The importance of a compound stimulus in conditioned drug-seeking behavior following one week of extinction from self-administered cocaine in rats

Abstract

Previous studies have demonstrated that conditioned stimuli can increase responding on a drug-associated lever after extinction from drug self-administration. The present study investigated singular stimuli (tone or light) or a compound stimulus (tone+light) for their ability to increase extinguished responding following chronic cocaine self-administration. Rats self-administered cocaine for 2 weeks on a fixed ratio (FR1) schedule of reinforcement, in which lever responding resulted in varied presentation of a tone, light, or tone+light combination. The rats were then exposed to 1 week of daily extinction sessions. Presentation of the tone+light on day 8 of extinction in the absence of cocaine reinforcement resulted in a significant increase in responding, while either stimulus component alone was much weaker or failed to produce any changes from extinction rates of responding. In addition, changing the duration of the single elements of the compound did not affect the magnitude of increased responding to the compound. Following three final extinction sessions, robust lever responding for cocaine infusions on day 12 of extinction was seen across all groups. These findings suggest that compound stimuli may be critical to fully activate drug-seeking behavior in conditions of craving and relapse following prolonged extinction.

Introduction

Conditioning to environmental stimuli is believed to play a significant role in the process of drug dependence and relapse (Childress et al., 1992, Margolin and Avants, 1992). For example, individuals with a history of cocaine abuse report conditioned drug craving 2–3 times more often than other types of conditioned responses (O’Brien et al., 1992). The multiple components of environmental stimuli present when an individual engages in drug-taking behavior may thus acquire incentive-motivational properties with repeated drug associations over time (Stewart et al. 1984). An understanding of how conditioned stimuli acquire control over behavior is of importance for understanding the basic mechanisms of relapse and furthering treatment of drug abuse and dependence.

Several studies using drug self-administration in animal models (Markou et al., 1993) have explicitly examined conditioned drug effects following extinction of drug-seeking behavior in monkeys (Goldberg et al., 1979, Goldberg et al., 1981) and rats (Davis and Smith, 1976, de Wit and Stewart, 1981). Based on the often long periods of abstinence observed in human drug dependence, we recently developed a model of assessing conditioned cocaine-seeking behavior after prolonged extinction by re-exposure to visual and auditory stimuli previously associated with cocaine self-administration in rats (Meil and See, 1996). In this paradigm, subjects self-administered daily cocaine for 2 weeks in the presence of a visual stimulus (light) and an auditory stimulus (infusion pump sound). This chronic maintenance phase was followed by 3 weeks of daily extinction trials in the self-administration chambers, during which the animals received no cocaine. For assessment of responding to conditioned stimuli, the animals were exposed to the light and pump sound in the absence of cocaine infusions. Presentation of these stimuli resulted in robust enhancement of drug-seeking behavior as measured by increased lever pressing.

A question that arises in determining the factors that mediate such conditioned responding in drug abuse is the nature of the multiple stimulus components which are associated with drug-taking behavior. The phenomenon of compound-stimulus conditioning has been broadly studied in the areas of both appetitive and aversive learning. In compound-stimulus conditioning, responses can be conditioned to a combination of different component stimuli. Reports dating back to Pavlov’s laboratory showed that a compound may produce conditioning, even when the components alone are completely ineffectual (Palladin, 1906). Several paradigms that have examined appetitive behaviors (e.g. food and water) have found that compound stimuli are often much more effective than single stimuli at producing conditioning (Razran, 1965, Weiss, 1972). However, little research has examined the issue of compound stimuli as it relates to drug-seeking behavior, particularly in the area of craving and relapse. While there are many possible differences between drug and non-drug reinforcers, compound stimuli may have the ability to maintain conditioned responding for drugs more effectively than singular stimuli. An understanding of the different roles of single versus compound stimuli in conditioned effects during chronic drug abuse may ultimately facilitate behavioral interventions for the treatment of recidivism.

Since a previous study (Meil and See 1996) utilized a compound stimulus of a light and sound, the present experiments were designed to systematically compare the ability of single versus compound stimuli to facilitate responding after prolonged extinction of lever pressing for cocaine. Thus, a stimulus light and discrete auditory tone were presented as a compound stimulus and compared with the singular presentation of each element for their ability to enhance responding on a drug-paired lever. Our prediction was that a compound stimulus would enhance conditioned responding at levels above those seen with either singular stimulus presentation alone. In addition, the duration of stimuli presentation can affect the degree of conditioning (Kamin, 1965) and prolonged stimulus durations during drug self-administration may lead to changes in the discriminative properties of the stimulus. Therefore, we systematically tested varied durations of the component elements of the compound for their possible effects on conditioned responding.