Elsevier

Behavioural Brain Research

Volume 87, Issue 2, September 1997, Pages 139-148
Behavioural Brain Research

Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine

https://doi.org/10.1016/S0166-4328(96)02270-XGet rights and content

Abstract

This study investigated the ability of bilateral excitotoxic lesions of the basolateral amygdala (BLA) to disrupt cocaine self-administration, responding during extinction sessions, and stimulus cued recovery of extinguished responding in rats. BLA and sham lesions following 7 days of 3 h limited access cocaine self-administration sessions (0.33 mg/infusion) on a fixed ratio 1 (FR1) schedule of reinforcement failed to alter cocaine intake and responding on 7 subsequent days of self-administration. This lack of effect suggests that the BLA is not paramount for the maintenance of cocaine's reinforcing effects. In contrast, BLA lesions, but not sham lesions, following 7 or 14 days of cocaine self-administration attenuated responding on a lever associated with cocaine infusions on the first day of extinction sessions and blocked the ability of drug associated stimuli to reinstate extinguished responding following 20 daily extinction sessions. However, lesions of the BLA did not attenuate stimulus cued recovery of responding following 43 days of withdrawal. These results are consistent with the hypothesis that the BLA is important for the conditioned incentive properties of reinforcers, but not primary reinforcement itself.

Introduction

Drug abuse has been called `a chronic relapsing disorder' [27]. One salient feature of drug abuse is the ability of drug associated cues (e.g. locations or drug paraphernalia) to elicit drug craving and facilitate relapse 19, 28, 37. Drug associated cues may be particularly important in perpetuating cocaine abuse, since termination of cocaine use has been suggested to produce a psychological withdrawal syndrome characterized by phasic changes in drug craving in the absence of gross physical withdrawal symptoms [24]. An extensive clinical literature has characterized the ability of cocaine associated cues to facilitate relapse 13, 31. Furthermore, under controlled laboratory conditions, cocaine addicts frequently report enhanced drug craving and show increased signs of physiological arousal following exposure to drug associated cues 13, 19, 38. An understanding of how environmental cues associated with drug use facilitate relapse may contribute to our knowledge of drug abuse and has already yielded potential treatment interventions 13, 38.

Recently, drug craving has been conceptualized according to incentive motivation theories of behavior [3]and defined as the incentive motivation to administer a previously consumed psychoactive substance [32]. According to these theories, reinforcing stimuli possess response reinforcing properties as well as incentive properties which facilitate investigatory, instrumental and consummatory behaviors. Therefore, previously neutral stimuli acquire both response reinforcing (conditioned reinforcement) and incentive-motivational properties through classical conditioning. Exposure to drug associated cues in drug dependent individuals may consequently elicit conditioned incentive behaviors (craving) which increase the probability of relapse.

Several paradigms have been used to investigate the reinforcing and conditioned incentive properties of psychoactive drugs in laboratory animals [32]. However, many of these paradigms measure the conditioned incentive properties of a drug confounded by unconditioned incentive properties such as reinforcement and locomotor activity. Moreover, researchers rarely examine both reinforcement and conditioned effects within the same paradigm, e.g. [20]. In contrast, the extinction paradigm 15, 32, 34represents a procedure in which both the reinforcing and conditioned incentive properties of a drug can be independently investigated. According to this procedure, animals initially acquire stable drug self-administration behavior which provides a measure of a drug's immediate reinforcing effects [50]. Animals then undergo extinction sessions in which responding no longer results in a drug infusion. The ability of stimuli previously paired with self-administration to subsequently reinstate extinguished responding may then be used to assess the conditioned incentive properties of that drug. The extinction paradigm of examining the ability of drug associated cues to reinstate extinguished responding following withdrawal from drug self-administration provides a model analogous to the ability of drug associated cues to facilitate relapse in humans 32, 34.

Several studies have documented stimulus cued recovery of extinguished responding in rats 15, 17, 34and monkeys [25]using the extinction paradigm. However, this paradigm has not been previously used to investigate the neuroanatomical substrates underlying the conditioned incentive properties of abused drugs. Instead, the conditioned place preference test has generally been the procedure of choice to investigate the conditioned incentive properties of reinforcers. The ability of stimuli to acquire response reinforcing properties has been examined using the conditioned reinforcement, secondary reinforcement and acquisition of a new response paradigms [22]. Research using these paradigms suggests that both the conditioned incentive and response reinforcing properties of conditioned stimuli appear dependent upon the integrity of excitatory limbic efferents to the ventral striatum, particularly those originating from the basolateral amygdala (BLA) 4, 8. BLA lesions result in a selective decrease in responding for conditioned reinforcement, independent of concomitant nucleus accumbens (NAcc) dopamine (DA) activation by amphetamine microinjection [8]. Furthermore, lesions of the BLA and ventral subiculum, but not the prefrontal cortex, attenuated approach to a conditioned stimulus predictive of reward and the acquisition of a new response for conditioned reinforcement [4]. However, lesions of the ventral subiculum abolished the ability of intra-accumbens amphetamine to increase locomotor activity and potentiate responding for a conditioned reinforcer, whereas BLA lesions blocked responding for conditioned reinforcement independent of effects on locomotor activity [4]. Furthermore, lesions of the BLA, NAcc, or combined unilateral lesions of the BLA with contralateral NAcc lesions attenuated conditioned place preference for sucrose [21]. The sum of this research suggests that the projection from the BLA to the ventral striatum may exercise a selective effect in stimulus-reward associations.

While several studies implicate the BLA as a critical component in the formation of associations between primary reinforcers and neutral stimuli, the role of this structure in the unconditioned effects of reinforcers remains unclear. Lesions of the amygdala have been observed to alter an animal's ability to detect changes in the magnitude of reinforcement 16, 26, 29. However, the extent to which these studies have examined reinforcement independent of its conditioned effects is unclear. In fact, some data suggest that amygdala lesions are selective for the conditioned effects of reinforcers. For example, amygdala lesions have little effect on the initial enhanced locomotor response to cocaine, but block the context-dependent development of behavioral sensitization [40]and conditioned place preference [5]. Additionally, lesions of the BLA attenuate responding for a secondary reinforcer associated with sexual reinforcement, but do not alter sexual behavior itself [20]. Neurochemical alterations within the amygdala also appear selectively sensitive to conditioned reward. For example, a single cocaine injection enhances fos-expression in the amygdala and NAcc, but this effect is observed only in the amygdala following the establishment of conditioned place preference for cocaine [7]. In addition to studies using laboratory animals, recent evidence using human subjects has implicated the amygdala in the conditioned incentive properties of psychoactive drugs, in that, exposure to cocaine associated cues in abstinent cocaine patients has been reported to increase regional cerebral blood flow in the amygdala and temporal pole [14].

The purpose of the present study was to investigate the role of the BLA in the reinforcing and conditioned incentive properties of cocaine using the extinction paradigm, a model relevant to the investigation of stimulus cued relapse in humans. Rats received bilateral excitotoxic or sham lesions of the BLA following 7 or 14 days of cocaine self-administration. Lesions were performed following day 7 to assess whether they disrupted responding on 7 subsequent days of cocaine self-administration (maintenance of self-administration) and subsequent stimulus cued recovery of responding during extinction (conditioned incentive properties). For comparison, lesions were made in a second group of rats following 14 days of cocaine self-administration in order to examine whether stimulus cued recovery of extinguished responding was similarly affected in rats who had self-administered cocaine with an intact amygdala. Rats underwent 20 daily extinction sessions in order to model the prolonged effects which drug associated cues exert upon the behavior of drug dependent individuals. The ability of these lesions to block stimulus cued recovery of responding was then assessed on day 21 of extinction sessions and on day 43 of withdrawal. By investigating the effects of BLA lesions upon cocaine self-administration and stimulus cued recovery of responding, this study attempted to further delineate the role of the BLA in mediating the reinforcing and conditioned incentive properties of cocaine.

Section snippets

Subjects

Twenty nine male, Sprague–Dawley rats (340–440 g) served as subjects. Rats were double housed and maintained on a reverse 12-h light/dark cycle. Animals were maintained at 85% of free feeding body weight for the duration of the experiment.

Surgical procedures

Prior to surgery, rats were anesthetized with i.m. ketamine (100 mg/kg) and xylazine (2 mg/kg). Penicillin (DiPen, 0.05 ml, i.m.) was administered following surgery. Animals were allowed 3 days to recover from surgery prior to testing.

Jugular catheters

Rats were implanted with

Self-administration

Fig. 1 illustrates self-administration, extinction and stimulus cued recovery for rats receiving sham lesions (top), or BLA lesions (bottom) following day 7 of cocaine self-administration. Neither sham lesions nor BLA lesions significantly altered subsequent cocaine intake (mg/kg) or responding. There were no significant differences between sham and BLA lesioned animals for drug intake and responding on the 3 days prior to lesioning, the 3 days after lesioning, and the final 3 days of cocaine

Discussion

The results of the present study are in agreement with the hypothesis that the BLA is important for the conditioned incentive properties of reinforcement, but not for primary reinforcement itself. Both sham and excitotoxic lesions of the BLA following 7 days of cocaine self-administration failed to alter drug intake and responding during 7 subsequent days of cocaine self-administration. This lack of effect suggests that the BLA is not paramount for the maintenance of cocaine's immediate

Acknowledgements

This research was supported in part by funds provided for medical and biological research by the State of Washington Initiative Measure No. 171. Cocaine was provided by the Research Technology Branch of NIDA.

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