Previous Exposure to THC Alters the Reinforcing Efficacy and Anxiety-Related Effects of Cocaine in Rats

Abstract

The hypothesis that prior cannabis exposure increases the likelihood of becoming addicted to other drugs can be evaluated by giving rats a history of tetrahydrocannabinol (THC) exposure, then allowing them to self-administer other drugs. In Experiment 1, THC preexposure did not alter the acquisition of cocaine self-administration or the amount of cocaine taken under a fixed-ratio 1 (FR1) schedule, with one response required for each injection. Under a progressive-ratio schedule, with the response requirement increasing exponentially with each injection, cocaine-seeking was significantly reduced in THC-exposed rats, suggesting that the regimen of THC exposure used in the present study caused cocaine to be devalued as a reinforcer. In contrast, in an earlier study that used the same regimen, a history of THC exposure did not alter the value of heroin as a reinforcer under the progressive-ratio schedule, but it increased heroin self-administration under the FR1 schedule. Experiment 2 examined how this regimen of THC pre-exposure alters the locomotor effects of cocaine and heroin. THC pre-exposure produced cross-tolerance to the motor-depressant effects of heroin; this may explain the shortened post-injection pauses exhibited by THC-exposed rats under FR1 heroin self-administration. When given cocaine, THCexposed rats exhibited normal increases in locomotion, but they avoided the center of the open field, suggesting that this THC preexposure regimen enhances the anxiogenic effects of cocaine. This enhanced anxiogenic effectFwhich was verified in Experiment 3 using another model of anxiety, the light-dark testFmay explain the reduced reinforcing value of cocaine observed in THC-exposed rats in Experiment 1.

Augmented Acquisition of Cocaine Self-Administration and Altered Brain Glucose Metabolism in Adult Female but not Male Rats Exposed to a Cannabinoid Agonist during Adolescence

“…Cocaine is known for exerting both rewarding and anxiogenic effects (Ettenberg, 2004), so the higher selfadministration rates shown by CP-females in our study could reflect either an increase in the rewarding actions of cocaine or a decrement in its anxiogenic effect (Panlilio et al, 2007). There is evidence that fails to support the former speculation.…”

“…A few studies had examined the causal link between a prior tetrahydrocannabinol (THC) exposure and a subsequent enhanced drug self-administration; however, they used adult THC pre-treated rats that subsequently underwent heroin or cocaine self-administration (Panlilio et al, 2007;Solinas et al, 2004). Since these designs did not incorporate the developmental component that is cardinal to the gateway hypothesis, a full experimental validation of the hypothesis was still missing.…”

Context-Specific Reversal of Cocaine Sensitization by the CB1 Cannabinoid Receptor Antagonist Rimonabant

“…It is popularly debated whether or not chronic cannabis use in humans can promote a neurobiological vulnerability to other drugs of abuse (Kandel et al, 2006;Tarter et al, 2006). In laboratory animal models, experiments have tested the notion that CB 1 receptor agonists such as THC can influence self-administration (Panlilio et al, 2007), conditioned place preference (CPP; Parker et al, 2004) or cross-sensitization to psychostimulants (Arnold et al, 1998;Ellgren et al, 2004). These studies have largely found no evidence that previous exposure to cannabinoids can enhance the rewarding efficacy of cocaine (Arnold, 2005;Panlilio et al, 2007).…”

Modulation of the endocannabinoid system: Therapeutic potential against cocaine dependence

“…In a recent report using Sprague Dawley rats, prior exposure to delta-9-THC did not affect the acquisition and subsequent rates of cocaine selfadministration under a fixed-ratio 1 schedule of injection, but did reduce the number of "cocaine-seeking" responses under a progressive-ratio schedule (145). Thus the sensitivity to delta-9-THC exposure may vary with behavioral procedure.…”

“…In the report by Panlilio and colleagues (145), delta-9-THC pre-exposure also decreased both the number of entries in the center-zone of an open-field arena, and the time spent in the lighted compartment of the dark-light box (two different predictors of an anxiety response) in cocaine-treated rats. The authors suggested that the reduced effectiveness of cocaine as a reinforcer after delta-9-THC pre-exposure may be because the previous exposure to the cannabinoid agonist enhanced the aversive/anxiogenic effects of cocaine (145).…”