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.

Keywords: Antipsychotic; Cholinergic; Cognition; Nicotinic receptor; Schizophrenia.

Fig. 1

Effects of risperidone 2.5 mg/kg/day (TOP) and quetiapine 25.0 mg/kg/day (Bottom) treatment in drinking water for 30 days on amphetamine (1.5 mg/kg s.c.)-induced locomotor activity in an open field arena. Amphetamine (AMP) was administered after a 60 min habituation period and the subjects were recorded for an additional 60 min period. For the risperidone evaluation, statistical analysis of ambulatory counts revealed the following, main effect of group, F(1,12) = 1.13, p=0.31, time period, F(23,276) = 55.74, p<0.001, group x time period interaction, F(23,276) = 1.95, p=0.007. In the quetiapine evaluation, statistical analysis revealed the following, main effect of group, F(1,13) = 2.93, p=0.11, time period, F(23,299) = 42.86, p<0.001, group x time period interaction, F(23,299) = 2.36, p<0.001. Data are expressed as the mean ± S.E.M. for each treatment group. * represents a significant difference (p<0.05 post hoc comparison) between the exploratory activity of antipsychotic-treated versus vehicle-treated (control) animals at the same respective time point. n = 7 per group.

Fig. 2

Effects of risperidone 2.5 mg/kg/day in drinking water for 30 days plus vehicle or tropisetron on the performance of a spontaneous novel object recognition task in rats. In these experiments, tropisetron (or vehicle) was administered by subcutaneous injection 30 min before the training (A/A) trial at the end of the antipsychotic treatment period. The mean (± S.E.M.) exploration times of the familiar and novel objects after 48 hr delays (A/B retention sessions) are illustrated in the main figures. The insets illustrate the mean (± S.E.M.) discrimination (d2) ratios. d2 ratio = (novel − familiar)/(novel + familiar). For the exploration times, the following statistical results were obtained, main effect of group F(3,28)=1.17, p=0.34, object type, F(1,28)= 226.64, p<0.001), group by object type interaction, F(3,28)= 64.74, p<0.001). For the D2 ratios, the following statistical results were obtained, F(3,28)= 44.58, p<0.001. Post hoc results were as follows: +++p<0.001 novel vs familiar object; *** p<0.001 vs VEH-VEH. n=8 for each group. Abbreviations, VEH (vehicle), RISP (risperidone), TROP (tropisetron).

Fig. 3

Effects of risperidone 2.5 mg/kg/day in drinking water for 90 days plus vehicle or tropisetron on the performance of a spontaneous novel object recognition task in rats. In these experiments, tropisetron (or vehicle) was administered by subcutaneous injection 30 min before the training (A/A) trial at the end of the antipsychotic treatment period. The mean (± S.E.M.) exploration times of the familiar and novel objects after 48 hr delays (A/B retention sessions) are illustrated in the main figures. The insets illustrate the mean (± S.E.M.) discrimination (d2) ratios. d2 ratio = (novel − familiar)/(novel + familiar). For the exploration times, the following statistical results were obtained main effect of group F(3,27)=0.54, p=0.66, object type F(1,27)= 81.19, p<0.001, group by object type interaction, F(3,27)= 9.44, p<0.001. For the D2 ratios, the following statistical results were obtained, F(3,27)=15.22, p<0.001. Post hoc results were as follows: +p<0.05, +++p<0.001 novel vs familiar object; *** p<0.001 vs VEH-VEH. n=7–8 for each group. Abbreviations, VEH (vehicle), RISP (risperidone), TROP (tropisetron).

Fig. 4

Effects of quetiapine 25.0 mg/kg/day in drinking water for 30 days plus vehicle or tropisetron on the performance of a spontaneous novel object recognition task in rats. In these experiments, tropisetron (or vehicle) was administered by subcutaneous injection 30 min before the training (A/A) trial at the end of the antipsychotic treatment period. The mean (± S.E.M.) exploration times of the familiar and novel objects after 48 hr delays (A/B retention sessions) are illustrated in the main figures. The insets illustrate the mean (± S.E.M.) discrimination (d2) ratios. d2 ratio = (novel − familiar)/(novel + familiar). For exploration times, the following statistical results were obtained, main effect of group, F(3,28)=1.12, p=0.36, object type F(1,28)= 184.54, p<0.001), group x by object type interaction (F(3,28)= 60.02, p<0.001. For the D2 ratios, the following statistical results were obtained, F(3,28)=49.84, p<0.001. Post hoc results were as follows: +++p<0.001 novel vs familiar object; *** p<0.001 vs VEH-VEH. n=8 for each group. Abbreviations, VEH (vehicle), QUET (quetiapine), TROP (tropisetron).

Fig. 5

Effects of quetiapine 25.0 mg/kg/day in drinking water for 90 days plus vehicle or tropisetron on the performance of a spontaneous novel object recognition task in rats. In these experiments, tropisetron (or vehicle) was administered by subcutaneous injection 30 min before the training (A/A) trial at the end of the antipsychotic treatment period. The mean (± S.E.M.) exploration times of the familiar and novel objects after 48 hr delays (A/B retention sessions) are illustrated in the main figures. The insets illustrate the mean (± S.E.M.) discrimination (d2) ratios. d2 ratio = (novel − familiar)/(novel + familiar). For exploration times, the following statistical results were obtained main effect of group F(3,25)=0.47, p=0.71, object type F(1,25)= 76.51, p<0.001, group by object type interaction, F(3,25)= 6.38, p=0.002. For the D2 ratios, the following statistical results were obtained, F(3,25)=12.10, p<0.001. Post hoc results were as follows: +p<0.05, +++p<0.001 novel vs familiar object; *** p<0.001 vs VEH-VEH. n=7–8 for each group. Abbreviations, VEH (vehicle), QUET (quetiapine), TROP (tropisetron).