Neuroadaptations in the dorsal hippocampus underlie cocaine seeking during prolonged abstinence

Autor(es):Mostrar menos -

Werner, Craig T. ^[1] ; Mitra, Swarup ^[1] ; Auerbach, Benjamin D. ^[2] ; Wang, Zi-Jun ^[1] ; Martin, Jennifer A. ^[1] ; Stewart, Andrew F. ^[1] ; Gobira, Pedro H. ^{[1, 3]} ; Iida, Madoka ^[1] ; An, Chunna ^[1] ; Cobb, Moriah M. ^{[1, 4]} ; Caccamise, Aaron ^[1] ; Salvi, Richard J. ^[2] ; Neve, Rachael L. ^[5] ; Gancarz, Amy M. ^[4] ; Dietz, David M. ^{[6, 1]}

Afiliação do(s) autor(es)

^[1] SUNY Buffalo, Jacobs Sch Med & Biomed Sci, Dept Pharmacol & Toxicol, Program Neurosci, Buffalo, NY 14214 - USA

^[2] SUNY Buffalo, Ctr Hearing & Deafness, Buffalo, NY 14214 - USA

^[3] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Phys & Chem, BR-14040 Ribeirao Preto, SP - Brazil

^[4] Calif State Univ Bakersfield, Dept Psychol, Bakersfield, CA 93311 - USA

^[5] Massachusetts Gen Hosp, Gene Delivery Technol Core, Cambridge, MA 02114 - USA

^[6] SUNY Buffalo, Dept Psychol, Buffalo, NY 14260 - USA

• Tipo de documento: Artigo Científico
• Fonte: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 117, n. 42, p. 26460-26469, OCT 20 2020.
• Citações Web of Science: 0

Resumo

Relapse vulnerability in substance use disorder is attributed to persistent cue-induced drug seeking that intensifies (or ``incubates{''}) during drug abstinence. Incubated cocaine seeking has been observed in both humans with cocaine use disorder and in preclinical relapse models. This persistent relapse vulnerability is mediated by neuroadaptations in brain regions involved in reward and motivation. The dorsal hippocampus (DH) is involved in context-induced reinstatement of cocaine seeking but the role of the DH in cocaine seeking during prolonged abstinence has not been investigated. Here we found that transforming growth factor-beta (TGF-beta) superfamily member activin A is increased in the DH on abstinence day (AD) 30 but not AD1 following extended-access cocaine self-administration compared to saline controls. Moreover, activin A does not affect cocaine seeking on AD1 but regulates cocaine seeking on AD30 in a bidirectional manner. Next, we found that activin A regulates phosphorylation of NMDA receptor (NMDAR) subunit GluN2B and that GluN2B-containing NMDARs also regulate expression of cocaine seeking on AD30. Activin A and GluN2B-containing NMDARs have both previously been implicated in hippocampal synaptic plasticity. Therefore, we examined synaptic strength in the DH during prolonged abstinence and observed an increase in moderate long-term potentiation (LTP) in cocaine-treated rats compared to saline controls. Lastly, we examined the role of DH projections to the lateral septum (LS), a brain region implicated in cocaine seeking and found that DH projections to the LS govern cocaine seeking on AD30. Taken together, this study demonstrates a role for the DH in relapse behavior following prolonged abstinence from cocaine self-administration. (AU)

• Processo FAPESP: 17/19284-0 - Envolvimento da acetilação de histonas na modulação da vulnerabilidade aos efeitos da cocaína induzida pela exposição a canabinoides durante a adolescência
• Beneficiário: Pedro Henrique Gobira Nunes
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado