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- W4377029101 abstract "<b>Abstract ID 24537</b> <b>Poster Board 547</b> Transmission via 5-HT<sub>2A</sub> receptors (<b>5-HT<sub>2A</sub>R</b>) in medial prefrontal cortex (<b>mPFC</b>) is implicated in the regulation of impulsive action which can be assessed in models which evaluate inhibitory control over prepotent motor responses. Systemic administration of a selective 5-HT<sub>2A</sub>R antagonist consistently attenuates impulsive action in choice serial reaction time (<b>CSRT</b>) tasks of motor impulsivity. Intra-mPFC 5-HT<sub>2A</sub>R blockade induces subtle enhancements in inhibitory control. Intriguingly, high-impulsive rats exhibit higher levels of 5-HT<sub>2A</sub>R expression and function. Here, we tested the hypothesis that stable knockdown of the 5-HT<sub>2A</sub>R locally in the mPFC regulates inhibitory control involving cues in the sucrose-reinforced 1-choice CSRT task. <b>Methods:</b> A short hairpin RNA (<b>5-HT<sub>2A</sub>R-shRNA</b>) that efficiently knocks down over 90% of 5-HT<sub>2A</sub>R mRNA<i> in vitro</i> was designed, validated, and packaged into an adeno-associated viral (<b>AAV</b>) vector; a non-silencing control (<b>NSC</b>) hairpin was designed and assessed to have no effect on 5-HT<sub>2A</sub>R mRNA expression. Male Sprague-Dawley rats were trained to stability in a sucrose-reinforced 1-CSRT task with a cued inter-trial interval (<b>ITI</b>) of 5-sec (<b>ITI-5s</b>) and challenged in sessions with ITI 8-sec (<b>ITI-8s</b>) prior to surgical delivery of viral vectors. Rats received bilateral stereotaxic infusions of 5-HT<sub>2A</sub>R-shRNA-eGFP AAV (n=8) or NSC-eGFP-AAV (n=8) into the mPFC (AP: +3.0 mm; ML: +1.4 mm; DV: -5.1, -4.1, -3.1 mm; relative to Bregma ). After recovery, rats were restabilized in the 1-CSRT task with ITI-5s with two post-surgery probes in ITI-8s. <b>Results:</b> Statistical analysis of performance on the ITI-5s and ITI-8s parameters did not yield significant effects of the knockdown of 5-HT<sub>2A</sub>R in mPFC. Further analysis centered on the effects of increased ITI challenges revealed that, normalized to the ITI-5s baseline, intra-mPFC 5-HT<sub>2A</sub>R knockdown significantly increased ITI-8s premature responding as compared to pre-surgery baselines. Thus, intra-mPFC 5-HT<sub>2A</sub>R knockdown revealed an increased impact of longer cued ITIs (ITI-8s) relative to baseline (ITI-5s) on premature responding for sucrose in 1CSRT task. <b>Conclusions:</b> These results suggest that 5-HT<sub>2A</sub>R transmission in the mPFC modulates impulsive action related to cues associated with a task and/or reward. Therefore, identification of 5-HT<sub>2A</sub>R distribution along neural circuits governing inhibitory control of motivated behavior could lead to a new mechanistic understanding of behavioral impulsivity. We are currently conducting tract-tracing studies to determine the anatomical distribution of 5-HT<sub>2A</sub>R-containing mPFC afferents to uncover the involvement of downstream connectivity that regulates impulsive behavior. <b>Financial Support:</b> T32DA07287, P50DA033935" @default.
- W4377029101 created "2023-05-19" @default.
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- W4377029101 date "2023-05-18" @default.
- W4377029101 modified "2023-10-12" @default.
- W4377029101 title "Involvement of the Rat Medial Prefrontal Cortex 5-HT<sub>2A</sub>Receptor in Impulsive Action" @default.
- W4377029101 doi "https://doi.org/10.1124/jpet.122.245370" @default.
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