0.10, 0.30 mg/kg) in consecutive balanced Latin square designs with flanking reference measurements. The antagonists were subsequently examined for effects on locomotor activity.
RESULTS
SCH showed similar effects in both schedules, and the effects were reference-dependent in the vITI schedule. SCH reduced responding, but improved response accuracy, impulsivity, discriminability, and locomotor activity. RAC showed mixed effects on responsivity, but improved accuracy and discriminability. The discriminability improvement was driven by an increase in hit rate in the vITI schedule and a reduction in false alarm rate in the vSD schedule. RAC also decreased locomotor activity.
CONCLUSION
Both D and D receptor antagonism reduced responding, but the outcome on discriminability differed, stemming from individual effects on hit and false alarm rate, and the weight of omissions within the calculation. The effects of SCH and RAC suggest that endogenous DA increases responding and impulsivity, but reduces accuracy and shows mixed effects on discriminability.
Topics: Mice; Animals; Female; Dopamine Antagonists; Rodentia; Mice, Inbred C57BL; Receptors, Dopamine D1; Attention; Impulsive Behavior; Dopamine D2 Receptor Antagonists; Benzazepines; Dose-Response Relationship, Drug
PubMed: 37378887
DOI: 10.1007/s00213-023-06387-7 -
Nutrients Jun 2023The overconsumption of palatable energy-dense foods drives obesity, but few human studies have investigated dopamine (DA) release in response to the consumption of a...
Milkshake Acutely Stimulates Dopamine Release in Ventral and Dorsal Striatum in Healthy-Weight Individuals and Patients with Severe Obesity Undergoing Bariatric Surgery: A Pilot Study.
The overconsumption of palatable energy-dense foods drives obesity, but few human studies have investigated dopamine (DA) release in response to the consumption of a palatable meal, a putative mediator of excess intake in obesity. We imaged [C]raclopride in the brain with positron emission tomography (PET) to assess striatal dopamine (DA) receptor binding pre- and post-consumption of a highly palatable milkshake (250 mL, 420 kcal) in 11 females, 6 of whom had severe obesity, and 5 of whom had healthy-weight. Those with severe obesity underwent assessments pre- and 3 months post-vertical sleeve gastrectomy (VSG). Our results demonstrated decreased post- vs. pre-meal DA receptor binding in the ventral striatum ( = 0.032), posterior putamen ( = 0.012), and anterior caudate ( = 0.018), consistent with meal-stimulated DA release. Analysis of each group separately suggested that results in the caudate and putamen were disproportionately driven by meal-associated changes in the healthy-weight group. Baseline (pre-meal) DA receptor binding was lower in severe obesity than in the healthy-weight group. Baseline DA receptor binding and DA release did not change from pre- to post-surgery. The results of this small pilot study suggest that milkshake acutely stimulates DA release in the ventral and dorsal striatum. This phenomenon likely contributes to the overconsumption of highly palatable foods in the modern environment.
Topics: Female; Humans; Dopamine; Pilot Projects; Obesity, Morbid; Receptors, Dopamine D2; Obesity; Positron-Emission Tomography; Bariatric Surgery; Ventral Striatum
PubMed: 37375579
DOI: 10.3390/nu15122671 -
Neuropsychopharmacology : Official... Sep 2023Brain imaging studies using positron emission tomography (PET) have shown that long-term cocaine use is associated with lower levels of dopamine (DA) D2/D3 receptors...
Brain imaging studies using positron emission tomography (PET) have shown that long-term cocaine use is associated with lower levels of dopamine (DA) D2/D3 receptors (D2/D3R); less consistent are the effects on DA transporter (DAT) availability. However, most studies have been conducted in male subjects (humans, monkeys, rodents). In this study, we used PET imaging in nine drug-naïve female cynomolgus monkeys to determine if baseline measures of DAT, with [F]FECNT, and D2/D3R availability, with [C]raclopride, in the caudate nucleus, putamen and ventral striatum were associated with rates of cocaine self-administration and if these measures changed during long-term (~13 months) cocaine self-administration and following time-off (3-9 months) from cocaine. Cocaine (0.2 mg/kg/injection) and 1.0 g food pellets were available under a multiple fixed-interval (FI) 3-min schedule of reinforcement. In contrast to what has been observed in male monkeys, baseline D2/D3R availability was positively correlated with rates of cocaine self-administration only during the first week of exposure; DAT availability did not correlate with cocaine self-administration. D2/D3R availability decreased ~20% following cumulative intakes of 100 and 1000 mg/kg cocaine; DAT availability did not significantly change. These reductions in D2/D3R availability did not recover over 9 months of time-off from cocaine. To determine if these reductions were reversible, three monkeys were implanted with osmotic pumps that delivered raclopride for 30 days. We found that chronic treatment with the D2/D3R antagonist raclopride increased D2/D3R availability in the ventral striatum but not in the other regions when compared to baseline levels. Over 13 months of self-administration, tolerance did not develop to the rate-decreasing effects of self-administered cocaine on food-reinforced responding, but number of injections and cocaine intake significantly increased over the 13 months. These data extend previous findings to female monkeys and suggest sex differences in the relationship between D2/D3R availability related to vulnerability and long-term cocaine use.
Topics: Haplorhini; Animals; Female; Positron-Emission Tomography; Dopamine Plasma Membrane Transport Proteins; Receptors, Dopamine D3; Cocaine; Self Administration; Raclopride
PubMed: 37349473
DOI: 10.1038/s41386-023-01622-3 -
BioRxiv : the Preprint Server For... Jun 2023There is now evidence from multiple Phase II clinical trials that psychedelic drugs can exert longlasting anxiolytic, anti-depressant, and anti-drug abuse (nicotine and...
There is now evidence from multiple Phase II clinical trials that psychedelic drugs can exert longlasting anxiolytic, anti-depressant, and anti-drug abuse (nicotine and ethanol) effects in patients. Despite these benefits, the hallucinogenic actions of these drugs at the serotonin 2A receptor (5-HT2AR) limit their clinical use in diverse settings. Activation of the 5-HT2AR can stimulate both G protein and β-arrestin (βArr) -mediated signaling. Lisuride is a G protein biased agonist at the 5-HT2AR and, unlike the structurally-related LSD, the drug does not typically produce hallucinations in normal subjects at routine doses. Here, we examined behavioral responses to lisuride, in wild-type (WT), βArr1-KO, and βArr2-KO mice. In the open field, lisuride reduced locomotor and rearing activities, but produced a U-shaped function for stereotypies in both βArr lines of mice. Locomotion was decreased overall in βArr1-KOs and βArr2-KOs, relative to WT controls. Incidences of head twitches and retrograde walking to lisuride were low in all genotypes. Grooming was depressed in βArr1 mice, but was increased then decreased in βArr2 animals with lisuride. Prepulse inhibition (PPI) was unaffected in βArr2 mice, whereas 0.5 mg/kg lisuride disrupted PPI in βArr1 animals. The 5-HT2AR antagonist MDL100907 failed to restore PPI in βArr1 mice, whereas the dopamine D2/D3 antagonist raclopride normalized PPI in WTs but not in βArr1-KOs. Using vesicular monoamine transporter 2 mice, lisuride reduced immobility times in tail suspension and promoted a preference for sucrose that lasted up to 2 days. Together, it appears βArr1 and βArr2 play minor roles in lisuride's actions on many behaviors, while this drug exerts anti-depressant drug-like responses without hallucinogenic-like activities.
PubMed: 37333376
DOI: 10.1101/2023.06.01.543310 -
Psychiatry Research. Neuroimaging Aug 2023Anhedonia is hypothesized to be associated with blunted mesocorticolimbic dopamine (DA) functioning in samples with major depressive disorder. The purpose of this study...
BACKGROUND
Anhedonia is hypothesized to be associated with blunted mesocorticolimbic dopamine (DA) functioning in samples with major depressive disorder. The purpose of this study was to examine linkages between striatal DA, reward circuitry functioning, anhedonia, and, in an exploratory fashion, self-reported stress, in a transdiagnostic anhedonic sample.
METHODS
Participants with (n = 25) and without (n = 12) clinically impairing anhedonia completed a reward-processing task during simultaneous positron emission tomography and magnetic resonance (PET-MR) imaging with [C]raclopride, a DA D2/D3 receptor antagonist that selectively binds to striatal DA receptors.
RESULTS
Relative to controls, the anhedonia group exhibited decreased task-related DA release in the left putamen, caudate, and nucleus accumbens and right putamen and pallidum. There were no group differences in task-related brain activation (fMRI) during reward processing after correcting for multiple comparisons. General functional connectivity (GFC) findings revealed blunted fMRI connectivity between PET-derived striatal seeds and target regions in the anhedonia group. Associations were identified between anhedonia severity and the magnitude of task-related DA release to rewards in the left putamen, but not mesocorticolimbic GFC.
CONCLUSIONS
Results provide evidence for reduced striatal DA functioning during reward processing and blunted mesocorticolimbic network functional connectivity in a transdiagnostic sample with clinically significant anhedonia.
Topics: Humans; Raclopride; Dopamine; Anhedonia; Depressive Disorder, Major; Positron-Emission Tomography; Magnetic Resonance Imaging
PubMed: 37301129
DOI: 10.1016/j.pscychresns.2023.111660 -
Cerebral Cortex (New York, N.Y. : 1991) Jun 2023In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system...
In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system in the human brain. Using positron emission tomography (PET), we address this gap by comparing hormonal contraceptive users and nonusers across multiple aspects of DA function: DA synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and DA release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n = 15 hormonal contraceptive users; n = 21 naturally cycling/non users of hormonal contraception), and men (n = 20) as a comparison group. A behavioral index of cognitive flexibility was assessed prior to PET imaging. Hormonal contraceptive users exhibited greater DA synthesis capacity than NC participants, particularly in dorsal caudate, and greater cognitive flexibility. Furthermore, across individuals, the magnitude of striatal DA synthesis capacity was associated with cognitive flexibility. No group differences were observed in D2/3 receptor binding or DA release. Analyses by sex alone may obscure underlying differences in DA synthesis tied to women's hormone status. Hormonal contraception (in the form of pill, shot, implant, ring, or intrauterine device) is used by ~400 million women worldwide, yet few studies have examined whether chronic hormonal manipulations impact basic properties of the DA system. Findings from this study begin to address this critical gap in women's health.
Topics: Male; Animals; Humans; Female; Raclopride; Dopamine; Contraceptive Agents; Positron-Emission Tomography; Receptors, Dopamine D2; Cognition
PubMed: 37160338
DOI: 10.1093/cercor/bhad134 -
Neuroscience Bulletin Sep 2023L-dopa (l-3,4-dihydroxyphenylalanine)-induced dyskinesia (LID) is a debilitating complication of dopamine replacement therapy for Parkinson's disease. The potential...
L-dopa (l-3,4-dihydroxyphenylalanine)-induced dyskinesia (LID) is a debilitating complication of dopamine replacement therapy for Parkinson's disease. The potential contribution of striatal D receptor (DR)-positive neurons and downstream circuits in the pathophysiology of LID remains unclear. In this study, we investigated the role of striatal DR neurons and downstream globus pallidus externa (GPe) neurons in a rat model of LID. Intrastriatal administration of raclopride, a DR antagonist, significantly inhibited dyskinetic behavior, while intrastriatal administration of pramipexole, a D-like receptor agonist, yielded aggravation of dyskinesia in LID rats. Fiber photometry revealed the overinhibition of striatal DR neurons and hyperactivity of downstream GPe neurons during the dyskinetic phase of LID rats. In contrast, the striatal DR neurons showed intermittent synchronized overactivity in the decay phase of dyskinesia. Consistent with the above findings, optogenetic activation of striatal DR neurons or their projections in the GPe was adequate to suppress most of the dyskinetic behaviors of LID rats. Our data demonstrate that the aberrant activity of striatal DR neurons and downstream GPe neurons is a decisive mechanism mediating dyskinetic symptoms in LID rats.
Topics: Rats; Animals; Levodopa; Dopamine; Parkinsonian Disorders; Oxidopamine; Dyskinesia, Drug-Induced; Corpus Striatum; Neurons; Receptors, Dopamine D2; Antiparkinson Agents
PubMed: 37022638
DOI: 10.1007/s12264-023-01054-5 -
Frontiers in Neuroscience 2023[This corrects the article DOI: 10.3389/fnins.2018.00074.].
[This corrects the article DOI: 10.3389/fnins.2018.00074.].
PubMed: 36992849
DOI: 10.3389/fnins.2023.1163637 -
Brain Research May 2023Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their...
Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their importance in mediating the abuse-related effects of cocaine, brain dopamine receptors are logical candidates for investigation. We analyzed data from two recently published studies that characterized availability of dopamine D2-like receptors (D2R) with [C]raclopride PET imaging and dopamine D receptor (DR) sensitivity with quinpirole-induced yawning in cocaine-naïve rhesus monkeys who subsequently acquired cocaine self-administration and completed a cocaine self-administration dose-effect curve. The present analysis compared D2R availability in several brain areas and characteristics of quinpirole-induced yawning, both acquired when monkeys were drug-naïve, with measures of initial sensitivity to cocaine. D2R availability in the caudate nucleus was negatively correlated with the ED of the cocaine self-administration curve, although the significance of this relationship was driven by an outlier and was not present after the outlier was removed. No other significant associations were observed between D2R availability in any examined brain region and measures of sensitivity to cocaine reinforcement. However, there was a significant negative correlation between DR sensitivity, represented by the ED of the quinpirole-induced yawning curve, and the dose at which monkeys acquired cocaine self-administration. We also report no change from baseline D2R availability when a second PET scan was conducted after completion of the dose-effect curves. These data suggest the utility of DR sensitivity, but not D2R availability, as a biomarker for vulnerability and resilience to cocaine. The well-established relationships between dopamine receptors and cocaine reinforcement in cocaine-experienced humans and animals may require extensive cocaine exposure.
Topics: Humans; Animals; Male; Cocaine; Dopamine; Quinpirole; Macaca mulatta; Receptors, Dopamine D3; Dopamine Agonists; Receptors, Dopamine D2; Self Administration; Dose-Response Relationship, Drug
PubMed: 36914041
DOI: 10.1016/j.brainres.2023.148323 -
Journal of Cerebral Blood Flow and... Jul 2023The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3...
Striatal dopamine transporter and receptor availability correlate with relative cerebral blood flow measured with [C]PE2I, [F]FE-PE2I and [C]raclopride PET in healthy individuals.
The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3 availability in healthy subjects. The data comprised dynamic PET scans with two dopamine transporter tracers [C]PE2I (n = 20) and [F]FE-PE2I (n = 20) and the D2/3 tracer [C]raclopride (n = 18). Subjects with a [C]PE2I scan also underwent a dynamic scan with the serotonin transporter tracer [C]DASB. Binding potential (BP) and relative tracer delivery (R) values were calculated on regional and voxel-level. Striatal R and BP values were correlated, using either an MRI-based volume of interest (VOI) or an isocontour VOI based on the parametric BP image. An inter-tracer comparison between [C]PE2I BP and [C]DASB R was done on a VOI-level and simulations were performed to investigate whether the constraints of the modeling could cause correlation of the parameters. A positive association was found between BP and R for all three dopamine tracers. A similar correlation was found for the inter-tracer correlation between [C]PE2I BP and [C]DASB R. Simulations showed that this relationship was not caused by cross-correlation between parameters in the kinetic model. In conclusion, these results suggest an association between resting-state striatal dopamine function and relative blood flow in healthy subjects.
Topics: Humans; Raclopride; Dopamine; Dopamine Plasma Membrane Transport Proteins; Retrospective Studies; Positron-Emission Tomography; Cerebrovascular Circulation
PubMed: 36912083
DOI: 10.1177/0271678X231160881