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The Journal of Neuroscience : the... Sep 2021Acetaldehyde (ACD), the first metabolite of ethanol, is implicated in several of ethanol's actions, including the reinforcing and aversive effects. The neuronal...
Acetaldehyde (ACD), the first metabolite of ethanol, is implicated in several of ethanol's actions, including the reinforcing and aversive effects. The neuronal mechanisms underlying ACD's aversive effect, however, are poorly understood. The lateral habenula (LHb), a regulator of midbrain monoaminergic centers, is activated by negative valence events. Although the LHb has been linked to the aversive responses of several abused drugs, including ethanol, little is known about ACD. We, therefore, assessed ACD's action on LHb neurons in rats. The results showed that intraperitoneal injection of ACD increased cFos protein expression within the LHb and that intra-LHb infusion of ACD induced conditioned place aversion in male rats. Furthermore, electrophysiological recording in brain slices of male and female rats showed that bath application of ACD facilitated spontaneous firing and glutamatergic transmission. This effect of ACD was potentiated by an aldehyde dehydrogenase (ALDH) inhibitor, disulfiram (DS), but attenuated by the antagonists of dopamine (DA) receptor (DAR) subtype 1 (SCH23390) and subtype 2 (raclopride), and partly abolished by the pretreatment of DA or DA reuptake blocker (GBR12935; GBR). Moreover, application of ACD initiated a depolarizing inward current () and enhanced the hyperpolarizing-activated currents in LHb neurons. Bath application of Rp-cAMPs, a selective cAMP-PKA inhibitor, attenuated ACD-induced potentiation of EPSCs and Finally, bath application of ZD7288, a selective blocker of hyperpolarization-activated cyclic nucleotide-gated channels, attenuated ACD-induced potentiation of firing, EPSCs, and These results show that ACD exerts its aversive property by exciting LHb neurons via multiple cellular mechanisms, and new treatments targeting the LHb may be beneficial for alcoholism. Acetaldehyde (ACD) has been considered aversive peripherally and rewarding centrally. However, whether ACD has a central aversive property is unclear. Here, we report that ACD excites the lateral habenula (LHb), a brain region associated with aversion and negative valence, through multiple cellular and molecular mechanisms. Intra-LHb ACD produces significant conditioned place aversion. These results suggest that ACD's actions on the LHb neurons might contribute to its central aversive property and new treatments targeting the LHb may be beneficial for alcoholism.
Topics: Acetaldehyde; Animals; Avoidance Learning; Disulfiram; Dopamine Antagonists; Dopamine Uptake Inhibitors; Glutamic Acid; Habenula; Male; Neurons; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Synaptic Transmission
PubMed: 34326141
DOI: 10.1523/JNEUROSCI.2913-20.2021 -
Drug and Alcohol Dependence Oct 2021Dopaminergic mechanisms that may underlie cannabis' reinforcing effects are not well elucidated in humans. This positron emission tomography (PET) imaging study used the...
BACKGROUND
Dopaminergic mechanisms that may underlie cannabis' reinforcing effects are not well elucidated in humans. This positron emission tomography (PET) imaging study used the dopamine D receptor antagonist [C]raclopride and kinetic modelling testing for transient changes in radiotracer uptake to assess the striatal dopamine response to smoked cannabis in a preliminary sample.
METHODS
PET emission data were acquired from regular cannabis users (n = 14; 7 M/7 F; 19-32 years old) over 90 min immediately after [C]raclopride administration (584 ± 95 MBq) as bolus followed by constant infusion (K = 105 min). Participants smoked a cannabis cigarette, using a paced puff protocol, 35 min after scan start. Plasma concentrations of Δ-THC and metabolites and ratings of subjective "high" were collected during imaging. Striatal dopamine responses were assessed voxelwise with a kinetic model testing for transient reductions in [C]raclopride binding, linear-parametric neurotransmitter PET (lp-ntPET) (cerebellum as a reference region).
RESULTS
Cannabis smoking increased plasma Δ-THC levels (peak: 0-10 min) and subjective high (peak: 0-30 min). Significant clusters (>16 voxels) modeled by transient reductions in [C]raclopride binding were identified for all 12 analyzed scans. In total, 26 clusters of significant responses to cannabis were detected, of which 16 were located in the ventral striatum, including at least one ventral striatum cluster in 11 of the 12 analyzed scans.
CONCLUSIONS
These preliminary data support the sensitivity of [C]raclopride PET with analysis of transient changes in radiotracer uptake to detect cannabis smoking-induced dopamine responses. This approach shows future promise to further elucidate roles of mesolimbic dopaminergic signaling in chronic cannabis use. ClinicalTrials.gov Identifier: NCT02817698.
Topics: Adult; Cannabis; Corpus Striatum; Dopamine; Humans; Marijuana Smoking; Positron-Emission Tomography; Raclopride; Ventral Striatum; Young Adult
PubMed: 34399137
DOI: 10.1016/j.drugalcdep.2021.108920 -
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 -
Journal of Cerebral Blood Flow and... Sep 2020In vivo dopamine D2-receptor availability is frequently assessed with C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for C-raclopride...
In vivo dopamine D2-receptor availability is frequently assessed with C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for C-raclopride in areas with low D2 receptor densities, the ligand has been considered unreliable for measurements outside the dopamine-dense striatum. Intriguingly, recent studies show that extrastriatal C-raclopride binding potential (BP) values are (i) reliably higher than in the cerebellum (where D2-receptor levels are negligible), (ii) correlate with behavior in the expected direction, and (iii) showed good test-retest reliability in a sample of younger adults. The present work demonstrates high seven-month test-retest reliability of striatal and extrastriatal C-raclopride BP values in healthy, older adults (n = 27, age: 64-78 years). Mean C-raclopride BP values were stable between test sessions in subcortical nuclei, and in frontal and temporal cortices (p > 0.05). Across all structures analyzed, intraclass correlation coefficients were high (0.85-0.96), absolute variability was low (mean: 4-8%), and coefficients of variance ranged between 9 and 25%. Furthermore, regional C-raclopride BP values correlated with previously determined F-fallypride BP values (ρ = 0.97 and 0.92 in correlations with and without striatal values, respectively, p < 0.01) and postmortem determined D2-receptor densities (including striatum: ρ = 0.92; p < 0.001; excluding striatum: ρ = 0.75; p = 0.067). These observations suggest that extrastriatal C-raclopride measurements represent a true D2 signal.
Topics: Adult; Aged; Benzamides; Carbon Radioisotopes; Cerebral Cortex; Corpus Striatum; Dopamine Agonists; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Pyrrolidines; Raclopride; Radiopharmaceuticals; Receptors, Dopamine D2; Reproducibility of Results; Young Adult
PubMed: 31506011
DOI: 10.1177/0271678X19874770 -
Frontiers in Molecular Biosciences 2023There is now evidence from multiple Phase II clinical trials that psychedelic drugs can exert long-lasting anxiolytic, anti-depressant, and anti-drug abuse (nicotine and...
There is now evidence from multiple Phase II clinical trials that psychedelic drugs can exert long-lasting 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 -arrestin (βArr) -mediated signaling. Lisuride is a G protein biased agonist at the 5-HT2AR and, unlike the structurally-related lysergic acid diethylamide (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-knockout (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 wild-type controls. Incidences of head twitches and retrograde walking to lisuride were low in all genotypes. Grooming was decreased in βArr1 mice, but was increased then decreased in βArr2 animals with lisuride. Serotonin syndrome-associated responses were present at all lisuride doses in WTs, but they were reduced especially in βArr2-KO mice. 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. Clozapine, SCH23390, and GR127935 restored PPI in both βArr1 genotypes. 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: 37900918
DOI: 10.3389/fmolb.2023.1233743 -
Frontiers in Pharmacology 2023Experimental and clinical evidence indicates a deficit of release and function of dopamine in schizophrenia and suggests that α-adrenoceptor antagonists rescue dopamine...
Combined α- and D-receptor blockade activates noradrenergic and dopaminergic neurons, but extracellular dopamine in the prefrontal cortex is determined by uptake and release from noradrenergic terminals.
Experimental and clinical evidence indicates a deficit of release and function of dopamine in schizophrenia and suggests that α-adrenoceptor antagonists rescue dopamine deficit and improve the antipsychotic efficacy of D-receptor antagonists. In anesthetized male rats, we investigated how the blockade of α- and D-receptors by atipamezole and raclopride, respectively, modified the firing of noradrenergic neurons in the locus coeruleus (LC) and dopaminergic neurons in the ventral tegmental area (VTA). In freely moving rats, we studied how atipamezole and raclopride modified extracellular noradrenaline, dopamine, and DOPAC levels in the medial prefrontal cortex (mPFC) through microdialysis. When administered alone, atipamezole activated LC noradrenaline but not VTA dopamine cell firing. Combined with raclopride, atipamezole activated dopamine cell firing above the level produced by raclopride. Atipamezole increased extracellular dopamine to the same level, whether administered alone or combined with raclopride. In the presence of the noradrenaline transporter (NET) inhibitor, atipamezole combined with raclopride increased extracellular dopamine beyond the level produced by either compound administered alone. The results suggest that a) the D-autoreceptor blockade is required for LC noradrenaline to activate VTA cell firing; b) the level of dopamine released from dopaminergic terminals is determined by NET; c) the elevation of extracellular dopamine levels in the mPFC is the resultant of dopamine uptake and release from noradrenergic terminals, independent of dopaminergic cell firing and release; and d) LC noradrenergic neurons are an important target for treatments to improve the prefrontal deficit of dopamine in neuropsychiatric pathologies.
PubMed: 37680715
DOI: 10.3389/fphar.2023.1238115 -
NeuroImage Nov 2020Receptor ligand-based dynamic Positron Emission Tomography (PET) permits the measurement of neurotransmitter release in the human brain. For single-scan paradigms, the...
Receptor ligand-based dynamic Positron Emission Tomography (PET) permits the measurement of neurotransmitter release in the human brain. For single-scan paradigms, the conventional method of estimating changes in neurotransmitter levels relies on fitting a pharmacokinetic model to activity concentration histories extracted after PET image reconstruction. However, due to the statistical fluctuations of activity concentration data at the voxel scale, parametric images computed using this approach often exhibit low signal-to-noise ratio, impeding characterization of neurotransmitter release. Numerous studies have shown that direct parametric reconstruction (DPR) approaches, which combine image reconstruction and kinetic analysis in a unified framework, can improve the signal-to-noise ratio of parametric mapping. However, there is little experience with DPR in imaging of neurotransmission and the performance of the approach in this application has not been evaluated before in humans. In this report, we present and evaluate a DPR methodology that computes 3-D distributions of ligand transport, binding potential (BP) and neurotransmitter release magnitude (γ) from a dynamic sequence of PET sinograms. The technique employs the linear simplified reference region model (LSRRM) of Alpert et al. (2003), which represents an extension of the simplified reference region model that incorporates time-varying binding parameters due to radioligand displacement by release of neurotransmitter. Estimation of parametric images is performed by gradient-based optimization of a Poisson log-likelihood function incorporating LSRRM kinetics and accounting for the effects of head movement, attenuation, detector sensitivity, random and scattered coincidences. A C-raclopride simulation study showed that the proposed approach substantially reduces the bias and variance of voxel-wise γ estimates as compared to standard methods. Moreover, simulations showed that detection of release could be made more reliable and/or conducted using a smaller sample size using the proposed DPR estimator. Likewise, images of BP computed using DPR had substantially improved bias and variance properties. Application of the method in human subjects was demonstrated using C-raclopride dynamic scans and a reward task, confirming the improved quality of the estimated parametric images using the proposed approach.
Topics: Brain; Computer Simulation; Humans; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; Synaptic Transmission
PubMed: 32679252
DOI: 10.1016/j.neuroimage.2020.117154 -
Brain Research Apr 2023Molecular mechanisms of the interaction between opioidergic and dopaminergic processing during pain-related experiences in the human brain are still incompletely... (Meta-Analysis)
Meta-Analysis
Molecular mechanisms of the interaction between opioidergic and dopaminergic processing during pain-related experiences in the human brain are still incompletely understood. This is partially due to the invasive nature of the available techniques to visualize and measure metabolic activity. Positron Emission Tomography (PET) radioligand studies using radioactive substances are still the only available modality to date that allows for the investigation of the molecular mechanisms in the human brain. The most commonly studied PET radiotracers are [C]-carfentanil (CFN) and [C]- or [F]-diprenorphine (DPN), which bind to opioid receptors, and [C]-raclopride (RAC) and [F]-fallypride (FAL) tracers, which bind to dopamine receptors. The current meta-analysis examines pain-related studies that used aforementioned opioid and dopamine radioligands in an effort to consolidate the available data into the most likely activated regions. Our primary goal was to identify regions of shared opioid/dopamine neurotransmission during pain-related experiences using within-subject approach. Seed-based d Mapping (SDM) analysis of previously published voxel coordinate data showed that opioidergic activations were strongest in the bilateral caudate, thalamus, right putamen, cingulate gyrus, midbrain, inferior frontal gyrus, and left superior temporal gyrus. The dopaminergic studies showed that the bilateral caudate, thalamus, right putamen, cingulate gyrus, and left putamen had the highest activations. We were able to see a clear overlap between opioid and dopamine activations in a majority of the regions during pain-related experiences, though there were some unique areas of dopaminergic activation such as the left putamen. Regions unique to opioidergic activation included the midbrain, inferior frontal gyrus, and left superior temporal gyrus. Here we provide initial evidence for the functional overlap between opioidergic and dopaminergic processing during aversive states in humans.
Topics: Humans; Dopamine; Analgesics, Opioid; Pain; Positron-Emission Tomography; Brain
PubMed: 36754138
DOI: 10.1016/j.brainres.2023.148268 -
Biomedicines May 2021Poly (ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme in the DNA repair process and the target of several FDA-approved inhibitors. Several of these inhibitors...
Poly (ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme in the DNA repair process and the target of several FDA-approved inhibitors. Several of these inhibitors have been radiolabeled for non-invasive imaging of PARP-1 expression or targeted radiotherapy of PARP-1 expressing tumors. In particular, derivatives of olaparib and rucaparib, which have reduced trapping potency by PARP-1 compared to talazoparib, have been radiolabeled for these purposes. Here, we report the first radiosynthesis of [F]talazoparib and its in vitro and in vivo evaluation. Talazoparib () and its bromo- or iodo-derivatives were synthesized as racemic mixtures (, and ), and these compounds exhibit high affinity to PARP-1 ( for talazoparib (): 0.65 ± 0.07 nM; : 2.37 ± 0.56 nM; : 1.92 ± 0.41 nM; : 1.73 ± 0.43 nM; known PARP-1 inhibitor Olaparib: 1.87 ± 0.10 nM; non-PARP-1 compound Raclopride: >20,000 nM) in a competitive binding assay using a tritium-labeled PARP-1 radioligand [H]WC-DZ for screening. [F]Talazoparib () was radiosynthesized via a multiple-step procedure with good radiochemical and chiral purities (98%) and high molar activity (28 GBq/μmol). The preliminary biodistribution studies in the murine PC-3 tumor model showed that [F]talazoparib had a good level of tumor uptake that persisted for over 8 h (3.78 ± 0.55 %ID/gram at 4 h and 4.52 ± 0.32 %ID/gram at 8 h). These studies show the potential for the bromo- and iodo- derivatives for PARP-1 targeted radiotherapy studies using therapeutic radionuclides.
PubMed: 34069967
DOI: 10.3390/biomedicines9050565 -
NeuroImage Feb 2020
Topics: Brain; Carbon Radioisotopes; Corpus Striatum; Dopamine; Humans; Positron-Emission Tomography; Raclopride; Reproducibility of Results
PubMed: 31539589
DOI: 10.1016/j.neuroimage.2019.116203