LIGANDS OF THE DELTA-OPIOID RECEPTOR AND TRACE AMINE ASSOCIATED RECEPTOR 1 EXERT SIMILAR EFFECTS ON MONOAMINERGIC TRANSMISSION IN RATS

Abstract Background It has been reported in previous studies that the agonists of delta opioid receptor (DOR)[1] and trace amine associated receptor 1 (TAAR1)[2] have anxiolytic and antidepressant-like effects in rodents. It has been also suggested that these behavioural effects are mediated, at least in part, via the modification of central monoaminergic transmission. Aims & Objectives We aimed to examine the effects of acute and chronic administration of agonists of the DOR (SNC80) and TAAR1 (RO5256390) on the excitability of serotonergic (5-HT) neurons of the dorsal raphe nucleus (DRN), dopaminergic neurons of the ventral tegmental area (VTA), and noradrenergic neurons of the locus coeruleus (LC). Methods To assess the effect of chronic SNC80 and RO5256390, the rats were pre-treated with these compounds for 14 days (SNC80: 1.5 mg/kg, subcutaneously, twice a day; RO5256390: 1.5 mg/kg, orally, twice a day). Control animals were treated with corresponding vehicles. On day 15, animals were anesthetized with chloral hydrate (0.4 g/kg, intraperitoneally) and mounted in a stereotaxic frame. The electrodes were inserted into the DRN, and VTA, or LC, and 5-HT, dopaminergic, and noradrenergic neurons were identified according to their excitability pattern and the waveform of the action potentials[3]. The excitability of the neurons in the SNC80 or RO5256390-treated rats was compared with the excitability of the corresponding neurons in animals treated with the corresponding vehicle. In acute experiments, SNC80 (1-3 mg/kg) or RO5256390 (0.5-1 mg/kg) were administered to the drug-naï ve rats, during the recording from the same neuron. The neuronal firing rate after the administration of each dose of SNC80 or RO5256390 was compared to the basal firing activity of the same neuron. Results Acute SNC80 or RO5256390 dose-dependently inhibited 5-HT and dopaminergic, but not noradrenergic neurons. Animals’ pre-treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) diminished the inhibitory effect of acute RO5256390 on 5-HT neurons. Surprisingly, chronic SNC80 had no effect on 5-HT and stimulated dopaminergic neurons. With regards to RO5256390, its chronic administration increased the firing rate of dopaminergic and the burst activity of 5-HT and dopaminergic neurons. Discussion & Conclusion We suggest that the inhibitory effects of acute SNC80 or RO5256390 are the results of DOR[1] and TAAR1[4]-mediated increase in extracellular 5-HT and/or dopamine concentrations and activation of 5-HT1A/2C and/or D2 receptors, rather than a direct output of the activation of DOR or TAAR1 receptors. After chronic treatment with SNC80 or RO5256390, receptors responsible for the extracellular 5-HT and/or dopamine-induced inhibition of the neuronal firing activity putatively desensitize, and a stimulatory effect of the activation of DOR or TAAR1 is observed. The stimulatory effect of the DOR and TAAR1 agonists might explain, at least in part, their anxiolytic, and antidepressant-like effects. The pharmacodynamic similarity between DOR or TAAR1 ligands is surprising and motivates further investigation. This work was supported by the Slovak Research and Development Agency (grant APVV-20-0202) and Scientific Grant Agency of Ministry of Education of Slovak Republic and Slovak Academy of Sciences (grant VEGA-2/0057/22). References 1)Saitoh, A.; Yamada, M.; Yamada, M.; Takahashi, K.; Yamaguchi, K.; Murasawa, H.; Nakatani, A.; Tatsumi, Y.; Hirose, N.; Kamei, J., Antidepressant-like effects of the delta-opioid receptor agonist SNC80 ([(+)-4- [(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-me thoxyphenyl)methyl]-N,N- diethylbenzamide) in an olfactory bulbectomized rat model. Brain Res 2008, 1208, 160-9. 2)Revel, F. G.; Moreau, J. L.; Pouzet, B.; Mory, R.; Bradaia, A.; Buchy, D.; Metzler, V.; Chaboz, S.; Groebke Zbinden, K.; Galley, G.; Norcross, R. D.; Tuerck, D.; Bruns, A.; Morairty, S. R.; Kilduff, T. S.; Wallace, T. L.; Risterucci, C.; Wettstein, J. G.; Hoener, M. C., A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight. Mol Psychiatry 2013, 18, (5), 543-56. 3)Grinchii, D.; Lacinová, Ľ.; Dremencov, E., Effects of delta-opioid receptor ligands on the excitability of rat hippocampal glutamate and brainstem monoamine neurons in vivo. Gen Physiol Biophys 2023, 42, (3), 273-83. 4) Revel, F. G.; Meyer, C. A.; Bradaia, A.; Jeanneau, K.; Calcagno, E.; Andre, C. B.; Haenggi, M.; Miss, M. T.; Galley, G.; Norcross, R. D.; Invernizzi, R. W.; Wettstein, J. G.; Moreau, J. L.; Hoener, M. C., Brain-specific overexpression of trace amine-associated receptor 1 alters monoaminergic neurotransmission and decreases sensitivity to amphetamine. Neuropsychopharmacology 2012, 37, (12), 2580-92.