Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine

Abstract

Second order schedules of IV cocaine reinforcement in rats provide a reliable method for evaluating the effects of conditioned stimuli on cocaine-seeking behaviour, and for measuring the motivational aspects of cocaine reinforcement. In the procedure established here, each infusion of cocaine (0.25 mg/infusion) was initially made contingent on a lever press and was paired with a 20-s light conditioned stimulus (CS). When rats acquired stable rates of cocaine self-administration, the response requirement for cocaine was increased progressively to a second-order schedule of the type FI15 min(FR10:S), whereby the IV cocaine infusion was self-administered following the completion of the first FR10 responses (and CS presentation) after a 15-min fixed interval (FI) had elapsed. Evaluation of the animals' responding during the first, drug-free interval of each daily session provided a measure of cocaine-seeking behaviour, independent of other pharmacological effects of the self-administered drug. Thus, a dose-response study (dose range: 0.083, 0.25 and 0.50 mg/infusion) revealed that responding under this schedule during the initial, drug-free interval changed monotonically with dose, whereas an inverse relationship between cocaine dose and response level tended to appear during the rest of the session, after rats had self-administered the drug. Responding under this schedule was also shown to occur under the control of the CS, which had acquired conditioned reinforcing properties. Thus, a decrease in responding and an increase in the latency to initiate responding followed the omission of the CS for 3 consecutive days. In addition, extinction of cocaine-seeking behaviour was slower when contingent CS presentations occurred compared to extinction when the CS was not present. Furthermore, the reinstatement of responding for cocaine, which followed a brief period of non-contingent CS presentations, was retarded when this conditioned reinforcer had been extinguished together with cocaine. Finally, cocaine-seeking behaviour decreased markedly for the first 6 h that followed a 12-h period of continuous access to cocaine, when compared to responding 6 h after a 90-min session of limited access to the drug. Responding subsequently increased to baseline levels within 72 h. These results emphasise the utility of second-order schedules for studying drug-seeking behaviour and the importance of drug-associated cues in maintaining such responding for cocaine.

Nicotine-Associated Cues Maintain Nicotine-Seeking Behavior in Rats Several Weeks after Nicotine Withdrawal: Reversal by the Cannabinoid (CB1) Receptor Antagonist, Rimonabant (SR141716)

“…In contrast, cues paired with saline delivery did not acquire motivational effects. Previous studies have shown that contingent presentations of cocaine-(but not heroin-) associated stimuli retarded extinction of behavior under second-order schedules of reinforcement (Arroyo et al, 1998;Alderson et al, 2000) and that cocaine-and ethanolassociated stimuli reinstated responding several weeks after self-administration behavior has been extinguished Liu and Weiss, 2002). Here we report that conditioned stimuli can maintain responding after extensive testing in the absence of the drug.…”

The GABAB Receptor Agonist Baclofen Attenuates Cocaine- and Heroin-Seeking Behavior by Rats

“…Under the second-order schedule of reinforcement used in the present study, the drug was available after a fixed time interval. We have previously demonstrated that high rates of responding under this schedule are maintained by contingent presentation of a drug-paired conditioned reinforcer, as omission of the drug cue decreased responding both before and after drug self-administration (Alderson et al, 2000;Arroyo et al, 1998). Furthermore, drugseeking after psychostimulant self-administration was increased (Arroyo et al, 1998;Pilla et al, 1999), reflecting the ability of these drugs to increase the control over behavior by conditioned reinforcers (Arroyo et al, 1998;Cador et al, 1991;Everitt et al, 2001;Killcross et al, 1997;Taylor and Robbins, 1984).…”

“…Response rates before and after drug self-administration have been shown to be maintained by the contingent presentation of drugassociated stimuli acting, therefore, as conditioned reinforcers (Alderson et al, 2000;Arroyo et al, 1998;Everitt and Robbins, 2000). Therefore, the first cocaine-or heroin-free interval can be viewed as a period of cue-maintained drugseeking, while subsequent intervals provide a measure of the influence of self-administered drug on subsequent cuemaintained drug-seeking.…”

“…Although response rates under second-order schedules of drug reinforcement are maintained by contingent presentations of the conditioned reinforcer (Arroyo et al, 1998;Goldberg 1973Goldberg , 1976Goldberg et al, 1975;Pilla et al, 1999), the primary reinforcer also supports responding and in particular influences response patterning. Observation of cumulative records of responding in the present study revealed an acceleration of responding towards the end of each interval.…”

Fractionating Impulsivity: Contrasting Effects of Central 5-HT Depletion on Different Measures of Impulsive Behavior

“…However, behavior is also strongly influenced by associations formed through Pavlovian conditioning. For example, it is well-known that stimuli which are associated with addictive drugs are critically implicated in the maintenance and relapse of drug-seeking in humans and laboratory animals (Arroyo et al, 1998;Childress et al, 1992;Everitt and Robbins, 2000;Gawin, 1991), and subjects which exhibit greater tendencies to form and respond to Pavlovian stimulus-reward associations may be more vulnerable to substances of abuse (Tomie, 1996). Furthermore, it has been hypothesized that an increase in impulsive behavior plays a key role in the development and maintenance of drug addiction (Jentsch and Taylor, 1999;Volkow and Fowler, 2000), and increases in empirical measurements of impulsivity have been reported in substance abusers (Fillmore and Rush, 2002).…”