Abstract
Rationale.
Environmental stimuli previously paired with cocaine can induce craving in humans and reinstate extinguished cocaine-seeking behavior in laboratory animals. Previous evidence has implicated the amygdala and the prefrontal cortex (PFC) as possible substrates for conditioned-cued relapse.
Objectives.
In order to test directly the role of the PFC in a model of relapse, the present study examined the effects of reversible inactivation of three medial PFC areas, the anterior cingulate (ACing), the prelimbic cortex (PL), and the infralimbic cortex (IL), on the expression of conditioned-cued reinstatement of extinguished cocaine-seeking behavior. We also tested the involvement of the basolateral amygdala (BLA) and the parietal cortex immediately dorsal to the BLA, sensory cortex area 1 – barrel field (S1BF).
Methods.
During daily 3-h sessions, rats pressed a lever for IV cocaine infusions that were paired with a light-tone (LT) presentation. Following extinction of lever pressing in the absence of the LT, reinstatement of extinguished lever pressing was measured during response-contingent presentations of the LT in the absence of cocaine. For localized reversible inactivation, tetrodotoxin (TTX) (5 ng/0.5 µl/side) or vehicle was bilaterally infused just prior to reinstatement testing.
Results.
TTX inactivation of the BLA, ACing, or PL impaired the ability of LT presentations to reinstate extinguished lever pressing for cocaine-paired stimuli. In contrast, inactivation of the IL or the S1BF had no effect on conditioned-cued reinstatement. Furthermore, there was no effect of TTX in any of the tested brain regions on general locomotor activity.
Conclusions.
These results support a role for the dorsomedial PFC and the BLA in the circuitry that mediates drug-seeking behavior elicited by cocaine-associated stimuli. Placed within the context of recent studies using drug-primed and stress-induced reinstatement models, we suggest that the dorsomedial PFC may serve as a common link in the neural circuitry underlying reinstatement of drug-seeking behavior.
Similar content being viewed by others
References
Ambrogi Lorenzini CG, Baldi E, Bucherelli C, Sacchetti B, Tassoni G (1997) Analysis of mnemonic processing by means of totally reversible neural inactivations. Brain Res Brain Res Protoc 1:391–398
Baldwin AE, Holahan MR, Sadeghian K, Kelley AE (2000) N-methyl-D-aspartate receptor-dependent plasticity within a distributed corticostriatal network mediates appetitive instrumental learning. Behav Neurosci 114:84–98
Bussey TJ, Everitt BJ, Robbins TW (1997) Dissociable effects of cingulate and medial frontal cortex lesions on stimulus-reward learning using a novel Pavlovian autoshaping procedure for the rat: implications for the neurobiology of emotion. Behav Neurosci 111:908–919
Cador M, Robbins TW, Everitt BJ (1989) Involvement of the amygdala in stimulus-reward associations: interaction with the ventral striatum. Neuroscience 30:77–86
Capriles N, Amir S, Stewart J (2001) Inactivation of prefrontal and orbitofrontal regions by tetradotoxin attenuates stress-induced reinstatement of cocaine seeking. Soc Neurosci Abstr 27:4422
Childress AR, McLellan AT, Ehrman R, O'Brien CP (1988) Classically conditioned responses in opioid and cocaine dependence: a role in relapse? NIDA Res Monogr 84:25–43
Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O'Brien CP (1999) Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156:11–18
Ciccocioppo R, Sanna PP, Weiss F (2001) Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: reversal by D1 antagonists. Proc Natl Acad Sci USA 98:1976–1981
Coleman-Mesches K, Salinas JA, McGaugh JL (1996) Unilateral amygdala inactivation after training attenuates memory for reduced reward. Behav Brain Res 77:175–180
Conde F, Maire-Lepoivre E, Audinat E, Crepel F (1995) Afferent connections of the medial frontal cortex of the rat II: Cortical and subcortical afferents. J Comp Neurol 352:567–593
Davis WM, Smith SG (1976) Role of conditioned reinforcers in the initiation, maintenance and extinction of drug-seeking behavior. Pavlov J Biol Sci 11:222–236
de Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75:134–143
de Wit H, Stewart J (1983) Drug reinstatement of heroin-reinforced responding in the rat. Psychopharmacology 79:29–31
Everitt BJ, Robbins TW (2000) Second-order schedules of drug reinforcement in rats and monkeys: measurement of reinforcing efficacy and drug-seeking behaviour. Psychopharmacology 153:17–30
Everitt BJ, Parkinson JA, Olmstead MC, Arroyo M, Robledo P, Robbins TW (1999) Associative processes in addiction and reward. The role of amygdala-ventral striatal subsystems. Ann NY Acad Sci 877:412–438
Everitt BJ, Cardinal RN, Hall J, Parkinson JA, Robbins TW (2000) Differential involvement of amygdala subsystems in appetitive conditioning and drug addiction. In: Aggleton JP (ed) The amygdala: a functional analysis. Oxford University Press, Oxford, pp 353–390
Fuster JM (2000) Memory networks in the prefrontal cortex. Prog Brain Res 122:309–316
Garavan H, Pankiewicz J, Bloom A, Cho JK, Sperry L, Ross TJ, Salmeron BJ, Risinger R, Kelley D, Stein EA (2000) Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli. Am J Psychiatry 157:1789–1798
Gawin FH (1991) Cocaine addiction: psychology and neurophysiology. Science 251:1580–1586
Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C, Phillips RL, Kimes AS, Margolin A (1996) Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci USA 93:12040–12045
Grimm JW, See RE (2000) Dissociation of primary and secondary reward-relevant limbic nuclei in an animal model of relapse. Neuropsychopharmacology 22:473–479
Hatfield T, Han JS, Conley M, Gallagher M, Holland P (1996) Neurotoxic lesions of basolateral, but not central, amygdala interfere with Pavlovian second-order conditioning and reinforcer devaluation effects. J Neurosci 16:5256–5265
Jaffe J (1992) Current concepts of addiction. Res Publ Assoc Res Nerv Ment Dis 70:1–21
Jentsch JD, Taylor JR (1999) Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology 146:373–390
Kalivas PW, McFarland K, See RE (2002) The pathophysiology of addiction. In: Lieberman J, Kay J, Tasman A (eds) Psychiatry. Wiley, New York (in press)
Kilts CD, Schweitzer JB, Quinn CK, Gross RE, Faber TL, Muhammad F, Ely TD, Hoffman JM, Drexler KP (2001) Neural activity related to drug craving in cocaine addiction. Arch Gen Psychiatry 58:334–341
Kolb B (1984) Functions of the frontal cortex of the rat: a comparative review. Brain Res 320:65–98
Kruzich PJ, See RE (2001) Differential contributions of the basolateral and central amygdala in the acquisition and expression of conditioned relapse to cocaine-seeking behavior. J Neurosci 21:RC155
Maas LC, Lukas SE, Kaufman MJ, Weiss RD, Daniels SL, Rogers VW, Kukes TJ, Renshaw PF (1998) Functional magnetic resonance imaging of human brain activation during cue-induced cocaine craving. Am J Psychiatry 155:124–126
McDonald AJ (1998) Cortical pathways to the mammalian amygdala. Prog Neurobiol 55:257–332
McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21:8655–8663
Meil WM, See RE (1996) Conditioned cued responding following prolonged withdrawal from self-administered cocaine in rats: an animal model of relapse. Behav Pharmacol 7:754–763
Meil WM, See RE (1997) Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine. Behav Brain Res 87:139–148
Miller EK (2000) The prefrontal cortex and cognitive control. Nat Rev Neurosci 1:59–65
Neisewander JL, Baker DA, Fuchs RA, Tran-Nguyen LT, Palmer A, Marshall JF (2000) Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment. J Neurosci 20:798–805
O'Brien C, Childress AR, Ehrman R, Robbins S, McLellan AT (1992) Conditioning mechanisms in drug dependence. Clin Neuropharmacol 15:66A–67A
O'Brien CP, Childress AR, Ehrman R, Robbins SJ (1998) Conditioning factors in drug abuse: can they explain compulsion? J Psychopharmacol 12:15–22
Paxinos G, Watson D (1986) The rat brain in stereotaxic coordinates. Academic Press, New York
Pierce RC, Reeder DC, Hicks J, Morgan ZR, Kalivas PW (1998) Ibotenic acid lesions of the dorsal prefrontal cortex disrupt the expression of behavioral sensitization to cocaine. Neuroscience 82:1103–1114
Pitkanen A (2000) Connectivity of the rat amygdaloid complex. In: Aggleton JP (ed) The amygdala: a functional analysis. Oxford University Press, Oxford, pp 31–115
Porrino LJ, Lyons D (2000) Orbital and medial prefrontal cortex and psychostimulant abuse: studies in animal models. Cereb Cortex 10:326–333
Salinas JA, McGaugh JL (1996) The amygdala modulates memory for changes in reward magnitude: involvement of the amygdaloid GABAergic system. Behav Brain Res 80:87–98
Sandkuhler J, Maisch B, Zimmermann M (1987) The use of local anaesthetic microinjections to identify central pathways: a quantitative evaluation of the time course and extent of the neuronal block. Exp Brain Res 68:168–178
Schuster CR, Woods JH (1968) The conditioned reinforcing effects of stimuli associated with morphine reinforcement. Int J Addict 3:223–230
See RE, Kruzich PJ, Grimm JW (2001) Dopamine, but not glutamate, receptor blockade in the basolateral amygdala attenuates conditioned reward in a rat model of relapse to cocaine-seeking behavior. Psychopharmacology 154:301–310
Sesack SR, Deutch AY, Roth RH, Bunney BS (1989) Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J Comp Neurol 290:213–242
Shaham Y, Erbs S, Stewart J (2000) Stress-induced relapse to heroin and cocaine-seeking in rats: a review. Brain Res Brain Res Rev 33:13–33
Sinha R, Fuse T, Aubin LR, O'Malley SS (2000) Psychological stress, drug-related cues and cocaine craving. Psychopharmacology 152:140–148
Sokolowski JD, Salamone JD (1994) Effects of dopamine depletions in the medial prefrontal cortex on DRL performance and motor activity in the rat. Brain Res 642:20–28
Spealman RD, Barrett-Larimore RL, Rowlett JK, Platt DM, Khroyan TV (1999) Pharmacological and environmental determinants of relapse to cocaine-seeking behavior. Pharmacol Biochem Behav 64:327–336
Stewart J, de Wit H, Eikelboom R (1984) Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants. Psychol Rev 91:251–268
Stretch R, Gerber GJ, Wood, SM (1971) Factors affecting behavior maintained by response-contingent intravenous infusions of amphetamine in squirrel monkeys. Can J Physiol Pharmacol 49:581–589
Tzschentke TM, Schmidt WJ (2000) Differential effects of discrete subarea-specific lesions of the rat medial prefrontal cortex on amphetamine- and cocaine-induced behavioural sensitization. Cereb Cortex 10:488–498
Uylings HB, van Eden CG (1990) Qualitative and quantitative comparison of the prefrontal cortex in rat and in primates, including humans. Prog Brain Res 85:31–62
Volkow ND, Fowler JS (2000) Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. Cereb Cortex 10:318–325
Weiss F, Maldonado-Vlaar CS, Parsons LH, Kerr TM, Smith DL, Ben-Shahar O (2000) 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 97:4321–4326
Weissenborn R, Robbins TW, Everitt BJ (1997) Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats. Psychopharmacology 134:242–257
Wexler BE, Gottschalk CH, Fulbright RK, Prohovnik I, Lacadie CM, Rounsaville BJ, Gore JC (2001) Functional magnetic resonance imaging of cocaine craving. Am J Psychiatry 158:86–95
Whitelaw RB, Markou A, Robbins TW, Everitt BJ (1996) Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement. Psychopharmacology 127:213–224
Worley CM, Valadez A, Schenk S (1994) Reinstatement of extinguished cocaine-taking behavior by cocaine and caffeine. Pharmacol Biochem Behav 48:217–221
Zhuravin IA, Brozek G, Bures J (1994) Differential contribution of motor cortex and caudate nucleus to instrumental tongue forelimb synchronization in rats: a functional ablation study. Neuroscience 58:193–200
Acknowledgements.
The authors would like to thank Morgan Bell, Tonya Mahanes, and Rita Fuchs for their technical assistance. This research was supported by National Institute on Drug Abuse grant DA10462 (R.E.S.).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
McLaughlin, J., See, R.E. Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology 168, 57–65 (2003). https://doi.org/10.1007/s00213-002-1196-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-002-1196-x