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.
Subscribe to Journal
Get full journal access for 1 year
only $30.69 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
McLaughlin J, See RE. Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology. 2003;168:57–65.
Capriles N, Rodaros D, Sorge RE, Stewart J. A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacology. 2003;168:66–74.
McFarland K, Davidge SB, Lapish CC, Kalivas PW. Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J Neurosci. 2004;24:1551–1560.
McFarland K, Kalivas PW. The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci. 2001;21:8655–8663.
Moorman DE, James MH, McGlinchey EM, Aston-Jones G. Differential roles of medial prefrontal subregions in the regulation of drug seeking. Brain Res. 2015;1628:130–146.
Chen BT, Yau H-J, Hatch C, Kusumoto-Yoshida I, Cho SL, Hopf FW, et al. Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature. 2013;496:359–362.
Mihindou C, Guillem K, Navailles S, Vouillac C, Ahmed SH. Discriminative inhibitory control of cocaine seeking involves the prelimbic prefrontal cortex. Biol Psychiatry. 2013;73:271–279.
Stefanik MT, Moussawi K, Kupchik YM, Smith KC, Miller RL, Huff ML, et al. Optogenetic inhibition of cocaine seeking in rats. Addict Biol. 2013;18:50–53.
Stefanik MT, Kupchik YM, Kalivas PW. Optogenetic inhibition of cortical afferents in the nucleus accumbens simultaneously prevents cue-induced transient synaptic potentiation and cocaine-seeking behavior. Brain Struct Funct. 2016;221:1681–1689.
McGlinchey EM, James MH, Mahler SV, Pantazis C, Aston-Jones G. Prelimbic to accumbens core pathway is recruited in a dopamine-dependent manner to drive cued reinstatement of cocaine Seeking. J Neurosci. 2016;36:8700–8711.
McFarland K, Lapish CC, Kalivas PW. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci. 2003;23:3531–3537.
Jhou TC, Geisler S, Marinelli M, Degarmo BA, Zahm DS. The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta. J Comp Neurol. 2009;513:566–596.
Jhou TC, Fields HL, Baxter MG, Saper CB, Holland PC. The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron. 2009;61:786–800.
Kaufling J, Veinante P, Pawlowski SA, Freund-Mercier M-J, Barrot M. Afferents to the GABAergic tail of the ventral tegmental area in the rat. J Comp Neurol. 2009;513:597–621.
Balcita-Pedicino JJ, Omelchenko N, Bell R, Sesack SR. The inhibitory influence of the lateral habenula on midbrain dopamine cells: ultrastructural evidence for indirect mediation via the rostromedial mesopontine tegmental nucleus. J Comp Neurol. 2011;519:1143–1164.
Barrot M, Sesack SR, Georges F, Pistis M, Hong S, Jhou TC. Braking dopamine systems: a new GABA master structure for mesolimbic and nigrostriatal functions. J Neurosci. 2012;32:14094–14101.
Bourdy R, Sánchez-Catalán M-J, Kaufling J, Balcita-Pedicino JJ, Freund-Mercier M-J, Veinante P, et al. Control of the nigrostriatal dopamine neuron activity and motor function by the tail of the ventral tegmental area. Neuropsychopharmacology. 2014;39:2788–2798.
Yetnikoff L, Cheng AY, Lavezzi HN, Parsley KP, Zahm DS. Sources of input to the rostromedial tegmental nucleus, ventral tegmental area, and lateral habenula compared: a study in rat. J Comp Neurol. 2015;523:2426–2456.
Fu R, Zuo W, Gregor D, Li J, Grech D, Ye J-H. Pharmacological manipulation of the rostromedial tegmental nucleus changes voluntary and operant ethanol self-administration in rats. Alcohol Clin Exp Res. 2016;40:572–582.
Huff ML, LaLumiere RT. The rostromedial tegmental nucleus modulates behavioral inhibition following cocaine self-administration in rats. Neuropsychopharmacology. 2015;40:861–873.
Li H, Vento PJ, Parrilla-Carrero J, Pullmann D, Chao YS, Eid M. et al. Three rostromedial tegmental afferents drive triply dissociable aspects of punishment learning and aversive valence encoding. Neuron. 2019;104:987–999.e4.
Caggiula AR, Donny EC, White AR, Chaudhri N, Booth S, Gharib MA, et al. Environmental stimuli promote the acquisition of nicotine self-administration in rats. Psychopharmacology. 2002;163:230–237.
Bastle RM, Kufahl PR, Turk MN, Weber SM, Pentkowski NS, Thiel KJ, et al. Novel cues reinstate cocaine-seeking behavior and induce Fos protein expression as effectively as conditioned cues. Neuropsychopharmacology. 2012;37:2109–2120.
Deroche-Gamonet V, Piat F, Le Moal M, Piazza PV. Influence of cue-conditioning on acquisition, maintenance and relapse of cocaine intravenous self-administration. Eur J Neurosci. 2002;15:1363–1370.
Fuchs RA, Evans KA, Parker MC, See RE. Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology. 2004;176:459–465.
Chang Y, Du C, Han L, Lv S, Zhang J, Bian G, et al. Enhanced AMPA receptor-mediated excitatory transmission in the rodent rostromedial tegmental nucleus following lesion of the nigrostriatal pathway. Neurochem Int. 2019;122:85–93.
Nolan BC, Saliba M, Tanchez C, Ranaldi R. Behavioral activating effects of selective AMPA receptor antagonism in the ventral tegmental area. Pharmacology. 2010;86:336–343.
Corbit LH, Nie H, Janak PH. Habitual responding for alcohol depends upon both AMPA and D2 receptor signaling in the dorsolateral striatum. Front Behav Neurosci. 2014;8:301.
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 7th ed. Academic Press; 2013.
Smith RJ, Vento PJ, Chao YS, Good CH, Jhou TC. Gene expression and neurochemical characterization of the rostromedial tegmental nucleus (RMTg) in rats and mice. Brain Struct Funct. 2019;224:219–238.
James MH, McGlinchey EM, Vattikonda A, Mahler SV, Aston-Jones G. Cued reinstatement of cocaine but not sucrose seeking is dependent on dopamine signaling in prelimbic cortex and is associated with recruitment of prelimbic neurons that project to contralateral nucleus accumbens core. Int J Neuropsychopharmacol. 2018;21:89–94.
Gourley SL, Taylor JR. Going and stopping: dichotomies in behavioral control by the prefrontal cortex. Nat Neurosci. 2016;19:656–664.
Peters J, Kalivas PW, Quirk GJ. Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem. 2009;16:279–288.
Warden MR, Selimbeyoglu A, Mirzabekov JJ, Lo M, Thompson KR, Kim S-Y, et al. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature. 2012;492:428–432.
Fuchs RA, Eaddy JL, Su Z-I, Bell GH. Interactions of the basolateral amygdala with the dorsal hippocampus and dorsomedial prefrontal cortex regulate drug context-induced reinstatement of cocaine-seeking in rats. Eur J Neurosci. 2007;26:487–498.
Peters J, LaLumiere RT, Kalivas PW. Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J Neurosci. 2008;28:6046–6053.
Bossert JM, Stern AL, Theberge FRM, Marchant NJ, Wang H-L, Morales M, et al. Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking. J Neurosci. 2012;32:4982–4991.
Hart G, Bradfield LA, Fok SY, Chieng B, Balleine BW. The bilateral prefronto-striatal pathway is necessary for learning new goal-directed actions. Curr Biol. 2018;28:2218.e7.
Mahler SV, Aston-Jones GS. Fos activation of selective afferents to ventral tegmental area during cue-induced reinstatement of cocaine seeking in rats. J Neurosci. 2012;32:13309–13326.
Weiss F, Maldonado-Vlaar CS, Parsons LH, Kerr TM, Smith DL, Ben-Shahar O. Control of cocaine-seeking behavior by drug-associated stimuli in rats: effects on recovery of extinguished operant-responding and extracellular dopamine levels in amygdala and nucleus accumbens. Proc Natl Acad Sci USA. 2000;97:4321–4326.
Nomikos GG, Damsma G, Wenkstern D, Fibiger HC. In vivo characterization of locally applied dopamine uptake inhibitors by striatal microdialysis. Synapse. 1990;6:106–112.
You Z-B, Wang B, Zitzman D, Azari S, Wise RA. A role for conditioned ventral tegmental glutamate release in cocaine seeking. J Neurosci. 2007;27:10546–10555.
Wise RA, Wang B, You Z-B. Cocaine serves as a peripheral interoceptive conditioned stimulus for central glutamate and dopamine release. PLoS ONE. 2008;3:e2846.
Sombers LA, Beyene M, Carelli RM, Wightman RM. Synaptic overflow of dopamine in the nucleus accumbens arises from neuronal activity in the ventral tegmental area. J Neurosci. 2009;29:1735–1742.
Kufahl PR, Zavala AR, Singh A, Thiel KJ, Dickey ED, Joyce JN, et al. c-Fos expression associated with reinstatement of cocaine-seeking behavior by response-contingent conditioned cues. Synapse. 2009;63:823–835.
Mahler SV, Smith RJ, Aston-Jones G. Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology. 2013;226:687–698.
Lecca S, Melis M, Luchicchi A, Muntoni AL, Pistis M. Inhibitory inputs from rostromedial tegmental neurons regulate spontaneous activity of midbrain dopamine cells and their responses to drugs of abuse. Neuropsychopharmacology. 2012;37:1164–1176.
Vento PJ, Burnham NW, Rowley CS, Jhou TC. Learning from one’s mistakes: a dual role for the rostromedial tegmental nucleus in the encoding and expression of punished reward seeking. Biol Psychiatry. 2017;81:1041–1049.
Lavezzi HN, Parsley KP, Zahm DS. Modulation of locomotor activation by the rostromedial tegmental nucleus. Neuropsychopharmacology. 2015;40:676–687.
Hu M, Crombag HS, Robinson TE, Becker JB. Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology. 2004;29:81–85.
Zhou L, Pruitt C, Shin CB, Garcia AD, Zavala AR, See RE. Fos expression induced by cocaine-conditioned cues in male and female rats. Brain Struct Funct. 2014;219:1831–1840.
Becker JB. Sex differences in addiction. Dialogues Clin Neurosci. 2016;18:395–402.
Kokane SS, Perrotti LI. Sex differences and the role of estradiol in mesolimbic reward circuits and vulnerability to cocaine and opiate addiction. Front Behav Neurosci. 2020;14:74.
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).
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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). https://doi.org/10.1038/s41386-020-00909-z
From head to tail (of the VTA): role of projections from prelimbic cortex to rostromedial tegmental nucleus in cocaine reinstatement
Monosynaptic Retrograde Tracing From Prelimbic Neuron Subpopulations Projecting to Either Nucleus Accumbens Core or Rostromedial Tegmental Nucleus
Frontiers in Neural Circuits (2021)