2025
Dopaminergic frontostriatal pathways in major depressive disorder and childhood sexual abuse: a multimodal neuroimaging investigation
Borchers L, Dan R, Belleau E, Kaiser R, Clegg R, Goer F, Pechtel P, Beltzer M, Wooten D, El Fakhri G, Normandin M, Pizzagalli D. Dopaminergic frontostriatal pathways in major depressive disorder and childhood sexual abuse: a multimodal neuroimaging investigation. Molecular Psychiatry 2025, 1-9. PMID: 40926089, DOI: 10.1038/s41380-025-03218-3.Peer-Reviewed Original ResearchResting-state functional connectivityMajor depressive disorderChildhood sexual abuseDopamine transporter availabilityDepressive disorderPathophysiology of Major Depressive DisorderStriatal dopamine transporter availabilitySexual abuseReward-related regionsSeed-based RSFCVentral tegmental areaDA dysregulationVentral striatumMDD episodeTegmental areaFrontostriatal pathwaysUnmedicated individualsChildhood maltreatmentNeuroimaging investigationsFunctional connectivityTransporter availabilityTreatment targetMRI studiesAbuseCo-occurrenceReduced DJ-1-F1Fo ATP synthase association correlates with midbrain dopaminergic neuron vulnerability in idiopathic Parkinson’s disease
Abulimiti A, Bae H, Ali A, Balakrishnan S, Tsujishita M, Gveric D, Tierney T, Jonas E, Smith P, Gentleman S, Alavian K. Reduced DJ-1-F1Fo ATP synthase association correlates with midbrain dopaminergic neuron vulnerability in idiopathic Parkinson’s disease. Science Advances 2025, 11: eads3051. PMID: 40479058, PMCID: PMC12143374, DOI: 10.1126/sciadv.ads3051.Peer-Reviewed Original ResearchConceptsProximity ligation assayVentral tegmental areaF1Fo-ATP synthaseProximity ligation assay signalsMetabolic efficiencyVentral tegmental area neuronsMitochondrial metabolic efficiencyProtein productionLigation assayMitochondrial activityMetabolic homeostasisIntracellular compartmentsMitochondrial efficiencyDistal neuritesParkinson's diseaseControl postmortem brainsImpaired mitochondrial efficiencySubstantia nigra pars compactaDopaminergic neuron vulnerabilityMesDA neuronsMesencephalic dopaminergicNeuronal vulnerabilityTegmental areaNeuronal subpopulationsIdiopathic Parkinson's diseaseDiminished reward circuit response underlies pain avoidance learning deficits in problem drinkers
Le T, Oba T, Li C. Diminished reward circuit response underlies pain avoidance learning deficits in problem drinkers. NeuroImage Clinical 2025, 45: 103762. PMID: 40009903, PMCID: PMC11908557, DOI: 10.1016/j.nicl.2025.103762.Peer-Reviewed Original ResearchConceptsPosterior cingulate cortexAvoidance learningReward circuitDrinking severityReward deficiencyLearning deficitsPain avoidanceProblem drinkersAlcohol useAvoidance learning deficitMedial orbitofrontal cortexReward circuit dysfunctionVentral tegmental areaPoor avoidance learningAssociated with problem drinkingOrbitofrontal cortexTegmental areaGo/NoGo taskCingulate cortexNeural correlatesBehavioral findingsCircuit dysfunctionAdult drinkersBrain regionsNeural processesMapping cross-modal functional connectivity of major neurotransmitter systems in the human brain
Saiz-Masvidal C, De la Peña-Arteaga V, Bertolín S, Diez I, Juaneda-Seguí A, Martínez-Zalacaín I, Chavarría-Elizondo P, Subirà M, Menchón J, Sepulcre J, Fullana M, Soriano-Mas C. Mapping cross-modal functional connectivity of major neurotransmitter systems in the human brain. Brain Structure And Function 2025, 230: 137. PMID: 40828212, PMCID: PMC12364969, DOI: 10.1007/s00429-025-02996-4.Peer-Reviewed Original ResearchConceptsDorsal raphe nucleusVentral tegmental areaSubstantia nigra pars compactaFunctional connectivityMonoaminergic systemsRs-FCLocus coeruleusMedial frontal cortexResting-state functional MRIDorsal raphe nucleus projectsRs-fMRI analysisPrefrontal cortexTegmental areaFrontal cortexNeurotransmitter systemsRaphe nucleusDopaminergic pathwaysNeuropsychiatric conditionsInsular cortexNeurotransmitter networksBehavioral flexibilityMonoaminergic nucleiSubcortical regionsFunctional MRIBrain activity
2024
Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release
Zhou X, Stine C, Prada P, Fusca D, Assoumou K, Dernic J, Bhat M, Achanta A, Johnson J, Pasqualini A, Jadhav S, Bauder C, Steuernagel L, Ravotto L, Benke D, Weber B, Suko A, Palmiter R, Stoeber M, Kloppenburg P, Brüning J, Bruchas M, Patriarchi T. Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release. Nature Communications 2024, 15: 5353. PMID: 38918403, PMCID: PMC11199706, DOI: 10.1038/s41467-024-49712-0.Peer-Reviewed Original ResearchConceptsOpioid peptide releaseVentral tegmental areaAcute brain slicesN/OFQ actionsChemogenetic activationIn vivo studiesNociceptin/orphanin FQTegmental areaFibre photometryOpioid peptidesBrain slicesPharmacological profileGenetically encoded sensorIntracellular signal transducersReceptor ligandsPeptide releaseMammalian brainFunctional relevanceNeuronsBehavioral processesSignal transducerReleasePotential interactionsRegulatory functionsN/OFQ
2023
Ventral Tegmental Area M5 Muscarinic Receptors Mediate Effort-Choice Responding and Nucleus Accumbens Dopamine in a Sex-Specific Manner
Nunes E, Kebede N, Haight J, Foster D, Lindsley C, Conn P, Addy N. Ventral Tegmental Area M5 Muscarinic Receptors Mediate Effort-Choice Responding and Nucleus Accumbens Dopamine in a Sex-Specific Manner . Journal Of Pharmacology And Experimental Therapeutics 2023, 385: 146-156. PMID: 36828630, PMCID: PMC10108441, DOI: 10.1124/jpet.122.001438.Peer-Reviewed Original ResearchConceptsNucleus accumbens coreVentral tegmental areaM5 receptorsDA releaseMale ratsVTA infusionsDepressive disorderNucleus accumbensMuscarinic M5 receptorsSelective negative allosteric modulatorM5 muscarinic receptorsNegative allosteric modulatorsEffort-related choicePhasic DA releasePotential sex differencesSex-specific mannerACh toneVTA administrationCholinergic effectsMuscarinic receptorsFemale ratsTegmental areaPreclinical modelsDopamine releaseTherapeutic target
2022
L-type calcium channel regulation of dopamine activity in the ventral tegmental area to nucleus accumbens pathway: Implications for substance use, mood disorders and co-morbidities
Nunes E, Addy N. L-type calcium channel regulation of dopamine activity in the ventral tegmental area to nucleus accumbens pathway: Implications for substance use, mood disorders and co-morbidities. Neuropharmacology 2022, 224: 109336. PMID: 36414149, PMCID: PMC11215796, DOI: 10.1016/j.neuropharm.2022.109336.Peer-Reviewed Original ResearchConceptsL-type calcium channelsVentral tegmental areaPre-clinical modelsTegmental areaSubstance useLTCC blockersMood disordersCalcium channelsCo-morbid psychiatric diagnosesDA neuronal activityVoltage-gated calcium channelsMood-related behaviorsSubstance use disordersCalcium channel regulationStress-induced plasticityAccumbens pathwayCardiac medicationsDopamine neuronsLTCC subtypesNeuronal activityNeuronal firingUse disordersPsychiatric diagnosisCalcium entryDopamine activityAgRP neurons control structure and function of the medial prefrontal cortex
Stutz B, Waterson MJ, Šestan-Peša M, Dietrich MO, Škarica M, Sestan N, Racz B, Magyar A, Sotonyi P, Liu ZW, Gao XB, Matyas F, Stoiljkovic M, Horvath TL. AgRP neurons control structure and function of the medial prefrontal cortex. Molecular Psychiatry 2022, 27: 3951-3960. PMID: 35906488, PMCID: PMC9891653, DOI: 10.1038/s41380-022-01691-8.Peer-Reviewed Original ResearchConceptsMedial prefrontal cortexAgRP neuronsNon-selective dopamine receptor antagonistBrain functionPrefrontal cortexHypothalamic AgRP neuronsMedial thalamic neuronsAdministration of clozapineDopamine receptor antagonistVentral tegmental areaOscillatory network activityHigher-order brain functionsHypothalamic agoutiThalamic neuronsChemogenetic inhibitionDopaminergic neuronsReceptor antagonistTegmental areaNeuronal pathwaysSensorimotor gatingAdult miceModulatory impactAmbulatory behaviorConstitutive impairmentNeuronsBrain-wide electrical dynamics encode individual appetitive social behavior
Mague SD, Talbot A, Blount C, Walder-Christensen KK, Duffney LJ, Adamson E, Bey AL, Ndubuizu N, Thomas GE, Hughes DN, Grossman Y, Hultman R, Sinha S, Fink AM, Gallagher NM, Fisher RL, Jiang YH, Carlson DE, Dzirasa K. Brain-wide electrical dynamics encode individual appetitive social behavior. Neuron 2022, 110: 1728-1741.e7. PMID: 35294900, PMCID: PMC9126093, DOI: 10.1016/j.neuron.2022.02.016.Peer-Reviewed Original Research
2021
Sex Differences in the Ventral Tegmental Area and Nucleus Accumbens Proteome at Baseline and Following Nicotine Exposure
Lee AM, Mansuri MS, Wilson RS, Lam TT, Nairn AC, Picciotto MR. Sex Differences in the Ventral Tegmental Area and Nucleus Accumbens Proteome at Baseline and Following Nicotine Exposure. Frontiers In Molecular Neuroscience 2021, 14: 657064. PMID: 34335180, PMCID: PMC8317211, DOI: 10.3389/fnmol.2021.657064.Peer-Reviewed Original ResearchVentral tegmental areaC3H/HeJ miceGlial fibrillary acidic proteinChronic nicotine administrationNicotine administrationProtein abundanceProteomeIsobaric labelingNicotine exposureFemale miceTegmental areaHeJ miceNucleus accumbensNicotine addictionProteinSex differencesSample fractionationPathwayFibrillary acidic proteinTandem mass spectrometryNetwork analysisMouse strainsChronic nicotineMesolimbic systemNicotine reward
2020
Examining the role of muscarinic M5 receptors in VTA cholinergic modulation of depressive-like and anxiety-related behaviors in rats
Nunes EJ, Rupprecht LE, Foster DJ, Lindsley CW, Conn PJ, Addy NA. Examining the role of muscarinic M5 receptors in VTA cholinergic modulation of depressive-like and anxiety-related behaviors in rats. Neuropharmacology 2020, 171: 108089. PMID: 32268153, PMCID: PMC7313677, DOI: 10.1016/j.neuropharm.2020.108089.Peer-Reviewed Original ResearchConceptsSucrose preference testVentral tegmental areaMuscarinic M5 receptorsCholinergic toneM5 receptorsBehavioral effectsFemale ratsDepressive-like behavioral effectsIntra-VTA infusionAnxiogenic-like effectsAcetylcholinesterase inhibitor physostigmineAnxiety-related behaviorVTA administrationCholinergic modulationCholinergic receptorsMuscarinic receptorsInhibitor physostigmineSwim testTegmental areaMale ratsMood disordersVTA infusionsFST behaviorRatsPhysostigmine
2019
Assessment of Striatal Dopamine Transporter Binding in Individuals With Major Depressive Disorder
Pizzagalli D, Berretta S, Wooten D, Goer F, Pilobello K, Kumar P, Murray L, Beltzer M, Boyer-Boiteau A, Alpert N, Fakhri G, Mechawar N, Vitaliano G, Turecki G, Normandin M. Assessment of Striatal Dopamine Transporter Binding in Individuals With Major Depressive Disorder. JAMA Psychiatry 2019, 76: 854-861. PMID: 31042280, PMCID: PMC6495358, DOI: 10.1001/jamapsychiatry.2019.0801.Peer-Reviewed Original ResearchConceptsMajor depressive disorderDA transporter availabilityVentral tegmental areaDA transporterDAT availabilityTegmental areaDepressive disorderDA signalingPositron emission tomographyDAT expressionMcLean HospitalHealthy controlsMajor depressive disorder groupsNumbers of depressive episodesStriatal dopamine transporter bindingDA transporter levelsLevels of DAT expressionStriatal DAT expressionStriatal DAT availabilityDA transporter densityDAT binding potentialDopamine transporter bindingOlder healthy controlsMesolimbic pathwayDA clearanceCholinergic Receptor Blockade in the VTA Attenuates Cue-Induced Cocaine-Seeking and Reverses the Anxiogenic Effects of Forced Abstinence
Nunes EJ, Bitner L, Hughley SM, Small KM, Walton SN, Rupprecht LE, Addy NA. Cholinergic Receptor Blockade in the VTA Attenuates Cue-Induced Cocaine-Seeking and Reverses the Anxiogenic Effects of Forced Abstinence. Neuroscience 2019, 413: 252-263. PMID: 31271832, PMCID: PMC6661179, DOI: 10.1016/j.neuroscience.2019.06.028.Peer-Reviewed Original ResearchConceptsCue-induced cocaineAnxiety-related behaviorDrug relapseOpen arm timeCholinergic receptor blockadeCocaine abstinenceVentral tegmental areaSubstance abuseSelf-administer intravenous cocaineMuscarinic receptor antagonist scopolaminePeriod of abstinenceAnxiogenic effectsReceptor blockadeCholinergic mechanismsCocaine-naïve ratsNicotinic acetylcholine receptor antagonist mecamylamineMale Sprague-Dawley ratsDrug abstinenceSprague-Dawley ratsDose-dependent increaseCocaine-naive ratsAntagonist scopolamineEPM behaviorSaline ratsAbstinence
2018
The novel psychoactive substance methoxetamine induces persistent behavioral abnormalities and neurotoxicity in rats
Costa G, Serra M, Pintori N, Casu M, Zanda M, Murtas D, De Luca M, Simola N, Fattore L. The novel psychoactive substance methoxetamine induces persistent behavioral abnormalities and neurotoxicity in rats. Neuropharmacology 2018, 144: 219-232. PMID: 30366005, DOI: 10.1016/j.neuropharm.2018.10.031.Peer-Reviewed Original ResearchConceptsEffects of methoxetamineElevated plus mazePersistent behavioral abnormalitiesBehavioral effectsPlus mazeLocomotor activityBehavioral abnormalitiesDensity of dopamine transportersLocomotor activity of ratsImpaired non-spatial memoryNovel object recognition testEmission of ultrasonic vocalizationsMedial prefrontal cortexMarble burying testVentral tegmental areaPersistent behavioral effectsNon-spatial memoryNovel object recognitionObject recognition testActivity of ratsNeurotoxic effectsSubstantia nigra pars compactaSerotonergic damageNucleus accumbensBurying testGranulocyte-Colony-Stimulating Factor Alters the Proteomic Landscape of the Ventral Tegmental Area
Mervosh NL, Wilson R, Rauniyar N, Hofford RS, Kutlu MG, Calipari ES, Lam TT, Kiraly DD. Granulocyte-Colony-Stimulating Factor Alters the Proteomic Landscape of the Ventral Tegmental Area. Proteomes 2018, 6: 35. PMID: 30249060, PMCID: PMC6313867, DOI: 10.3390/proteomes6040035.Peer-Reviewed Original ResearchGranulocyte-colony stimulating factorVentral tegmental areaTegmental areaG-CSF treatmentLimbic brain regionsCombination of cocaineMesolimbic dopamine circuitG-CSF functionInjection of cocaineStudy miceAvailable pharmacotherapiesAberrant plasticityDopamine releaseTreatment groupsSynaptic plasticityDopamine circuitsNeuronal morphologyBrain regionsSoluble cytokinesGranulocyte colonyCocaine addictionBrain functionStimulating factorProtein expressionSignificant tollGIRK currents in VTA dopamine neurons control the sensitivity of mice to cocaine-induced locomotor sensitization
Rifkin R, Huyghe D, Li X, Parakala M, Aisenberg E, Moss S, Slesinger P. GIRK currents in VTA dopamine neurons control the sensitivity of mice to cocaine-induced locomotor sensitization. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: e9479-e9488. PMID: 30228121, PMCID: PMC6176583, DOI: 10.1073/pnas.1807788115.Peer-Reviewed Original ResearchConceptsVentral tegmental areaVentral tegmental area dopamine neuronsCocaine-induced locomotor sensitizationDopamine neuronsLocomotor sensitizationVTA dopamine neuronsSubstantia nigra pars compactaGIRK currentsG-protein-gated inwardly rectifying potassium channelsCocaine addictionReward circuitTegmental areaGIRK channelsEndosomal adaptor proteinTreat addictionGIRK3 subunitsNeural circuitsInwardly rectifying potassium channelsRectifying potassium channelsDopamineGABAAddictionSpike firingSource of inhibitionGIRKThe L-type calcium channel blocker, isradipine, attenuates cue-induced cocaine-seeking by enhancing dopaminergic activity in the ventral tegmental area to nucleus accumbens pathway
Addy NA, Nunes EJ, Hughley SM, Small KM, Baracz SJ, Haight JL, Rajadhyaksha AM. The L-type calcium channel blocker, isradipine, attenuates cue-induced cocaine-seeking by enhancing dopaminergic activity in the ventral tegmental area to nucleus accumbens pathway. Neuropsychopharmacology 2018, 43: 2361-2372. PMID: 29773910, PMCID: PMC6180103, DOI: 10.1038/s41386-018-0080-2.Peer-Reviewed Original ResearchConceptsL-type calcium channelsCocaine relapseLever depressionVentral tegmental areaCocaine self-administration trainingOriginal training contextLight cue presentationSelf-administration trainingSubjective effectsCocaine-seeking behaviorTegmental areaBehavioral effectsCocaine's subjective effectsL-type calcium channel blockerCue presentationMale Sprague-Dawley ratsTraining contextCocaine cuesNucleus accumbens coreNatural rewardsDA receptor activationCalcium channel blockersSprague-Dawley ratsPhasic dopaminePotential therapeutic targetAdolescent Nicotine Exposure Alters GABAA Receptor Signaling in the Ventral Tegmental Area and Increases Adult Ethanol Self-Administration
Thomas A, Ostroumov A, Kimmey B, Taormina M, Holden W, Kim K, Brown-Mangum T, Dani J. Adolescent Nicotine Exposure Alters GABAA Receptor Signaling in the Ventral Tegmental Area and Increases Adult Ethanol Self-Administration. Cell Reports 2018, 23: 68-77. PMID: 29617674, PMCID: PMC5983379, DOI: 10.1016/j.celrep.2018.03.030.Peer-Reviewed Original ResearchConceptsVentral tegmental areaAdolescent nicotine exposureNicotine exposureTegmental areaChloride extrusionLateral ventral tegmental areaSubsequent ethanol intakeVTA GABA neuronsNicotine-treated animalsGlucocorticoid receptor activationGABAA Receptor SignalingEthanol Self‐AdministrationGABA neuronsPathological drinkingVTA GABAAlcohol drinkingEthanol intakeReceptor activationSelf-AdministrationRisk profileGABANeuron responsesAdolescent smokingReceptor signalingReversal potential
2017
The Effects of Age, from Young to Middle Adulthood, and Gender on Resting State Functional Connectivity of the Dopaminergic Midbrain
Peterson AC, Zhang S, Hu S, Chao HH, Li CR. The Effects of Age, from Young to Middle Adulthood, and Gender on Resting State Functional Connectivity of the Dopaminergic Midbrain. Frontiers In Human Neuroscience 2017, 11: 52. PMID: 28223929, PMCID: PMC5293810, DOI: 10.3389/fnhum.2017.00052.Peer-Reviewed Original ResearchSubstantia nigra pars compactaVentral tegmental areaAttention-deficit/ hyperactivity disorderState functional connectivityAge-related changesEffect of ageFunctional connectivityParahippocampal gyrusParkinson's diseaseMiddle adulthoodDopaminergic ventral tegmental areaBilateral angular gyrusOrbital frontal regionsBlood oxygenation level-dependent (BOLD) signalLevel-dependent signalPosterior orbital gyrusTime courseNeural basisDopaminergic midbrainHyperactivity disorderNeural mechanismsAngular gyrusPars compactaFrontal regionsDopaminergic structures
2016
Elevated Dopamine D2/3 Receptor Availability in Obese Individuals: A PET Imaging Study with [11C](+)PHNO
Gaiser EC, Gallezot JD, Worhunsky PD, Jastreboff AM, Pittman B, Kantrovitz L, Angarita GA, Cosgrove KP, Potenza MN, Malison RT, Carson RE, Matuskey D. Elevated Dopamine D2/3 Receptor Availability in Obese Individuals: A PET Imaging Study with [11C](+)PHNO. Neuropsychopharmacology 2016, 41: 3042-3050. PMID: 27374277, PMCID: PMC5101552, DOI: 10.1038/npp.2016.115.Peer-Reviewed Original ResearchConceptsBody mass indexVentral striatumObese individualsD2/3R availabilityOB individualsReward regionsSubstantia nigra/ventral tegmental areaDopamine D2/3 receptor availabilityNormal-weight individualsTreatment of obesityVentral tegmental areaNovel pharmacologic targetsD2/3 receptor availabilitySN/VTAAgonist tracersOverweight cohortMass indexWeight individualsTegmental areaBrain reward regionsAntagonist tracersPharmacologic targetReceptor availabilitySecondary analysisNW individuals
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