, Volume 113, Issue 1, pp 123–130 | Cite as

Differential effects of excitotoxic lesions of the amygdala on cocaine-induced conditioned locomotion and conditioned place preference

  • Erin E. Brown
  • Hans C. Fibiger
Original Investigations


The reinforcing properties of cocaine can readily become associated with salient environmental stimuli that acquire secondary reinforcing properties. This type of classical conditioning is of considerable clinical relevance, as intense drug craving can be evoked by the presentation of stimuli previously associated with the effects of cocaine. Given the large body of evidence that implicates the amygdaloid complex in the learning of stimulus-reward associations, the present experiments examined the effects of quinolinic acid lesions of the amygdala on cocaine-induced conditional locomotion and conditioned place preference (CPP). Destruction of the amygdala did not affect basal or cocaine-induced locomotion, suggesting that the amygdala does not mediate the unconditioned psychomotor stimulant effects of this drug. Preconditioning lesions also failed to affect cocaine-induced conditional locomotion. Specifically, exposure of both lesioned and non-lesioned rats to a cocaine-paired environment produced significant conditional increases in locomotion. This lack of effect was contrasted by a complete blockade of cocaine-induced CPP by the amygdaloid lesions. These data demonstrate that cocaine-induced stimulus-reward conditioning can be differentially affected by lesions of the amygdala.

Key words

Amygdala Classical conditioning Cocaine Conditioned place preference Conditioned locomotion Substance abuse 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aggleton JP (1985) A description of intra-amygdaloid connections in the old world monkeys. Exp Brain Res 57:390–399Google Scholar
  2. Applegate CD, Frysinger RC, Kapp BS, Gallagher M (1982) Multiple unit activity recorded from the amygdala central nucleus during Pavlovian heart rate conditioning in rabbit. Brain Res 238:457–462Google Scholar
  3. Barr GA, Sharpless NS, Cooper S, Schiff SR (1983) Classical conditioning, decay and extinction of cocaine-induced hyperactivity and stereotypy. Life Sci 33:1341–1351Google Scholar
  4. Beninger RJ, Hahn BL (1983) Pimozide blocks the establishment but not expression of amphetamine-produced environment-specific conditioning. Science 220:1304–1306Google Scholar
  5. Beninger RJ, Herz RS (1986) Pimozide blocks the establishment but not expression of cocaine-produced environment-specific conditioning. Life Sci 38:1425–1431Google Scholar
  6. Bermudez-Rattoni F, McGaugh JL (1991) Insular cortex and amygdala lesions differentially affect acquisition on inhibitory and conditioned taste aversion. Brain Res 549:165–170Google Scholar
  7. Brown EE, Fibiger HC (1992) Cocaine-induced conditioned locomotion: absence of increases in dopamine release. Neuroscience 48:621–629Google Scholar
  8. Brown EE, Finlay JM, Wong JTF, Damsma G, Fibiger HC (1991) Behavioral and neurochemical interactions between cocaine and buprenorphine: implications for the pharmacotherapy of cocaine abuse. J Pharmacol Exp Ther 256:119–126Google Scholar
  9. Brown EE, Robertson GS, Fibiger HC (1992) Evidence for conditional neuronal activation following exposure to a cocaine-paired environment: role of forebrain limbic structures. J Neurosci 12:4112–4121Google Scholar
  10. Cador M, Robbins TW, Everitt BJ (1989) Involvement of the amygdala in stimulus-reward associations: interactions with the ventral striatum. Neuroscience 30:77–86Google Scholar
  11. Cahill L, McGaugh JL (1990) Amygdaloid complex lesions differentially affect retention of tasks using appetitive and aversive reinforcement. Behav Neurosci 104:532–543Google Scholar
  12. Carey RJ (1992) Pavlovian conditioning of L-dopa induced movement. Psychopharmacology 107:203–210Google Scholar
  13. Davis M (1992) The role of the amygdala in fear and anxiety. Annu Rev Neurosci 15:353–375Google Scholar
  14. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85:5274–5278Google Scholar
  15. Drew KL, Glick SD (1990) Role of D-1 and D-2 receptor stimulation in sensitization to amphetamine-induced circling behavior and in expression and extinction of the Pavlovian conditioned response. Psychopharmacology 101:465–471Google Scholar
  16. Dunn LT, Everitt BJ (1988) Double dissociations of the effects of amygdala and insular cortex lesions on conditioned taste aversions, passive avoidance, and neophobia in the rat using the excitotoxin ibotenic acid. Behav Neurosci 102:3–22Google Scholar
  17. Everitt BJ, Morris KA, O'Brien A, Robbins TW (1991) The basolateral amygdala-ventral striatal system and conditioned place preference: further evidence of limbic-striatal interactions underlying reward-related processes. Neuroscience 42:1–18Google Scholar
  18. Fibiger HC, Phillips AG (1987) Role of catecholamine transmitters in brain reward systems: Implications for the neurobiology of affect. In: Engel J, Oreland L (eds) Brain reward systems and abuse. Raven, New York, pp 61–74Google Scholar
  19. Finlay JM, Jakubovic A, Phillips AG, Fibiger HC (1988) Fentanyl-induced conditional place preference: lack of associated conditional neurochemical events. Psychopharmacology 96:534–540Google Scholar
  20. Gaffan D, Harrison S (1987) Amygdalectomy and disconnection in visual learning for auditory secondary reinforcement by monkeys. J Neurosci. 7:2285–2292Google Scholar
  21. Gallagher M, Graham PW, Holland PC (1990) The amygdala central nucleus and appetitive Pavlovian conditioning: lesions impair one class of conditioned behavior. J Neurosci 10:1906–1911Google Scholar
  22. Gawin FH (1991) Cocaine addiction: psychology and neurophysiology. Science 251:1580–1586Google Scholar
  23. Gold LH, Swerdlow NR, Koob GF (1988) The role of mesolimbic dopamine in conditioned locomotion produced by amphetamine. Behav Neurosci 102:544–552Google Scholar
  24. Helmstetter FJ (1992) Contribution of the amygdala to learning and performance of conditioned fear. Physiol Behav 51:1271–1276Google Scholar
  25. Hiroi N, White NM (1991) The lateral nucleus of the amygdala mediates expression of the amphetamine-produced conditioned place preference. J Neurosci 11:2107–2116Google Scholar
  26. Hitchcock J, Davis M (1986) Lesions of the amygdala, but not of the cerebellum or red nucleus, block conditioned fear as measured with the potentiated startle paradigm. Behav Neurosci 100:11–22Google Scholar
  27. Hitchcock J, Davis M (1987) Fear potentiated startle using an auditory conditioned stimulus: effect of lesions of the amygdala. Physiol Behav 39:403–408Google Scholar
  28. Holland PC (1984) Origins of behavior in Pavlovian conditioning. Psychol Learn Motiv 18:129–174Google Scholar
  29. Jellestad FK, Cabrera IC (1986) Exploration and avoidance learning after ibotenic acid and radio-frequency lesions in the rat amygdala. Behav Neural Biol 46:195–215Google Scholar
  30. Jones B, Mishkin M (1972) Limbic lesions and the problem of stimulus-reinforcement associations. Exp Neurol 36:362–377Google Scholar
  31. Kentridge RW, Shaw C, Aggleton JP (1991) Amygdaloid lesion and stimulus-reward associations in the rat. Behav Brain Res 42:57–66Google Scholar
  32. Kesner RP, Walser RD, Winzenried G. (1989) Central but not basolateral amygdala mediates memory for positive affective experiences. Behav Brain Res 33:189–195Google Scholar
  33. Krettek JE, Price JL (1978) A description of the amygdaloid complex in the rat and cat with observations on intraamygdaloid connections. J Comp Neurol 178:255–280Google Scholar
  34. Lopez da Silva FH, Witter MP, Boeijinga PH, Lohman AHM (1990) Anatomic organization and physiology of the limbic cortex. Physiol Rev 70:453–511Google Scholar
  35. Lyness WH, Friedle NM, Moore KE (1979) Destruction of dopaminergic nerve terminals in nucleus accumbens: effects ond-amphetamine self-administration. Pharmacol Biochem Behav 11:553–556Google Scholar
  36. Mishkin M, Aggleton J (1981) Multiple functional contributions of the amygdala in the monkey. In: Ben-Ari Y (ed) Amygdaloid complex. Elsevier, Amsterdam, pp 409–420Google Scholar
  37. Möller H-G, Nowak K, Kuschinsky K (1987) Conditioning of pre- and postsynaptic behavioural responses to the dopamine receptor agonist apomorphine in rats. Psychopharmacology 91:50–55Google Scholar
  38. Murray EA (1991) Contributions of the amygdalar complex to behavior in macaque monkeys. In: Holstege G (ed) Progress in brain research, Vol 87. Elsevier, Amsterdam, pp 167–180Google Scholar
  39. Nitecka L, Amerski L, Narkiewicz O (1981) The organization of intraamygdaloid connections: an HRP study. J Hirnforsch 22:3–7Google Scholar
  40. O'Brien CP, Childress AR, McLellan AT, Ehrman R (1992) Classical conditioning in drug-dependent humans. In: Kalivas PW, Samson HH (eds) The neurobiology of drug and alcohol addiction, Vol 654. Annals of the New York Academy of Sciences, New York, pp 400–415Google Scholar
  41. Ottersen OP (1982) Connections of the amygdala of the rat: IV Corticoamygdaloid and intraamygdaloid connections as studied with axonal transport of horseradish peroxidase. J Comp Neurol 205:30–48Google Scholar
  42. Pascoe JP, Kapp BS (1985) Electrophysiological characteristics of amygdaloid central nucleus during Pavlovian fear conditioning in the rabbit. Behav Brain Res 16:117–133Google Scholar
  43. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, OrlandoGoogle Scholar
  44. Pellegrino L (1968) Amygdaloid lesions and behavioral inhibition in the rat. J Comp Physiol Psychol 65:483–491Google Scholar
  45. Pellegrino LK, Pellegrino AA, Cushman AJ (1979) A stereotaxic atlas of the rat brain. Plenum Press, New YorkGoogle Scholar
  46. Post RM, Weiss SRB, Pert A (1988) Cocaine-induced behavioral sensitization and kindling: implications for the emergence of psychopathology and seizures. In: Kalivas PW, Nemeroff CB (eds) The mesocortical dopamine system, Vol 537. Annals of the New York Academy of Sciences, New York, pp 292–308Google Scholar
  47. Powell DA, Buchanan SL, Gibbs CM (1990) Role of the prefrontalthalamic axis in classical conditioning. In: Uylings HBM, Van Eden CG, De Bruin JPC, Corner MA, Feenstra MGP (eds) Progress in brain research, Vol 85. Elsevier, New York, pp 433–466Google Scholar
  48. Riolobos AS, García AIM (1978) Open field activity and passive avoidance responses in rats after lesion of the central amygdaloid nucleus by electrocoagulation and ibotenic acid. Physiol Behav 39:715–720Google Scholar
  49. Roberts DCS, Corcoran ME, Fibiger HC (1977) On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine. Pharmacol Biochem Behav 6:615–620Google Scholar
  50. Roberts DCS, Loh EH, Vickers G (1989) Self-administration of cocaine on a progressive ratio schedule in rats: dose-response relationship and effect of haloperidol pretreatment. Psychopharmacology 97:535–538Google Scholar
  51. Sananes CB, Davis M (1992)N-methyl-D-aspartate lesions of the lateral and basolateral nuclei of the amygdala block fear-potentiated startle and shock sensitization of startle. Behav Neurosci 106:72–80Google Scholar
  52. Schuckman H, Kling A, Orbach J (1969) Olfactory discrimination in monkeys with lesions in the amygdala. J Comp Physiol Psychol 67:212–215Google Scholar
  53. Schwartzbaum JS (1965) Discrimination behavior after amygdalectomy in monkeys: visual and somaesthetic learning and perceptual capacity. J Comp Physiol Psychol 60:314–319Google Scholar
  54. Slotnick BM (1985) Olfactory discriminations in rats with anterior amygdala lesions. Behav Neurosci 99:956–963Google Scholar
  55. Smith BS, Millhouse OE (1985) The connections between basolateral and central nuclei. Neurosci Lett 56:307–309Google Scholar
  56. SPSS: X User's Guide, 3rd Edition (1988) SPSS, ChicagoGoogle Scholar
  57. 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 91:251–268Google Scholar
  58. Tatum AL, Seevers MH (1929) Experimental cocaine addiction. J Pharmacol Exp Ther 36:401–410Google Scholar
  59. Thomas E, Yadin E, Strickland CE (1991) Septal unit activity during classical conditioning: a regional comparison. Brain Res 547:303–308Google Scholar
  60. Walter S, Kuschinsky K (1989) Conditioning of morphine-induced locomotor activity and stereotyped behaviour in rats. J Neural Transm 78:231–247Google Scholar
  61. Weiskrantz L (1956) Behavioral changes associated with ablation of the amygdaloid complex in monkeys. J Comp Physiol Psychol 49:381–391Google Scholar
  62. Weiss SRB, Post RM, Pert A, Woodland R, Murman D (1989) Context-dependent cocaine sensitization: differential effect of haloperidol on development versus expression. Pharmacol Biochem Behav 34:655–661Google Scholar
  63. Wise RA (1989) The brain and reward. In: Liebman JM, Cooper SJ (eds) The neuropharmacological basis of reward. Clarendon, Oxford, pp 377–424Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Erin E. Brown
    • 1
  • Hans C. Fibiger
    • 1
  1. 1.Division of Neurological Sciences, Department of Psychiatry, Faculty of MedicineUniversity of British ColumbiaVancouverCanada

Personalised recommendations