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The targeted modulation of dopaminergic signaling serves as a cornerstone in developing therapeutic interventions for conditions such as Parkinson\u2019s disease, schizophrenia, and addiction. Despite the pivotal role of dopaminergic neurons, the ultrastructure of dopaminergic synapses remains poorly understood. Here, we establish and utilize a cryo-correlative light and electron microscopy process to investigate the micro\/nanoscale architecture and organelle content of dopaminergic varicosities. Using cryo-electron tomography and subtomogram averaging, we demonstrate the ability to resolve in situ complex structures of the TRiC\/CCT chaperone and the vacuolar-type ATPase. We combine our experimental setup with pharmacological treatments using dopamine or haloperidol, showing bidirectional modulation of vesicular content and mitochondrial calcium phosphate deposition. These findings contribute to our understanding of the composition and (re)organization of dopaminergic varicosities and provide a methodological platform for further studies of the structure and cell biology of dopaminergic neurons and their responses.<\/jats:p>","DOI":"10.1083\/jcb.202503059","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T06:21:20Z","timestamp":1774506080000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Ultrastructure of dopaminergic varicosities revealed by cryo-correlative light and electron microscopy"],"prefix":"10.1083","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8989-8192","authenticated-orcid":true,"given":"Matthew Domenic","family":"Lycas","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035b05819","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Copenhagen 1 Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, , Copenhagen,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4693-3220","authenticated-orcid":true,"given":"Dustin R.","family":"Morado","sequence":"additional","affiliation":[{"name":"SciLifeLab 2 , Solna,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0020-3807","authenticated-orcid":true,"given":"Ulrik","family":"Gether","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035b05819","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Copenhagen 1 Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, , Copenhagen,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3990-6910","authenticated-orcid":true,"given":"John A.G.","family":"Briggs","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04py35477","id-type":"ROR","asserted-by":"publisher"}],"name":"Max Planck Institute of Biochemistry 3 Department of Cell and Virus Structure, , Martinsried,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6378-870X","authenticated-orcid":true,"given":"Simon","family":"Erlendsson","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0435rc536","id-type":"ROR","asserted-by":"publisher"}],"name":"Structural Molecular Biology Group, Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical Sciences University of Copenhagen 4 , Copenhagen,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"2026060408512077500_bib1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/BF00508803","article-title":"Dopamine \u201cAutoreceptors\u201d: Pharmacological characterization by microiontophoretic single cell recording studies","volume":"297","author":"Aghajanian","year":"1977","journal-title":"Naunyn. 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