RT Journal Article
SR Electronic
T1 Estrous Cycle Influences Cell-Type-Specific Translatomic Signatures of Repeated Ketamine Exposure in the Rat Nucleus Accumbens
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0419-25.2025
DO 10.1523/ENEURO.0419-25.2025
VO 13
IS 1
A1 Saland, Samantha K.
A1 Duclot, Florian
A1 Lobo, Mary K.
A1 Kabbaj, Mohamed
YR 2026
UL http://www.eneuro.org/content/13/1/ENEURO.0419-25.2025.abstract
AB The growing therapeutic promise of repeated, low-dose ketamine treatment across various psychopathologies—including depression and drug addiction—warrants clarity on its potential addictive properties and their associated mechanisms in both sexes. Accordingly, the present work examined the effects of intermittent low-dose ketamine in male and female rats on behavioral sensitization to the locomotor-activating effects of ketamine, as well as associated molecular profiles in dopamine D1- and D2-receptor-expressing medium spiny neurons (D1- and D2-MSNs) of the nucleus accumbens (NAc). Following intra-NAc infusion of a Cre-inducible RiboTag virus, locomotor activity was measured in adult Drd1a-iCre and Drd2-iCre male and female rats in either diestrus or proestrus following repeated administration of ketamine (0, 10, or 20 mg/kg, i.p.) to evaluate the development of locomotor sensitization. Female—but not male—rats developed sensitization to the locomotor-activating effects of ketamine, occurring more rapidly in proestrus than in diestrus females at the lower dose tested. To examine enduring context- and cell-type-specific changes in translating mRNAs associated with sensitization to ketamine, RNA sequencing was performed on polyribosome-bound mRNA of D1- and D2-MSNs isolated from the NAc of sensitized females in a drug-free state. A greater number of differentially expressed genes were observed selectively in D1-MSNs of ketamine-treated proestrus versus diestrus females, which were broadly related to regulation of transcription and epitranscriptional modification. These findings provide novel evidence of cell-type-specific and estrous cycle-dependent molecular profiles responsive to intermittent ketamine treatment in female rats and identify posttranscriptional mechanisms with relevance to ketamine's effects on behavioral plasticity.