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Prelimbic cortical projections to rostromedial tegmental nucleus play a suppressive role in cue-induced reinstatement of cocaine seeking



The prelimbic (PL) region of prefrontal cortex has been implicated in both driving and suppressing cocaine seeking in animal models of addiction. We hypothesized that these opposing roles for PL may be supported by distinct efferent projections. While PL projections to nucleus accumbens core have been shown to be involved in driving reinstatement of cocaine seeking, PL projections to the rostromedial tegmental nucleus (RMTg) may instead suppress reinstatement of cocaine seeking, due to the role of RMTg in behavioral inhibition. Here, we used a functional disconnection approach to temporarily disrupt the PL-RMTg pathway during cue- or cocaine-induced reinstatement. Male Sprague Dawley rats self-administered cocaine during daily 2-h sessions for ≥10 days and then underwent extinction training. Reinstatement of extinguished cocaine seeking was elicited by cocaine-associated cues or cocaine prime. Prior to reinstatement, rats received microinjections of the GABA agonists baclofen/muscimol (1/0.1 mM) into unilateral PL and the AMPA receptor antagonist NBQX (1 mM) into contralateral or ipsilateral RMTg. Functional disconnection of PL-RMTg via contralateral inactivation markedly increased cue-induced reinstatement, but did not increase cocaine-induced reinstatement or drive reinstatement of extinguished cocaine seeking in the absence of cues or cocaine. Enhanced cue-induced reinstatement was also observed with ipsilateral inactivation of PL and RMTg, but not with unilateral inactivation of PL or RMTg alone, indicating that both ipsilateral and contralateral projections from PL to RMTg have an inhibitory influence on behavior. These data further support a suppressive role for PL in cocaine seeking by implicating PL efferent projections to RMTg in inhibiting cue-induced reinstatement.

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Fig. 1: Retrogradely-labeled PL neurons projecting to RMTg.
Fig. 2: Microinjection cannulae placements for PL and RMTg.
Fig. 3: Effects of PL-RMTg functional disconnection on cue-induced reinstatement.
Fig. 4: Effects of PL-RMTg functional disconnection on cocaine-induced reinstatement and extinction responding.


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We thank Lillian Laiks for help with conducting pilot experiments for this study. This work was supported by National Institutes of Health grant R21 DA037744 (RJS).

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RJS and TCJ conceived the study. RJS and AMC designed and analyzed experiments, and wrote the manuscript, with TCJ contributing revisions. AMC, HFS, and THK conducted the experiments. All authors approved the final version of the manuscript.

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Correspondence to Rachel J. Smith.

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Cruz, A.M., Spencer, H.F., Kim, T.H. et al. Prelimbic cortical projections to rostromedial tegmental nucleus play a suppressive role in cue-induced reinstatement of cocaine seeking. Neuropsychopharmacol. (2020).

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