, Volume 127, Issue 1–2, pp 213–224 | Cite as

Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement

  • Rachel B. Whitelaw
  • Athina Markou
  • Trevor W. Robbins
  • Barry J. Everitt
Original Investigation


In these experiments we sought to establish the intravenous (IV) self-administration of cocaine under a second-order schedule of reinforcement in order: (i) to obtain reliable, drug-free levels of responding with cocaine as a reinforcer, and (ii) to enable investigation of the neural mechanisms by which arbitrary cues gain motivational salience and, as conditioned reinforcers, control over drug-seeking behaviour. Initially, each infusion of cocaine was made contingent upon a response on one of two identical levers and was paired with a 20-s light conditioned stimulus (CS). Responses on the second lever weee recorded, but had no programmed consequence. When rats acquired stable rates of self-administration, a second-order schedule of the type FRx(FRy:S) was introduced, with values of “x” being increased progressively to 10 and then “y” from 2 through 8. Priming (i.e. non-contingent) infusions of cocaine were never given. Once the first infusion was obtained under the second-order schedule, further infusions were made contingent on each response (to a maximum of ten infusions/day). Each stage was repeated daily until the first infusion of each session was achieved within a 5-min criterion. Rats with bilateral, excitotoxic lesions of the basolateral amygdala readily acquired the IV self-administration of cocaine under a continuous reinforcement schedule, initially administering more infusions and maintaining a slightly elevated level of self-administration than controls. Despite increased numbers of CS/drug pairings, basolateral amygdala-lesioned rats were severely impaired in the acquisition of the second-order schedule of IV cocaine reinforcement. Lesioned rats showed a cocaine dose-response function that was shifted upwards relative to control subjects. There was no significant difference between drug-naive amygdala-lesioned and control animals in the locomotor response to intraperitoneal injections of cocaine. These experiments indicate the feasibility and utility of second-order schedules in studying the neurobehavioural basis of cocaine-seeking behaviour. They suggest a dissociation in the neural mechanisims underlying cocaine-taking and cocaine seeking behaviour, and demonstrate the potential importance of the basolateral amygdala in the processes by which previously neutral stimuli gain control over drug-seeking behaviour.

Key words

Cocaine Second-order schedule Conditioned reinforcer Nucleus accumbens Amygdala Reward Dopamine 


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  1. Arroyo M, Markou A, Robbins TW, Everitt BJ (1996) Establishment of a second-order schedule of intravenous cocaine reinforcement in rats: effects of contingent, non-contingent and free-access to cocaine. Behav Pharm Abstr 7 [Suppl. 1]: 3Google Scholar
  2. Burns LH, Everitt BJ, Robbins TW (1993) Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions ofd-amphetamine. Behav Brain Res 55: 167–183PubMedCrossRefGoogle Scholar
  3. Burns LH, Everitt BJ, Kelley AE, Robbins TW (1994) Glutamate-dopamine interactions in the ventral striatum: role in locomotor activity and responding with conditioned reinforcement. Psychopharmacology 115: 516–528PubMedCrossRefGoogle Scholar
  4. Cador M, Robbins TW, Everitt BJ (1989) Involvement of the amygdala in stimulus-reward associations: interaction with the ventral striatum. Neuroscience 30: 77–86PubMedCrossRefGoogle Scholar
  5. Caine SB, Lintz R, Koob GF (1992) Intravenous drug self-administration techniques in animals. In: Sahgal A (ed) Behavioral neuroscience: a practical approach. Oxford University Press, OxfordGoogle Scholar
  6. Caine SB, Heinrichs SC, Coffin VL, Koob GF (1995) Effects of the dopamine D1 antagonist SCH23390 microinjected into the accumbens, amygdala or striatum on self-administration in the rat. Brain Res 692: 47–56PubMedCrossRefGoogle Scholar
  7. Corrigall WA, Coen KM (1989) Fixed interval schedules for drug self-administration in the rat. Psychopharmacology 99: 136–139PubMedCrossRefGoogle Scholar
  8. Davis M (1992) The role of the amygdala in conditioned fear. In: Aggleton JP (ed) The amygdala. Wiley-Liss, New York, pp 255–306Google Scholar
  9. Davis M, Hitchcock JM, Bowers MB, Berridge CW (1994) Stress-induced activation of the prefrontal cortex dopamine turnover: blockade by lesions of the amygdala. Brain Res 664: 207–210PubMedCrossRefGoogle Scholar
  10. Ettenberg A, Geist TD (1991) Animal model for investigating the anxiogenic effects of self-administered cocaine. Psychopharmacology 103: 455–461PubMedCrossRefGoogle Scholar
  11. Everitt BJ, Robbins TW (1992) Amygdala-ventral striatal interactions and reward-related processes. In: Aggleton JP (ed) The amygdala. Wiley-Liss, New York, pp 401–430Google Scholar
  12. Everitt BJ, Cador M, Robbins TW (1989) Interactions between the amygdala and ventral striatum in stimulus-reward associations: studies using a second-order schedule of sexual reinforcement. Neuroscience 30: 63–75PubMedCrossRefGoogle Scholar
  13. Fray PF (1980) Onlibasic, a system for experimental control. Trends Neurosci 3: 13–14CrossRefGoogle Scholar
  14. Fontana DJ, Post RM, Pert A (1993) Conditioned increases in mesolimbic dopamine overflow by stimuli associated with cocaine. Brain Res 629: 31–39PubMedCrossRefGoogle Scholar
  15. Glick SD, Raucci J, Wang S, Keller RW Jr, Carlson JN (1994) Neurochemical predisposition to self-administer cocaine in rats: individual differences in dopamine and its metabolites. Brain Res 653: 148–154PubMedCrossRefGoogle Scholar
  16. Goldberg SR (1973) Comparable behavior maintained under fixed-ratio and second order schedules of food presentation, cocaine injection ord-amphetamine injection in the squirrel monkey. J Pharmacol Exp Ther 186: 18–30PubMedGoogle Scholar
  17. Goldberg SR, Tang AH (1977) Behavior maintained under second order schedules of intravenous morphine injection in squirrel and rhesus monkeys. Psychopharmacology 51: 235–242PubMedCrossRefGoogle Scholar
  18. Goldberg SR, Morse WH, Goldberg M (1976) Behavior maintained under a second-order schedule by intramuseular injection of morphine or cocaine in rhesus monkeys. J Pharmacol Exp Ther 199: 278–286PubMedGoogle Scholar
  19. Groenewegen HJ, Berendse HW, Meredith GE, Haber SN, Voorn P, Wolters JG, Lohman AHM (1991) Functional anatomy of the ventral, limbic system-innervated striatum. In: Willner P, Scheel-Kruger J (eds) The mesolimbic dopamine system: from motivation to action. Wiley, New York, pp 19–60Google Scholar
  20. Henke PG, Maxwell D (1973) Lesions in the amygdala and the frustration effect. Physiol Behav 10: 647–650PubMedCrossRefGoogle Scholar
  21. Hurd YL, Weiss F, Koob GF, NE, Ungerstedt U (1989) Cocaine reinforcement and extracellular dopamine overflow in rat nucleus accumbens: an in vivo microdialysis study. Brain Res 498: 199–203PubMedCrossRefGoogle Scholar
  22. Johanson CE, Schuster CR (1981) An analysis of drug seeking behavior in animals. Neurosci Biobehav Rev 5: 315–323PubMedCrossRefGoogle Scholar
  23. Katz JL (1979) A comparison of responding maintained under a second-order schedule of intramuscular cocaine injection or food presentation in the squirrel monkey. J Exp Anal Behav 32: 419–431PubMedCrossRefGoogle Scholar
  24. Kelley AE, Domesick VB, Nauta WJH (1982) The amygdalostriatal projection in the rat—an anatomical study by anterograde and retrograde tracing methods. Neuroscience 7: 615–630PubMedCrossRefGoogle Scholar
  25. Kelleher RT (1975) Characteristics of behavior controlled by scheduled injections of drugs. Psychopharmacol Rev 27: 307–323Google Scholar
  26. Kemble ED, Beckman GJ (1970) Runway performance of rats following amygdaloid lesions. Physiol Behav 4: 45–47CrossRefGoogle Scholar
  27. Koob GF (1992) Neural mechanisms of drug reinforcement. Ann NY Acad Sci 654: 171–191PubMedCrossRefGoogle Scholar
  28. LeDoux JE (1992) Emotion and the amygdala. In: Aggleton JP (ed) The amygdala. Wiley-Liss, New York, pp 339–351Google Scholar
  29. Loh EA, Roberts DCS (1990) Break-points on a progressive ratio schedule reinforced by intravenous cocaine increases following depletion of forebrain serotonin. Psychopharmacology 101: 262–266PubMedCrossRefGoogle Scholar
  30. Markou A, Weiss F, Gold LH, Caine SB, Schuteis G, Koob GF (1993) Animal models of drug craving. Psychopharmacology 112: 163–182PubMedCrossRefGoogle Scholar
  31. Markou A, Arroyo M, Everitt BJ (1996) Drug craving: utility of animal models such as second-order schedules of reinforcement. Behav Pharm Abstr 7 [Suppl 1]: 63Google Scholar
  32. McDonough JH, Manning FJ (1979) The effects of lesions in amygdala or dorsomedial frontal cortex on reinforcement omission and noncontingent reinforcement in rats. Physiol Psychol 7: 167–172Google Scholar
  33. McGregor A, Roberts DCS (1993a) Dopaminergic antagonism within the nucleus accumbens or the amygdala produces differential effects on intravenous cocaine self-administration under fixed and progressive ratio schedules of reinforcement. Brain Res 624: 245–252PubMedCrossRefGoogle Scholar
  34. McGregor A, Roberts DCS (1993b) Effect of intra-amygdaloid SCH23390 on the discriminative stimulus properties of cocaine. Soc Neurosci Abstr 19: 751.17Google Scholar
  35. McGregor A, Falkenberg T, Hurd YL (1995) Role of amygdala dopamine in cocaine self-administration and in vivo dopamine levels in the nucleus accumbens. Soc Neurosci Abstr 21: 285.8Google Scholar
  36. Meil WM, See RF (1995) Excitotoxic lesions of the basolateral amygdala attenuate the ability of drug associated cues to reinstate responding during the withdrawal from self-administration. Soc Neurosci 21: 767.17Google Scholar
  37. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, LondonGoogle Scholar
  38. Phillips AG, Fibiger HC (1990) Role of reward and enhancement of conditioned reward in persistence of responding for cocaine. Behav Pharmacol 1: 269–282PubMedGoogle Scholar
  39. Phillips AG, Pfaus JG, Blaha CD (1991) Dopamine and motivated behaviour: insights provided by in vivo analyses. In: Willner P, Scheel-Kruger J (eds) The mesolimbic dopamine system: from motivation to action. Wiley, New York, pp 199–224Google Scholar
  40. Phillips GD, Howes SR, Whitelaw RB, Robbins TW, Everitt BJ (1994a) Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbensd-amphetamine: impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists. Psychopharmacology 115: 419–429PubMedCrossRefGoogle Scholar
  41. Phillips GD, Howes SR, Whitelaw RB, Wilkinson LS, Robbins TW, Everitt BJ (1994b) Isolation rearing enhances the locomotor response to cocaine and a novel environment, but impairs the intravenous self-administration of cocaine. Psychopharmacology 115: 407–418PubMedCrossRefGoogle Scholar
  42. Pickens R, Thompson T (1968) Cocaine reinforced behaviour in rats: effects of reinforcement magnitude and fixed-ratio size. J Pharmacol Exp Ther 161: 122–129PubMedGoogle Scholar
  43. Robbins TW, Cador M, Taylor JR, Everitt BJ (1989) Limbic-striatal interactions in reward-related processes. Neurosci Biobehav Rev 13: 155–162PubMedCrossRefGoogle Scholar
  44. Robinson TE, Berridge KC (1993) The neural basis of drug craving. An incentive-sensitisation theory of drug addiction. Brain Res Rev 18: 247–291PubMedCrossRefGoogle Scholar
  45. Selden NRW, Everitt BJ, Jarrard LE, Robbins TW (1991) Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues. Neuroscience 42: 335–350PubMedCrossRefGoogle Scholar
  46. Swanson LW (1992) Brain maps: structure of the rat brain. Elsevier, AmsterdamGoogle Scholar
  47. Taylor JR, Robbins TW (1984) Enhanced behavioural control by conditioned reinforcers following microinjections ofd-amphetamine into the nucleus accumbens. Psychopharmacology 84: 405–412PubMedCrossRefGoogle Scholar
  48. Taylor JR, Robbins TW (1986) 6-Hydroxydopamine lesions of the nucleus accumbens, but not of the caudate nucleus, attenuate enhanced responding with reward related stimuli produced by intra-accumbensd-amphetamine. Psychopharmacology 90: 390–397PubMedCrossRefGoogle Scholar
  49. Vellucci SV, Martin PJ, Everitt BJ (1988) The discriminative stimulus produced by pentylenetetrazol: effects of systemic anxiolytics and anxiogenics, aggressive defeat and midazolam or muscimol into the amygdala. Psychopharmacology 2: 80–93CrossRefGoogle Scholar
  50. Vivian J, Weerts E, Miczek K (1994) Defeat engenders pentylenetetrazole-appropriate responding in rats: antagonism by midazolam. Psychopharmacology 116: 491–498PubMedCrossRefGoogle Scholar
  51. Wamsley JK, Gehlert DR, Filloux FM, Dawson TM (1989) Comparison of the distribution of D-1 and D-2 dopamine receptors in the rat brain. J Chem Neuroanat 2: 119–137PubMedGoogle Scholar
  52. Weissenborn R, Robbins TW, Everitt BJ (1995) The effects of medial prefrontal cortex lesions on cocaine self-administration and conditioned cocaine-seeking behaviour in rats. Soc Neurosci Abstr 21: 765.15Google Scholar
  53. Wilson JM, Nobrega JN, Corrigal WA, Coen KM, Shannak K, Kish SJ (1994) Amygdala dopamine levels are markedly elevated after self- but not passive administration of cocaine. Brain Res 668: 39–45PubMedCrossRefGoogle Scholar
  54. Winer BJ (1971) Statistical principles in experimental design. McGraw-Hill, New YorkGoogle Scholar
  55. Wise RA, Newton P, Leeb K, Burnette B, Pocock D, Justice JB Jr (1995) Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats. Psychopharmacology 120: 10–20PubMedCrossRefGoogle Scholar
  56. Wolterink G, Phillips GD, Cador M, Donselaar-Wolterink I, Robbins TW, Everitt BJ (1993) Relative roles of ventral striatal D1 and D2 dopamine receptors in responding with conditioned reinforcement. Psychopharmacology 110: 355–364PubMedCrossRefGoogle Scholar
  57. Yokel RA, Wise RA (1976) Attenuation of intravenous amphetamine reinforcement by central dopamine blockade in rats. Psychopharmacology 48: 311–318PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Rachel B. Whitelaw
    • 1
  • Athina Markou
    • 2
  • Trevor W. Robbins
    • 1
  • Barry J. Everitt
    • 1
  1. 1.Department of Experimental PsychologyUniversity of CambridgeCambridgeUK
  2. 2.Department of NeuropharmacologyScripps Research InstituteLa JollaUSA

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