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 the 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,) 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 compared to 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 post-transcriptional mechanisms with relevance to ketamine's effects on behavioral plasticity.Repeated low-dose ketamine treatment is often required to maintain its antidepressant efficacy. Given its history of recreational misuse, there is a need to identify predictors and neural signatures of susceptibility to ketamine's addictive liability using clinically relevant treatment regimens. Using a RiboTag viral vector approach in rats, we demonstrate that estrous cycle regulates both sensitized behavioral response to intermittent ketamine and enduring sensitization-associated post-transcriptional neuroadaptations in D1 receptor-expressing medium spiny neurons (MSNs) of the nucleus accumbens-a hub for reward and reinforcement. These changes occurred on a background of cycle-stage-specific MSN subtype translatomes at baseline, providing some basis for differential treatment response within these cell populations and insights into the interaction between estrous cycle and ketamine's effects on brain plasticity. i.p. Significance Statement
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