dc.contributor.author
Kruyer, Anna
dc.contributor.author
Parrilla-Carrero, Jeffrey
dc.contributor.author
Powell, Courtney
dc.contributor.author
Brandt, Lasse
dc.contributor.author
Gutwinski, Stefan
dc.contributor.author
Angelis, Ariana
dc.contributor.author
Chalhoub, Reda M.
dc.contributor.author
Jhou, Thomas C.
dc.contributor.author
Kalivas, Peter W.
dc.contributor.author
Amato, Davide
dc.date.accessioned
2023-07-26T14:24:21Z
dc.date.available
2023-07-26T14:24:21Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/40264
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-39984
dc.description.abstract
Antipsychotic-induced dopamine supersensitivity, or behavioral supersensitivity, is a problematic consequence of long-term antipsychotic treatment characterized by the emergence of motor abnormalities, refractory symptoms, and rebound psychosis. The underlying mechanisms are unclear and no approaches exist to prevent or reverse these unwanted effects of antipsychotic treatment. Here we demonstrate that behavioral supersensitivity stems from long-lasting pre, post and perisynaptic plasticity, including insertion of Ca2+-permeable AMPA receptors and loss of D2 receptor-dependent inhibitory postsynaptic currents (IPSCs) in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). The resulting hyperexcitability, prominent in a subpopulation of D2-MSNs (21%), caused locomotor sensitization to cocaine and was associated with behavioral endophenotypes of antipsychotic treatment resistance and substance use disorder, including disrupted extinction learning and augmented cue-induced cocaine-seeking behavior. Chemogenetic restoration of IPSCs in D2-MSNs in the NAcore was sufficient to prevent antipsychotic-induced supersensitivity, pointing to an entirely novel therapeutic direction for overcoming this condition.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
D2-MSN hyperactivity
en
dc.subject
antipsychotic-induced
en
dc.subject
behavioral supersensitivity
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.doi
10.1038/s41380-021-01235-6
dcterms.bibliographicCitation.journaltitle
Molecular Psychiatry
dcterms.bibliographicCitation.number
11
dcterms.bibliographicCitation.originalpublishername
Springer Nature
dcterms.bibliographicCitation.pagestart
6159
dcterms.bibliographicCitation.pageend
6169
dcterms.bibliographicCitation.volume
26
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.funding
Springer Nature DEAL
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
34349226
dcterms.isPartOf.issn
1359-4184
dcterms.isPartOf.eissn
1476-5578