403. Sustained administration of the full and partial agonists of trace amine associated receptor 1 (TAAR1) induces different effects on the excitability of central monoaminergic neurons

Abstract

Abstract Background Trace amine associated receptor 1 (TAAR1) is a promising target for the next generation of the central nervous system (CNS) drugs. It has been previously shown that the full (RO5256390) and partial (RO5263397) agonists of TAAR1 had anti-addictive, pro-cognitive, and antipsychotic- and antidepressant-like effects; these beneficial effects of TAAR1 ligands were linked, at least in part, with the altered excitability of serotonergic (5-HT) neurons of the dorsal raphe nucleus (DRN) and dopaminergic neurons of the ventral terminal area (VTA; Revel et al Mol Psychiatry 18:543, 2013). Aims & Objectives This study aimed to examine the effects of sustained administration of RO5256390 and RO5263397 on the excitability of 5-HT neurons of the DRN and dopaminergic neurons of the VTA in vivo conditions. Method Male Wistar rats, weighing 250-350 g, were pre-treated with RO5256390, RO5263397 (orally, 1.5 mg/kg, twice a day at 09:00 and 17:00) or with corresponding vehicles (0.3% polysorbate-80 in 0.9% NaCl) for 14 consecutive days. On the 15th day, one hour after the morning RO5256390, RO5263397, or vehicle administration, rats were anesthetized with chloralhydrate (0.4 g/kg) and mounted in a stereotaxic frame. Borosilicate electrodes filled with 2M NaCl (impedance 4-6 MΩ) were inserted into the DRN or VTA. Spontaneously active 5-HT and dopaminergic neurons were identified by the waveform of their action potentials and pattern of their generation. Since the burst-like, or phasic firing of 5-HT (Gartside et al Neuroscience 98:295, 2000) and dopaminergic (Cooper Neurochem Int 41:333, 2002) neurons results in increased release of corresponding neurotransmitter from the nerve terminals, the excitability mode of monoaminergic neurons was assessed. The onset of a burst was signified by the occurrence of two spikes with and inter-spike interval (ISI) < 0.08 s for dopaminergic and ISI < 0.01 s for 5-HT neurons. The termination of a burst was defined as an ISI > 0.16 s for dopaminergic and ISI > 0.010 s for 5-HT neurons. Results Sustained administration of RO5256390 had no effect on the mean basal firing rate of 5-HT neurons. It however increased the frequency of the phasic activity of these neurons. With respect to dopaminergic neurons, sustained treatment with RO5256390 stimulated their mean spontaneous basal firing rate, as well as the burst/phasic mode of activity. Sustained administration of RO5263397 increased the mean spontaneous basal firing rate of 5-HT neurons. The mode of their activity, however, was not altered. With respect to dopaminergic neurons, sustained treatment with RO5263397 did not affect their mean basal firing rate or mode of their activity. Discussion & Conclusions Chronic treatment with the full agonists of TAAR1 might have a robust stimulatory effect on the central dopaminergic neurotransmission. It may also stimulate 5-HT neurotransmission. Chronic treatment with the partial agonists of TAAR1 might have strong stimulatory effect on 5-HT, but they may have lesser effect on dopaminergic neurotransmission. This work was supported by the grants APVV-22-0061, APVV-24-0131, VEGA-2/0045/24, and VEGA- 2/0126/26. RO5256390 and RO5263397 were provided as a gift from Roche Innovation Center Basel.