Abstract
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 were 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.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
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]: 3
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: 167–183
Burns LH, Everitt BJ, Kelley AE, Robbins TW (1994) Glutamatedopamine interactions in the ventral striatum: role in locomotor activity and responding with conditioned reinforcement. Psychopharmacology 115: 516–528
Cador M, Robbins TW, Everitt BJ (1989) Involvement of the amygdala in stimulus-reward associations: interaction with the ventral striatum. Neuroscience 30: 77–86
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, Oxford
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: 47–56
Corrigall WA, Coen KM (1989) Fixed interval schedules for drug self-administration in the rat. Psychopharmacology 99: 136–139
Davis M (1992) The role of the amygdala in conditioned fear. In: Aggleton JP (ed) The amygdala. Wiley-Liss, New York, pp 255–306
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: 207–210
Ettenberg A, Geist TD (1991) Animal model for investigating the anxiogenic effects of self-administered cocaine. Psychopharmacology 103: 455–461
Everitt BJ, Robbins TW (1992) Amygdala-ventral striatal interactions and reward-related processes. In: Aggleton JP (ed) The amygdala. Wiley-Liss, New York, pp 401–430
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: 63–75
Fray PF (1980) Onlibasic, a system for experimental control. Trends Neurosci 3: 13–14
Fontana DJ, Post RM, Pert A (1993) Conditioned increases in mesolimbic dopamine overflow by stimuli associated with cocaine. Brain Res 629: 31–39
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: 148–154
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: 18–30
Goldberg SR, Tang AH (1977) Behavior maintained under second order schedules of intravenous morphine injection in squirrel and rhesus monkeys. Psychopharmacology 51: 235–242
Goldberg SR, Morse WH, Goldberg M (1976) Behavior maintained under a second-order schedule by intramuscular injection of morphine or cocaine in rhesus monkeys. J Pharmacol Exp Ther 199: 278–286
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 19–60
Henke PG, Maxwell D (1973) Lesions in the amygdala and the frustration effect. Physiol Behav 10: 647–650
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: 199–203
Johanson CE, Schuster CR (1981) An analysis of drug seeking behavior in animals. Neurosci Biobehav Rev 5: 315–323
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: 419–131
Kelley AE, Domesick VB, Nauta WJH (1982) The amygdalostriatal projection in the rat — an anatomical study by anterograde and retrograde tracing methods. Neuroscience 7: 615–630
Kelleher RT (1975) Characteristics of behavior controlled by scheduled injections of drugs. Psychopharmacol Rev 27: 307–323
Kemble ED, Beckman GJ (1970) Runway performance of rats following amygdaloid lesions. Physiol Behav 4: 45–47
Koob GF (1992) Neural mechanisms of drug reinforcement. Ann NY Acad Sci 654: 171–191
LeDoux JE (1992) Emotion and the amygdala. In: Aggleton JP (ed) The amygdala. Wiley-Liss, New York, pp 339–351
Loh EA, Roberts DCS (1990) Break-points on a progressive ratio schedule reinforced by intravenous cocaine increases following depletion of forebrain serotonin. Psychopharmacology 101: 262–266
Markou A, Weiss F, Gold LH, Caine SB Schuteis G, Koob GF (1993) Animal models of drug craving. Psychopharmacology 112: 163–182
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]: 63
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: 167–172
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: 245–252
McGregor A, Roberts DCS (1993b) Effect of intra-amygdaloid SCH23390 on the discriminative stimulus properties of cocaine. Soc Neurosci Abstr 19: 751.17
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: 285.8
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: 767.17
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, London
Phillips AG, Fibiger HC (1990) Role of reward and enhancement of conditioned reward in persistence of responding for cocaine. Behav Pharmacol 1: 269–282
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 199–224
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: 419–429
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: 407–418
Pickens R, Thompson T (1968) Cocaine reinforced behaviour in rats: effects of reinforcement magnitude and fixed-ratio size. J Pharmacol Exp Ther 161: 122–129
Robbins T W, Cador M, Taylor J R, Everitt B J (1989) Limbicstriatal interactions in reward-related processes. Neurosci Biobehav Rev 13: 155–162
Robinson TE, Berridge KC (1993) The neural basis of drug craving. An incentive-sensitisation theory of drug addiction. Brain Res Rev 18: 247–291
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: 335–350
Swanson LW (1992) Brain maps: structure of the rat brain. Elsevier, Amsterdam
Taylor JR, Robbins TW (1984) Enhanced behavioural control by conditioned reinforcers following microinjections ofd-amphetamine into the nucleus accumbens. Psychopharmacology 84: 405–412
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 intraaccumbensd-amphetamine. Psychopharmacology 90: 390–397
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: 80–93
Vivian J, Weerts E, Miczek K (1994) Defeat engenders pentylenetetrazole-appropriate responding in rats: antagonism by midazolam. Psychopharmacology 116: 491–498
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: 119–137
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: 765.15
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: 39–45
Winer B J (1971) Statistical principles in experimental design. McGraw-Hill, New York
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: 10–20
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: 355–364
Yokel RA, Wise RA (1976) Attenuation of intravenous amphetamine reinforcement by central dopamine blockade in rats. Psychopharmacology 48: 311–318
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Whitelaw, R.B., Robbins, T.W., Everitt, B.J. et al. Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement. Psychopharmacology 127, 213–224 (1996). https://doi.org/10.1007/BF02246129
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02246129