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.

Evaluation of Multi-target Drugs on the Cocaine-induced Locomotor Sensitization in Rats

“…Preclinical studies have shown that many of the addictive cocaine actions are mediated by an increase in DA, NE, and 5-HT release and activation of the different subtypes of DA, NE, and 5-HT receptors (D 1 , D 2 , a 1/2 , 5-HT 1 , 5-HT 2A/C and 5-HT 3 ) in cortical and subcortical areas (Fletcher et al, 2002;Vanderschuren et al, 2003). These studies show that 1) 5-HT 2A (ketanserin) and 5-HT 3 (ondansetron or tropisetron) receptor antagonists attenuate cocaine-induced locomotor sensitization and conditioned place preference (Zayara et al, 2011;King et al, 2000King et al, , 2002, cocaine self-administration (Pockros et al, 2011;Nic Dhonnchadha et al, 2009;Zhou et al, 2019), the Fos protein expression (Pockros et al, 2012;Humblot et al, 1998), and the cocaine-induced dopamine release (Auclair et al, 2004;Matell and King, 1997) and that 2) a 2 NE (clonidine) 5-HT 1A (8-OH-DPAT) and 5-HT 2c (Ro 60-0175) receptor agonists decrease cocaine-induced locomotor sensitization, inhibits cocaine-induced Fos expression, attenuated cocaine-induced reinstatement, and decrease cocaine-induced dopamine within the nucleus accumbens Based on these studies, various clinical and preclinical studies have evaluated the e cacy of different antidepressants (pindolol, uoxetine, trazodone, mirtazapine; Yaman and Bal, 2022; Agius et al, 2013;Gerra et al, 1995;Glatz et al, 2002;McMillen et al, 1994;Small and Purcell, 1985), antipsychotics (risperidone, ziprasidone; Okada et al, 2020;Loebl et al, 2008;Fukushiro et al, 2008;Duggal, 2007), antiemetic (ondansetron; Blevins et al, 2021;Johnson et al, 2006), and hypertensives drugs (prazosin; Tapp et al, 2006;Haile et al, 2012;Barbosa-Mendez et al, 2017d), to decrease the cocaine reinforcers effects. The rationale for this strategy is that these medications incorporate simultaneous (multitarget) NE α 1/2 or serotonin 5-HT 1A , 5-HT 2A/C , and 5-HT 3 receptors antagonism or agonism in their mechanism of action.…”

Evaluation of the 5-HT2C receptor drugs RO 60-0175, WAY 161503 and mirtazepine in a preclinical model of comorbidity of depression and cocaine addiction

“…The different effects of chronic administration of 5-HT 2C receptor agonists during extinction training on the reinstatement of seeking behavior induced by different stimuli (cue vs. cocaine) may be due to the involvement of, among others, localization of these receptors to separate regions of rat (sub)brain. For example, the prelimbic prefrontal cortex and infralimbic cortex, as well as the lateral orbitofrontal cortex and medial part of the orbitofrontal cortex, play an opposite role the reinstatement of cocaine-seeking [75][76][77][78] and in the localization of 5-HT 2C receptor mRNA and protein in those areas [70,79]. Furthermore, a lesion of the medial part of the orbitofrontal cortex enhances the reinstatement of seeking behavior induced by the priming dose of cocaine [76].…”

“…Furthermore, a lesion of the medial part of the orbitofrontal cortex enhances the reinstatement of seeking behavior induced by the priming dose of cocaine [ 76 ]. In contrast, a pharmacological inactivation or lesion of the lateral orbitofrontal cortex inhibited exploratory seeking behavior for cocaine after the presentation of the conditional stimulus [ 75 , 76 , 78 ].…”

Regulation of glutamate homeostasis in the nucleus accumbens by astrocytic CB1 receptors and its role in cocaine-motivated behaviors

“…Reinstatement of drug-seeking behavior is one of the diagnostic criteria for substance use disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), often appearing when exposed to the contextual environment, substance priming and stress. Vulnerability to relapse is attributed to drug-induced impairments in the cognitive control of motivated behavior [ 61 ], particularly when drug-seeking behaviors lead to aversive consequences [ 62 , 63 ]. Drug-related exteroceptive information is carried by glutamatergic afferents from the prefrontal cortex (PFC) to the NAc core [ 16 , 64 ].…”