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TAAR5) and Its Action on Brain Neurochemistry E P.833 Identifying the agonist of trace amine associated receptor 5 (TAAR5) and its action on brain neurochemistry E. V. Efimova, A.S. Gerasimov, I. Sukhanov, K.A. Antonova, M.A. Ptuha, A.B.Volnova, R.R. Gainetdinov 1. Institute of Translational Biomedicine, St. Petersburg State University, 199034, St. Petersburg, Russia. 2. Department of Physiology, St. Petersburg State University, 199034, St. Petersburg, Russia. 3. Skolkovo Institute of Science and Technology, Skolkovo, 143025, Moscow Region, Russia Introduction Influence on behavior Trace amines are structurally close to classical monoamine neurotransmitters and We measured locomotor activity using Omnitec they play an important role in regulation of movement, feeding and many other equipment for 90 min after injection of alpha-NETA functions. However many of other functions in mammals are still remain in three doses - 1, 3 and 10 mg/kg. unknown. Unraveling the role of trace amine in physiology could give answers to Injection of alpha-NETA caused significant pathologies and pharmacology of monoamine neurotransmission. Study of action decrease in locomotion and the effect was dose of TAAR5 agonist can elucidate the functions and modulatory influence of trace dependent. amines on classical neurotransmitters. Interestingly, the effect of alpha-NETA was delayed Fig. 5. Locomotor activity after alpha- and the change in activity started 20-30 min after NETA injection Time in open arms the injection. 350 For identification of TAAR5 ligands we performed screening of compounds from We also done elevated plus-maze to measure 300 commercially available compound libraries (The SCREEN-WELL® anxiety level. In this test we used video tracking 250 neurotransmitter library (Enzo Life Scienes) containing 661 compounds) on cAMP s time, software Noldus Ethovision. The test was done 35 responses in transfected cells. For cAMP determination we used Bioluminescence 200 min after injection of alpha-NETA in doses 5 and 150 Resonance Energy Transfer (BRET) approach with EPAC biosensor. 10 mg/kg. control We observed no change in time spent on open arms, Only 2-(α-Naphthoyl)- indicating that level of anxiety was unaltered. alpha-NETA, 5mg/kg ethyltrimethylammonium iodide alpha-NETA, 10mg/kg Fig. 6. Time in open arms in elevated plus- (alphaNETA) gave the positive signal as an maze. 35 min after alpha-NETA injection agonist of TAAR5. The dose-response experiments have been shown that the efficacy concentration of alphaNETA is approximately 150 nM. The Change in EcoG potency of alphaNETA in comparison to TMA was 115% (fig.1). Experiments were performed on 6 wild type We emphasize that while this compound male mice. Under general anesthesia mice incorporates tertiary amine group as choline, were implanted with epidural electrodes. After there was no response from other choline- 4 days of rehabilitation, each animal Fig. 1 Dose-response curve for alpha-NETA (a) like drugs tested. So we indentified a new underwent 4-8 experiments, no less than a day and TMA (b) on cAMP BRET responses and perspective chemotype of TAAR5 receptor in between each. Electrocorticogram (EcoG) their chemical structures (inserts). agonist. was recorded in freely moving mice in 6 time intervals of 10-15 mins: 3 before the injection and 3 after the injection. As the injection mice Level of monoamines in tissue were given either 5 mg/kg α-NETA or 0,2 ml of 0,9% NaCl. DA, Striatum ABCDOPAC, Striatum DOPAC/DA, Striatum 30 2.5 0.20 Mice that were given 5 mg/kg α-NETA 2.0 0.15 showed a significant increase in the power of 20 1.5 0.10 * the EcoG signal within the delta frequency 1.0 ratio 10 range (2.5-4.5 Hz) in all three time intervals 0.05 Fig. 7. Changes in power of EcoG signal after concentration, ng concentration, concentration, ng concentration, 0.5 injections of 5mg/kg α-NETA and NaCl during (t-test, p<0,05). The control NaCl injection 0 0.0 0.00 control alpha-NETA control alpha-NETA control alpha-NETA the second time interval. Significant increase was observed for all three time intervals after the did not lead to increase of the power signal. Fig. 2. Concentracion of dopamine (A), DOPAC (B) and DOPAC/DA ratio (C) in striatum 40 min after injection of α-NETA, therefore the second 5mg/kg alpha-NETA injection interval is presented as an example. DA, frontal cortex ABCDOPAC, fronta cortex DOPAC/DA, frontal cortex 3 0.4 1.5 0.3 2 1.0 0.2 ratio Conclusions: 1 0.5 0.1 concentration, ng concentration, concentration, ng concentration, 0 0.0 0.0 control alpha-NETA control alpha-NETA control alpha-NETA 1. We indentified a new perspective chemotype of TAAR5 receptor Fig. 3. Concentracion of dopamine (A), DOPAC (B) and DOPAC/DA ratio (C) in frontal cortex 40 min agonist. after 5mg/kg alpha-NETA injection 2. TAAR5 agonist alpha-NETA causes increase of dopamine level and To see the effect of alpha-NETA on monoamine system we measured level of decrease of DOPAC/DA ration after injection. norepinephrine, dopamine, serotonin and their metabolites in brain tissue 40 min after injection of alpha-NETA (5mg/kg). We measured monoamines in 3. Alpha-NETA decreases locomotor activity and does not change frontal cortex, striatum, hypothalamus, hippocampus. anxiety level. We observed a slightest increase in dopamine and DOPAC level (ns) in striatum. And the ration DOPAC/DA decreased in striatum (p<0.05) 4. Alpha-NETA increases power of the EcoG signal within the delta suggesting that injection of alpha-NETA could influence dopamine metabolism. frequency range (2.5-4.5 Hz) The work was supported by Russian Scientific Foundation grant N 14-50-00069 .
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