P.2.026 - No tolerance to anticompulsive activity of trace amine-associated receptor 1 agonist following repeated administration

Abstract

Introduction In clinical practice the treatment of psychiatric diseases usually requires long-term drug administration, but the effects of many psychiatric medications decrease upon repeated exposure, a phenomenon described as ‘tolerance’ [1]. Our previous study has shown that acute administration of partial Trace Amine-Associated Receptor 1 (TAAR1) agonist (RO5263397) attenuated adjunctive water drinking in schedule-induced polydipsia (SIP) [2], a successful model of compulsive behavior [3]. The present study was aimed to evaluate the anticompulsive activity of RO5263397 following repeated administration and analyze RO5263397 effects on the levels of monoamines and their metabolites in the striatum and frontal cortex. Methods To induce SIP, 16 Wistar rats were habituated to operant chambers and pellet feeding to fixed-time 60-second (FT-60 sec) schedule of food-pellet reinforcement. After the acquisition of stable adjunctive drinking behaviour, the animals were divided into two equal subgroups. The different subgroups were injected with either 12 mg/kg of RO5263397 or vehicle every 12 hours (9:00 and 21:00) during 7 consecutive days. The drug dose and the schedule of injections were chosen in concordance with a previously published information about pharmacokinetic of RO5263397 [4]. Thus, the serum concentration of RO5263397 was higher than 0.67 μg/ml (maximal concentration after i.p. administration of RO5263397 in dose 3 mg/kg which decreased SIP in our previous experiments [2]) for 14 hours in a day. To analyze monoamines tissue content high-performance liquid chromatography (HPLC) was used. HPLC measurements were carried out as described before [5]. Striatum and frontal cortex tissues were dissected from the rats subchronically treated with RO5263397 and levels of norepinephrine, dopamine, serotonin and their metabolites were evaluated. Results Before the start of the treatment there was no difference between the subgroups in water consumption in home cages and operant boxes (U-tests, Ps>0.05). Two-way repeated measures ANOVA showed that the treatment with RO5263397 significantly reduced SIP (F(1.13)=17.865, P At the same time, repeated treatment with RO5263397 significantly decreased dopamine metabolism and increased norepinephrine and serotonin levels in the striatum and prefrontal cortex (with exception of norepinephrine) (t- and U-tests, Ps Conclusions Thus, these findings indicate that the repeated administration did not influence SIP ameliorating effect of RO5263397 and further support previously proposed view that TAAR1 is promising target for the treatment of disorders accompanied by compulsive behavior. Moreover, HPLC results suggest that the mechanisms of the TAAR1 agonist anticompulsive activity might involve the modulation of not only dopamine but also other catecholamine systems. Certainly, additional studies aimed at analysis of neurochemical profile of activity of TAAR1 agonists are warranted.