Response-dependent versus response-independent presentation of cocaine: differences in the lethal effects of the drug

Abstract

The drug self-administration paradigm is routinely used to assess the abuse liability of psychoactive compounds. Investigations of the behavioral effects of drug use, however, often involve the response-independent (experiment-delivered) administration of the compound. It is frequently assumed that response-independent presentation of a compound has the same effects as response dependent deliveries. The present study examined directly the effects of response-dependent (self-administered) versus response-independent (experimenter-delivered) administration of cocaine on food intake and lethality. Littermate triads were exposed to either cocaine (0.33 mg/infusion) or saline using a yoked-box procedure. One member of the triad self-administered the drug under a fixed-ratio 2 schedule. The other two rats received response-independent infusions of either cocaine or saline. Groups of triads were exposed to two different cocaine access conditions. Daily sessions were terminated after 6 h for one group and after the delivery of 80 infusions for the other. The mean number of infusions delivered each session was 47 (+/- 12) and 70 (+/- 11), respectively, for the 6-h and 80-infusion condition. Under the 80-infusion condition, response-independent infusions of cocaine resulted in a significantly higher rate of mortality compared to littermates self-administering identical amounts of the drug. A fewer number of deaths occurred under 6-h condition; however, only rats exposed to response-independent infusions died under both access conditions. These data indicate that the presence or absence of response dependency can profoundly alter the lethal effects of cocaine.

Incentive Learning Underlying Cocaine-Seeking Requires mGluR5 Receptors Located on Dopamine D1 Receptor-Expressing Neurons

“…A potential limitation of this approach is that the extent to which neural circuitries that mediate associative learning for natural reinforcers (such as food) overlap with those engaged by drug reinforcers is not fully understood. However, attempts to employ purely Pavlovian conditioning procedures using a "drug US" have been hampered by the negative behavioral effects associated with nonresponse contingent drug delivery (Dworkin et al, 1995;Mitchell et al, 1996;Arroyo et al, 1998). Nevertheless, our findings that cocaine-seeking and specific incentive learning processes were both impaired in mutant mice provide empirical support for multiple contemporary theories of drug addiction, which propose that the ability of drug-paired stimuli to influence drug-seeking and relapse reflect the interactions of addictive drugs with neural systems that normally subserve associative reward-learning processes for natural reinforcers (Stewart et al, 1984;Tiffany, 1990;Robinson and Berridge, 1993;Everitt et al, 2001;Stephens and Duka, 2008;Thomas et al, 2008).…”

Nicotine Self-Administration, Extinction Responding and Reinstatement in Adolescent and Adult Male Rats: Evidence Against a Biological Vulnerability to Nicotine Addiction during Adolescence

“…brain and behavior (Wilson et al, 1994;Dworkin et al, 1995;Jacobs et al, 2003). In addition, it is not surprising that different results are obtained in a classical conditioning CPP procedure and an operant self-administration procedure; there is evidence in the literature for both similarities and differences in the anatomical substrates of the reinforcing effects of drugs, as measured in the two procedures (Bardo and Bevins, 2000).…”

Glutamatergic mechanisms in addiction

“…Animals that are forced to take drugs do not become addicted, and they show a greater vulnerability to toxic side effects and somatic dependence. 68,69 Thus drug-taking in a free choice situation is a prerequisite for addiction learning which implies that drugs are addictive only if the organism is in a certain anticipatory state.…”