Tropisetron enhances recognition memory in rats chronically treated with risperidone or quetiapine

Abstract

While impairments of cognition in schizophrenia have the greatest impact on long-term functional outcome, the currently prescribed treatments, antipsychotic drugs (APDs), do not effectively improve cognition. Moreover, while more than 20 years have been devoted to the development of new drugs to treat cognitive deficits in schizophrenia, none have been approved to date. One area that has not been given proper attention at the preclinical or clinical stage of drug development is the chronic medication history of the test subject. Hence, very little is known about how chronic treatment with drugs that affect multiple receptors like APDs influence the response to a potential pro-cognitive agent. Therefore, the purpose of this study was to evaluate the α7 nicotinic acetylcholine receptor (α7 nAChR) partial agonist, tropisetron in rats chronically treated with APDs with distinct pharmacological profiles. Rats were treated orally with either risperidone (2.5 mg/kg/day) or quetiapine (25.0 mg/kg/day) for 30 or 90 days and then an acute injection of vehicle or tropisetron (3.0 mg/kg) was administered before training in a novel object recognition (NOR) task. After a 48 h delay (when recollection of the familiar object was impaired in vehicle-treated animals) neither 30 nor 90 days of risperidone or quetiapine treatment improved NOR performance. In contrast, tropisetron markedly improved NOR performance in rats treated with either APD for 30 or 90 days. These animal data reinforce the argument that two commonly prescribed APDs are not pro-cognitive agents and that α7 nAChR ligands like tropisetron have potential as adjunctive treatments in schizophrenia.

Tropisetron Facilitates Footshock Suppression of Compulsive Cocaine Seeking

“…A study reported that co-infusion of tropisetron blocked the self-infusion of cocaine in the ventral tegmental area (Rodd et al, 2005). Given the importance of α7 nAchRs and the 5-HT 3 Rs on cognitive function, and the evidence of tropisetron’s efficacy on improving cognitive deficits in psychiatric disorders (Zhang et al, 2012; Hashimoto, 2015; Callahan et al, 2017; Poddar et al, 2018), the effect of tropisetron on compulsive behavior in footshock-resistant rats using STCTs implies that activating these receptors might restore impaired cognitive flexibility in drug-addicted rats (Dalley et al, 2007; Eagle et al, 2008; Gould, 2010).…”

“…was administrated to the footshock-resistant rats to examine its effect on compulsive seeking behavior. The dose of tropisetron was identified as effective in a rat model of phencyclidine-induced cognitive deficits (Hashimoto et al, 2006) and in memory-related task performance in rats (Callahan et al, 2017; Poddar et al, 2018). Pharmacokinetic analysis revealed the half‐life of tropisetron in the plasma was approximately 6 hours after i.v.…”

Cognitive Deficit in Schizophrenia: From Etiology to Novel Treatments

“…Tropisetron, another 5-HT 3 receptor antagonist, improved cognition in schizophrenic patients [ 96 ]. Tropisetron is also an agonist of α 7 nicotinic acetylcholine receptors, demonstrating that the synergy between acetylcholine receptor agonism and 5-HT 3 receptor antagonism is beneficial for the treatment of cognitive deficit in schizophrenia [ 140 ].…”

One-day tropisetron treatment improves cognitive deficits and P50 inhibition deficits in schizophrenia

“…Tropisetron, a commonly used medicine against nausea and vomiting caused by chemotherapy and surgical anesthesia, is both a potent serotonin-3 receptor antagonist and a high-affinity partial agonist of the nAChR [23][24][25]. Due to its nAChR activity, tropisetron has improved auditory inhibition and cognitive deficits in mice [26][27][28]. In patients with SCZ, 10 mg per day of tropisetron significantly enhanced P50 deficiencies and cognitive deficits [23][24][25]29].…”