Tropisetron Facilitates Footshock Suppression of Compulsive Cocaine Seeking

Abstract

Background: The hallmark characteristics of the murine model of drug addiction include the escalation of cocaine consumption and compulsive punishment-resistant drug seeking. In this study, we evaluated the motivation for drug seeking in cocaine self-administering rats exposed to an escalated dosing regimen that endeavored to mimic the characteristic of escalating drug intake in human addicts. Tropisetron is a 5-HT3 receptor antagonist and α7-nicotinic receptor partial agonist. Utilizing rats trained on the escalated-dosing regimen, we examined the effects of tropisetron on control over compulsive drug-seeking behavior that was defined as footshock-resistant lever pressing.

Methods: Rats were trained to self-administer cocaine with incremental-infusion doses (from 0.6 to 2.4 mg/kg/infusion) across training sessions (3 h/session) or with a long-access paradigm (i.e., 0.6 mg/kg/infusion, 6 h/d training session). The drug-seeking motivations of 2 groups were estimated by the patterns of drug intake and progressive-ratio schedule. The compulsivity for drug seeking of the group with an escalated dose was further evaluated using the footshock-associated seeking-taking chain task.

Results: The rats trained on the dose-escalated protocol achieved the same levels of motivated drug seeking as those subjected to a long-access paradigm, as indicated by cocaine intake per training session and breakpoints on a progressive ratio schedule. Tropisetron attenuated compulsive behavior of rats when pressing of the seeking lever potentially led to footshock. Intriguingly, tropisetron did not change the motivation to seek cocaine when footshock was absent. Tropisetron had no effect on locomotor activities or saccharin self-administration.

Conclusions: These results demonstrate that tropisetron restored control over compulsive cocaine seeking, and they indicate that 5-HT3/α7-nicotinic receptors may be potential therapeutic targets for relieving compulsive drug seeking.

Keywords: compulsive cocaine seeking; drug addiction; footshock; self-administration; tropisetron.

Figure 1.

Cocaine self-administration training in 3-hour sessions with escalated dosing achieved the same level of cocaine seeking as that of long access (LgA) training (6-hour sessions). (A) The paradigm of cocaine self-administration with escalated dosing or LgA. The arrows indicate the time for progressive ratio (PR) testing. (B) Active and inactive lever pressings during self-administration with escalated dosing (B1, n = 26) or LgA (B2, n = 11). (C) Left: cocaine intake per session during self-administration with escalated dosing or LgA. Right: the slope of drug intake over dose-escalated (DE) or LgA training period (i.e., from weeks 3 to 6). DE-trained rats show a greater slope of voluntary intake than LgA-trained rats (***P < .001 compared with LgA group). (D) The temporal pattern of drug-seeking behavior during the training. Both groups showed linear distributions, indicating invariable lever pressings during the training. (E) The breakpoint under PR testing. The first PR test represented the data from rats initially trained with a constant dose (0.6 mg/kg) and short access (2 hours) for 10 days. Then, these rats were randomly divided into LgA or DE groups. The breakpoints by the second and third PR tests represented the data from the LgA or DE group. Two-way ANOVA analysis indicated training history (escalated dosing vs LgA) had the same effect on the breakpoint. Data are represented as the mean values ± SEM.

Figure 2.

Following training of the seeking-taking chain tasks (STCT), a portion of the cocaine-trained rats with escalated dosing showed resistance to punishment. (A) The paradigm of the STCT with different parameters and punishment schedule. (B) The number of seeking responses and infusion (or rewarding) per session under different training schedules for cocaine (left) or saccharin water (right). *P < .05, ***P < .001 compared with schedule I using a Bonferroni’s post hoc. (C) The pie chart indicates the proportion of cocaine- (left) or saccharin-administered (right) rats failing or passing the stages of the seeking-taking chain schedule. (D) About 45% of cocaine-administering rats that passed all of the stages of the STCT showed resistance to punishment. (E) All of the saccharin-administered rats were sensitive to punishment. **P < .01, ***P < .001 compared with the session “0” using a Bonferroni’s post hoc. All of the data are represented as the mean values ± SEM.

Figure 3.

Tropisetron restored control over compulsive cocaine seeking. (A) Tropisetron (1.0 mg/kg) did not alter the seeking lever-press behavior, regardless of whether pressing could trigger a footshock. (B) Tropisetron (1 mg/kg) did not affect cocaine infusion or the latency to press the seeking levers at the second cycle of footshock testing. (C) Tropisetron (3.0 mg/kg) attenuated seeking responses when seeking lever pressing could potentially deliver footshock (*P < .05 from the 55th minute compared with the saline-pretreated group when footshock was available, Bonferroni’s post hoc test; right). (D) Tropisetron (3.0 mg/kg) reduced cocaine intake and extended the latency to seek lever press at the second cycle of footshock testing. *P < .05 compared with saline-pretreated group using a Bonferroni’s post hoc. All data are mean values ± SEM. (E) Examples of seeking lever presses from 1 rat during footshock session (2 hours) with vehicle without tropisetron (3.0 mg/kg, i.p.) treatment. Sticks and arrows represent seeking lever presses and footshock, respectively.

Figure 4.

Tropisetron did not affect locomotor activity or the motivation to seek natural reward and locomotor activity. (A) The number of nose-pokes for sweetened water and sweetened water intake after systemic tropisetron was the same as without tropisetron. (B) No difference in locomotor activity was measured between tropisetron- (n = 6) and saline-treated (n = 7) groups. Tropisetron or saline was administered 5 minutes before placing the animal into an open field chamber and locomotor activity was monitored. Data are represented as the mean values ± SEM.