Although impulsive action is strongly associated with addiction, the neural underpinnings of this relationship and how they are influenced by sex have not been well characterized. Here, we used a titrating reaction time task to assess differences in impulsive action in male and female Long Evans rats both before and after short (4–6 days) or long (25–27 days) abstinence from 2 weeks of cocaine or water/saline self-administration (6 h daily access). Neural activity in the prelimbic cortex (PrL) and nucleus accumbens (NAc) core was assessed at each time point. We found that a history of cocaine self-administration increased impulsivity in all rats following short, but not long, abstinence. Furthermore, male rats with an increased ratio of excited to inhibited neurons in the PrL at the start of each trial in the task exhibited higher impulsivity in the naïve state (before self-administration). Following short abstinence from cocaine, PrL activity in males became more inhibited, and this change in activity predicted the shift in impulsivity. However, PrL activity did not track impulsivity in female rats. Additionally, although the NAc core tracked several aspects of behavior in the task, it did not track impulsivity in either sex. Together, these findings demonstrate a sex-dependent role for the PrL in impulsivity both before and after a history of cocaine.
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.
De Wit H. Impulsivity as a determinant and consequence of drug use: a review of underlying processes. Addict Biol. 2009;14:22–31.
Pattij T, De Vries TJ. The role of impulsivity in relapse vulnerability. Curr Opin Neurobiol. 2013;23:700–5.
Evenden JL. Varieties of impulsivity. Psychopharmacology. 1999;146:348–61.
Dalley JW, Fryer TD, Brichard L, Robinson ES, Theobald DE, Lääne K, et al. Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science. 2007;315:1267–70.
Belin D, Mar AC, Dalley JW, Robbins TW, Everitt BJ. High impulsivity predicts the switch to compulsive cocaine-taking. Science. 2008;320:1352–5.
Economidou D, Pelloux Y, Robbins TW, Dalley JW, Everitt BJ. High impulsivity predicts relapse to cocaine-seeking after punishment-induced abstinence. Biol Psych. 2009;65:851–6.
Winstanley CA, Bachtell RK, Theobald DE, Laali S, Green TA, Kumar A, et al. Increased impulsivity during withdrawal from cocaine self-administration: role for ΔFosB in the orbitofrontal cortex. Cereb Cortex. 2009;19:435–44.
Broos N, van Mourik Y, Schetters D, De Vries TJ, Pattij T. Dissociable effects of cocaine and yohimbine on impulsive action and relapse to cocaine seeking. Psychopharmacology. 2017;234:3343–51.
Caprioli D, Hong YT, Sawiak SJ, Ferrari V, Williamson DJ, Jupp B, et al. Baseline-dependent effects of cocaine pre-exposure on impulsivity and D 2/3 receptor availability in the rat striatum: possible relevance to the attention-deficit hyperactivity syndrome. Neuropsychopharmacology. 2013;38:1460–71.
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;23:3531–7.
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.
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;36:8700–11.
Hearing M, Kotecki L, de Velasco EM, Fajardo-Serrano A, Chung HJ, Luján R, et al. Repeated cocaine weakens GABAB-Girk signaling in layer 5/6 pyramidal neurons in the prelimbic cortex. Neuron. 2013;80:159–70.
Robinson TE, Gorny G, Mitton E, Kolb B. Cocaine self‐administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex. Synapse. 2001;39:257–66.
Slaker ML, Jorgensen ET, Hegarty DM, Liu X, Kong Y, Zhang F, et al. Cocaine exposure modulates perineuronal nets and synaptic excitability of fast-spiking interneurons in the medial prefrontal cortex. Eneuro. 2018;5:ENEURO.0221-18.2018.
Kourrich S, Thomas MJ. Similar neurons, opposite adaptations: psychostimulant experience differentially alters firing properties in accumbens core versus shell. J Neurosci. 2009;29:12275–83.
Gipson CD, Kupchik YM, Shen H, Reissner KJ, Thomas CA, Kalivas PW. Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron. 2013;77:867–72.
Dobi A, Seabold GK, Christensen CH, Bock R, Alvarez VA. Cocaine-induced plasticity in the nucleus accumbens is cell specific and develops without prolonged withdrawal. J Neurosci. 2011;31:1895–904.
Hollander JA, Carelli RM. Abstinence from cocaine self-administration heightens neural encoding of goal-directed behaviors in the accumbens. Neuropsychopharmacology. 2005;30:1464–74.
Hollander JA, Carelli RM. Cocaine-associated stimuli increase cocaine seeking and activate accumbens core neurons after abstinence. J Neurosci. 2007;27:3535–9.
West EA, Saddoris MP, Kerfoot EC, Carelli RM. Prelimbic and infralimbic cortical regions differentially encode cocaine‐associated stimuli and cocaine‐seeking before and following abstinence. Eur J Neurosci. 2014;39:1891–902.
Saddoris MP, Wang X, Sugam JA, Carelli RM. Cocaine self-administration experience induces pathological phasic accumbens dopamine signals and abnormal incentive behaviors in drug-abstinent rats. J Neurosci. 2016;36:235–50.
Saddoris MP, Carelli RM. Cocaine self-administration abolishes associative neural encoding in the nucleus accumbens necessary for higher-order learning. Biol Psych. 2014;75:156–64.
Burton AC, Bissonette GB, Vazquez D, Blume EM, Donnelly M, Heatley KC, et al. Previous cocaine self-administration disrupts reward expectancy encoding in ventral striatum. Neuropsychopharmacology. 2018;43:2350–60.
Izaki Y, Fujiwara SE, Akema T. Involvement of the rat prefrontal cortex in a delayed reinforcement operant task. Neuroreport. 2007;18:1687–90.
Narayanan NS, Horst NK, Laubach M. Reversible inactivations of rat medial prefrontal cortex impair the ability to wait for a stimulus. Neuroscience. 2006;139:865–76.
Narayanan NS, Laubach M. Top-down control of motor cortex ensembles by dorsomedial prefrontal cortex. Neuron. 2006;52:921–31.
Narayanan NS, Cavanagh JF, Frank MJ, Laubach M. Common medial frontal mechanisms of adaptive control in humans and rodents. Nat Neurosci. 2013;16:1888.
Murphy ER, Fernando AB, Urcelay GP, Robinson ES, Mar AC, Theobald DE, et al. Impulsive behaviour induced by both NMDA receptor antagonism and GABA A receptor activation in rat ventromedial prefrontal cortex. Psychopharmacology. 2012;219:401–10.
Pattij T, Janssen MC, Vanderschuren LJ, Schoffelmeer AN, Van, Gaalen MM. Involvement of dopamine D1 and D2 receptors in the nucleus accumbens core and shell in inhibitory response control. Psychopharmacology. 2007;191:587–98.
Economidou D, Theobald DE, Robbins TW, Everitt BJ, Dalley JW. Norepinephrine and dopamine modulate impulsivity on the five-choice serial reaction time task through opponent actions in the shell and core sub-regions of the nucleus accumbens. Neuropsychopharmacology. 2012;37:2057–66.
Cheng RK, Liao RM. Regional differences in dopamine receptor blockade affect timing impulsivity that is altered by d-amphetamine on differential reinforcement of low-rate responding (DRL) behavior in rats. Behav Brain Res. 2017;331:177–87.
Narayanan NS, Laubach M. Delay activity in rodent frontal cortex during a simple reaction time task. J Neurophys. 2009;101:2859–71.
Totah NK, Jackson ME, Moghaddam B. Preparatory attention relies on dynamic interactions between prelimbic cortex and anterior cingulate cortex. Cereb Cortex. 2013;23:729–38.
Donnelly NA, Holtzman T, Rich PD, Nevado-Holgado AJ, Fernando AB, Van Dijck G, et al. Oscillatory activity in the medial prefrontal cortex and nucleus accumbens correlates with impulsivity and reward outcome. PloS ONE. 2014;9:e111300.
Donnelly NA, Paulsen O, Robbins TW, Dalley JW. Ramping single unit activity in the medial prefrontal cortex and ventral striatum reflects the onset of waiting but not imminent impulsive actions. Eur J Neurosci. 2015;41:1524–37.
Becker JB, Hu M. Sex differences in drug abuse. Front Neuroendocr. 2008;29:36–47.
Weafer J, de Wit H. Sex differences in impulsive action and impulsive choice. Addict Behav. 2014;39:1573–9.
Lynch WJ, Carroll ME. Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology. 1999;144:77–82.
Carroll ME, Morgan AD, Lynch WJ, Campbell UC, Dess NK. Intravenous cocaine and heroin self-administration in rats selectively bred for differential saccharin intake: phenotype and sex differences. Psychopharmacology. 2002;161:304–13.
Roth ME, Carroll ME. Sex differences in the escalation of intravenous cocaine intake following long-or short-access to cocaine self-administration. Pharm Biochem Be. 2004;78:199–207.
Lynch WJ, Carroll ME. Reinstatement of cocaine self-administration in rats: sex differences. Psychopharmacology. 2000;148:196–200.
Jentsch JD, Taylor JR. Sex-related differences in spatial divided attention and motor impulsivity in rats. Behav Neurosci. 2003;117:76–83.
Bayless DW, Darling JS, Stout WJ, Daniel JM. Sex differences in attentional processes in adult rats as measured by performance on the 5-choice serial reaction time task. Behav Brain Res. 2012;235:48–54.
Anker JJ, Gliddon LA, Carroll ME. Impulsivity on a Go/No-go task for intravenous cocaine or food in male and female rats selectively bred for high and low saccharin intake. Behav Pharm. 2008;19:615–29.
Burton CL, Fletcher PJ. Age and sex differences in impulsive action in rats: the role of dopamine and glutamate. Behav Brain Res. 2012;230:21–33.
Moschak TM, Terry DR, Daughters SB, Carelli RM. Low distress tolerance predicts heightened drug seeking and taking after extended abstinence from cocaine self‐administration. Addict Biol. 2018;23:130–41.
Marcondes FK, Bianchi FJ, Tanno AP. Determination of the estrous cycle phases of rats: some helpful considerations. Braz J Bio. 2002;62:609–14.
Moschak TM, Mitchell SH. Partial inactivation of nucleus accumbens core decreases delay discounting in rats without affecting sensitivity to delay or magnitude. Behav Brain Res. 2014;268:159–68.
Moschak TM, Carelli RM. Impulsive rats exhibit blunted dopamine release dynamics during a delay discounting task independent of cocaine history. ENeuro. 2017;4:ENEURO.0119-17.2017.
Sackett DA, Moschak TM, Carelli RM. Nucleus accumbens shell dopamine mediates outcome value, but not predicted value, in a magnitude decision‐making task. Eur J Neurosci. 2020;51:1526–38.
Winstanley CA, Floresco SB. Deciphering decision making: variation in animal models of effort-and uncertainty-based choice reveals distinct neural circuitries underlying core cognitive processes. J Neurosci. 2016;36:12069–79.
Moschak TM, Wang X, Carelli RM. A neuronal ensemble in the rostral agranular insula tracks cocaine-induced devaluation of natural reward and predicts cocaine seeking. J Neurosci. 2018;38:8463–72.
Dalley JW, Lääne K, Pena Y, Theobald DE, Everitt BJ, Robbins TW. Attentional and motivational deficits in rats withdrawn from intravenous self-administration of cocaine or heroin. Psychopharmacology. 2005;182:579–87.
Hayton SJ, Olmstead MC, Dumont EC. Shift in the intrinsic excitability of medial prefrontal cortex neurons following training in impulse control and cued-responding tasks. PLoS One. 2011;6:e23885.
Sharpe MJ, Killcross S. Modulation of attention and action in the medial prefrontal cortex of rats. Psychological Rev. 2018;125:822–43.
Risterucci C, Terramorsi D, Nieoullon A, Amalric M. Excitotoxic lesions of the prelimbic‐infralimbic areas of the rodent prefrontal cortex disrupt motor preparatory processes. Eur J Neurosc. 2003;17:1498–508.
Baratta MV, Leslie NR, Fallon IP, Dolzani SD, Chun LE, Tamalunas AM, et al. Behavioural and neural sequelae of stressor exposure are not modulated by controllability in females. Eur J Neurosci. 2018;47:959–67.
Bland ST, Schmid MJ, Der-Avakian A, Watkins LR, Spencer RL, Maier SF. Expression of c-fos and BDNF mRNA in subregions of the prefrontal cortex of male and female rats after acute uncontrollable stress. Brain Res. 2005;1051:90–9.
Anderson LC, Petrovich GD. Sex specific recruitment of a medial prefrontal cortex-hippocampal-thalamic system during context-dependent renewal of responding to food cues in rats. Neurobiol Learn Mem. 2017;139:11–21.
Heilbronner SR, Rodriguez-Romaguera J, Quirk GJ, Groenewegen HJ, Haber SN. Circuit-based corticostriatal homologies between rat and primate. Biol Psych. 2016;80:509–21.
Li CS, Huang C, Constable RT, Sinha R. Gender differences in the neural correlates of response inhibition during a stop signal task. Neuroimage. 2006;32:1918–29.
Garavan H, Hester R, Murphy K, Fassbender C, Kelly C. Individual differences in the functional neuroanatomy of inhibitory control. Brain Res. 2006;1105:130–42.
Vertes RP. Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse. 2004;51:32–58.
Rogers RD, Baunez C, Everitt BJ, Robbins TW. Lesions of the medial and lateral striatum in the rat produce differential deficits in attentional performance. Behav Neurosci. 2001;115:799.
Belin-Rauscent A, Daniel ML, Puaud M, Jupp B, Sawiak S, Howett D, et al. From impulses to maladaptive actions: the insula is a neurobiological gate for the development of compulsive behavior. Mol Psychiatr. 2016;21:491–9.
Prasad JA, Macgregor EM, Chudasama Y. Lesions of the thalamic reuniens cause impulsive but not compulsive responses. Brain Struct Funct. 2013;218:85–96.
Sun W, Rebec GV. Repeated cocaine self-administration alters processing of cocaine-related information in rat prefrontal cortex. J Neurosci. 2006;26:8004–8.
Zavala AR, Osredkar T, Joyce JN, Neisewander JL. Upregulation of Arc mRNA expression in the prefrontal cortex following cue‐induced reinstatement of extinguished cocaine‐seeking behavior. Synapse. 2008;62:421–31.
Hearing MC, Miller SW, See RE, McGinty JF. Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats. Psychopharmacology. 2008;198:77–91.
Smith WC, Rosenberg MH, Claar LD, Chang V, Shah SN, Walwyn WM, et al. Frontostriatal circuit dynamics correlate with cocaine cue-evoked behavioral arousal during early abstinence. Eneuro. 2016;3:ENEURO.0105-16.2016.
Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O’Brien CP. Limbic activation during cue-induced cocaine craving. Am J Psychiatry. 1999;156:11–8.
Garavan H, Pankiewicz J, Bloom A, Cho JK, Sperry L, Ross TJ, et al. Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli. Am J Psychiatr. 2000;157:1789–98.
Bonson KR, Grant SJ, Contoreggi CS, Links JM, Metcalfe J, Weyl HL, et al. Neural systems and cue-induced cocaine craving. Neuropsychopharmacology. 2002;26:376–86.
Wilcox CE, Teshiba TM, Merideth F, Ling J, Mayer AR. Enhanced cue reactivity and fronto-striatal functional connectivity in cocaine use disorders. Drug Alcohol Depend. 2011;115:137–44.
Chen BT, Yau HJ, Hatch C, Kusumoto-Yoshida I, Cho SL, Hopf FW, et al. Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature. 2013;496:359–62.
Gozzi A, Tessari M, Dacome L, Agosta F, Lepore S, Lanzoni A, et al. Neuroimaging evidence of altered fronto-cortical and striatal function after prolonged cocaine self-administration in the rat. Neuropsychopharmacology. 2011;36:2431–40.
Lu H, Zou Q, Chefer S, Ross TJ, Vaupel DB, Guillem K, et al. Abstinence from cocaine and sucrose self-administration reveals altered mesocorticolimbic circuit connectivity by resting state MRI. Brain Connect. 2014;4:499–510.
McCracken CB, Grace AA. Persistent cocaine-induced reversal learning deficits are associated with altered limbic cortico-striatal local field potential synchronization. J Neurosci. 2013;33:17469–82.
Dong Y, Nasif FJ, Tsui JJ, Ju WY, Cooper DC, Hu XT, et al. Cocaine-induced plasticity of intrinsic membrane properties in prefrontal cortex pyramidal neurons: adaptations in potassium currents. J Neurosci. 2005;25:936–40.
Sepulveda-Orengo MT, Healey KL, Kim R, Auriemma AC, Rojas J, Woronoff N, et al. Riluzole impairs cocaine reinstatement and restores adaptations in intrinsic excitability and GLT-1 expression. Neuropsychopharmacology. 2018;43:1212–23.
Goldstein RZ, Alia-Klein N, Tomasi D, Carrillo JH, Maloney T, Woicik PA, et al. Anterior cingulate cortex hypoactivations to an emotionally salient task in cocaine addiction. P Natl Acad Sci. 2009;106:9453–8.
Koob GF. Hedonic homeostatic dysregulation as a driver of drug-seeking behavior. Drug Discov Today: Dis Models. 2008;5:207–15.
Hayen A, Meese-Tamuri S, Gates A, Ito R. Opposing roles of prelimbic and infralimbic dopamine in conditioned cue and place preference. Psychopharmacology. 2014;231:2483–92.
Peters J, Kalivas PW, Quirk GJ. Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem. 2009;16:279–88.
Pattij T, Janssen MC, Vanderschuren LJ, Schoffelmeer AN, Van, Gaalen MM. Involvement of dopamine D 1 and D 2 receptors in the nucleus accumbens core and shell in inhibitory response control. Psychopharmacology. 2007;191:587–98.
Feja M, Hayn L, Koch M. Nucleus accumbens core and shell inactivation differentially affects impulsive behaviours in rats. Prog Neuro-Psychoph. 2014;54:31–42.
We thank Joey Sloand, Caitlin Nygren, Iniya Muthukumaren, and Elijah Richardson for technical assistance.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Moschak, T.M., Carelli, R.M. A sex-dependent role for the prelimbic cortex in impulsive action both before and following early cocaine abstinence. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01024-3