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Dual inhibitory action of trazodone on dorsal raphe serotonergic neurons through 5-HT1A receptor partial agonism and α1-adrenoceptor antagonism


Autoři: Alberto Montalbano aff001;  Boris Mlinar aff001;  Francesco Bonfiglio aff001;  Lorenzo Polenzani aff002;  Maurizio Magnani aff002;  Renato Corradetti aff001
Působiště autorů: NEUROFARBA—Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Università di Firenze, Firenze, Italia aff001;  Angelini RR&D (Research, Regulatory & Development), Angelini S.p.A, S.Palomba-Pomezia (Roma), Italia aff002
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0222855

Souhrn

Trazodone is an antidepressant drug with considerable affinity for 5-HT1A receptors and α1-adrenoceptors for which the drug is competitive agonist and antagonist, respectively. In this study, we used cell-attached or whole-cell patch-clamp recordings to characterize the effects of trazodone at somatodendritic 5-HT1A receptors (5-HT1AARs) and α1-adrenoceptors of serotonergic neurons in rodent dorsal raphe slices. To reveal the effects of trazodone at α1-adrenoceptors, the baseline firing of 5-HT neurons was facilitated by applying the selective α1-adrenoceptor agonist phenylephrine at various concentrations. In the absence of phenylephrine, trazodone (1–10 μM) concentration-dependently silenced neurons through activation of 5-HT1AARs. The effect was fully antagonized by the selective 5-HT1A receptor antagonist Way-100635. With 5-HT1A receptors blocked by Way-100635, trazodone (1–10 μM) concentration-dependently inhibited neuron firing facilitated by 1 μM phenylephrine. Parallel rightward shift of dose-response curves for trazodone recorded in higher phenylephrine concentrations (10–100 μM) indicated competitive antagonism at α1-adrenoceptors. Both effects of trazodone were also observed in slices from Tph2-/- mice that lack synthesis of brain serotonin, showing that the activation of 5-HT1AARs was not mediated by endogenous serotonin. In whole-cell recordings, trazodone activated 5-HT1AAR-coupled G protein-activated inwardly-rectifying (GIRK) channel conductance with weak partial agonist efficacy (~35%) compared to that of the full agonist 5-CT. Collectively our data show that trazodone, at concentrations relevant to its clinical effects, exerts weak partial agonism at 5-HT1AARs and disfacilitation of firing through α1-adrenoceptor antagonism. These two actions converge in inhibiting dorsal raphe serotonergic neuron activity, albeit with varying contribution depending on the intensity of α1-adrenoceptor stimulation.

Klíčová slova:

Antidepressants – Cell membranes – Drug administration – Neurons – Sleep – Serotonin receptors – Serotonin – Partial agonists


Zdroje

1. Cools R, Roberts AC, Robbins TW. Serotoninergic regulation of emotional and behavioural control processes. Trends Cogn Sci. 2008; 12: 31–40. doi: 10.1016/j.tics.2007.10.011 18069045

2. Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron 2010; 68:1023–1042 doi: 10.1016/j.neuron.2010.11.032 21172606

3. Cespuglio R. Serotonin: its place today in sleep preparation, triggering or maintenance. Sleep Med. 2018; 49:, 31–39. doi: 10.1016/j.sleep.2018.05.034 30029993

4. Lesch KP, Araragi N, Waider J, van den Hove D, Gutknecht L. Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour. Philos Trans R Soc Lond B Biol Sci. 2012; 67: 2426–2443.

5. Owens MJ., Morgan WN, Plott SJ, Nemeroff CB. Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther. 1997; 283: 1305–1322. 9400006

6. Cusack B, Nelson A, Richelson E. Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl) 1994; 114: 559–565.

7. Stahl SM. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr. 2009; 14: 536–346. 20095366

8. Levine ES, Jacobs BL. Neurochemical afferents controlling the activity of serotonergic neurons in the dorsal raphe nucleus: microiontophoretic studies in the awake cat. J Neurosci. 1992; 12: 4037–4044. 1357117

9. McGinty DJ, Harper RM. Dorsal raphe neurons: depression of firing during sleep in cats. Brain Res. 1976; 101: 569–575. doi: 10.1016/0006-8993(76)90480-7 1244990

10. Chazalon M, Dumas S, Bernard JF, Sahly I, Tronche F, de Kerchove d'Exaerde A, et al. The GABAergic Gudden's dorsal tegmental nucleus: A new relay for serotonergic regulation of sleep-wake behavior in the mouse. Neuropharmacology 2018; 138: 315–330. doi: 10.1016/j.neuropharm.2018.06.014 29908240

11. Fornal CA, Metzler CW, Gallegos RA, Veasey SC, McCreary AC, Jacobs BL. WAY-100635, a potent and selective 5-hydroxytryptamine1A antagonist, increases serotonergic neuronal activity in behaving cats: comparison with (S)-WAY-100135. J Pharmacol Exp Ther. 1996; 278: 752–762. 8768728

12. Mlinar B, Montalbano A, Baccini G, Tatini F, Berlinguer Palmini R, Corradetti R. Nonexocytotic serotonin release tonically suppresses serotonergic neuron activity. J Gen Physiol. 2015; 145: 225–251. doi: 10.1085/jgp.201411330 25712017

13. Blier P, de Montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci. 1994; 15: 220–226. doi: 10.1016/0165-6147(94)90315-8 7940983

14. Blier P, Ward NM. Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry 2003; 53: 193–203. doi: 10.1016/s0006-3223(02)01643-8 12559651

15. Artigas F, Romero L, De Montigny C, Blier P. Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. 1996; Trends Neurosci. 19: 378–383. doi: 10.1016/S0166-2236(96)10037-0 8873352

16. Piñeyro G, Blier P. Autoregulation of serotonin neurons: role in antidepressant drug action. 1999; Pharmacol Rev. 51: 533–591. 10471417

17. Portella MJ, de Diego-Adeliño J, Ballesteros J, Puigdemont D, Oller S, Santos B, et al. Can we really accelerate and enhance the selective serotonin reuptake inhibitor antidepressant effect? A randomized clinical trial and a meta-analysis of pindolol in nonresistant depression. 2011; J Clin Psychiatry 72: 962–969. doi: 10.4088/JCP.09m05827blu 21034693

18. Artigas F, Bortolozzi A, Celada P. Can we increase speed and efficacy of antidepressant treatments? Part I: General aspects and monoamine-based strategies. 2018; Eur Neuropsychopharmacol. 28: 445–456. doi: 10.1016/j.euroneuro.2017.10.032 29174531

19. Scuvée-Moreau J, Dresse A. Effect of trazodone on the firing rate of central monoaminergic neurons. Comparison with various antidepressants. 1982; Arch Int Pharmacodyn Ther 260: 299–301. 7165436

20. Ghanbari R, El Mansari M, Blier P. Sustained Administration of Trazodone Enhances Serotonergic Neurotransmission: In Vivo Electrophysiological Study in the Rat Brain. 2010a; J Pharmacol Exp Ther; 335: 197–206. doi: 10.1124/jpet.110.169417 20647493

21. Odagaki Y, Toyoshima R, Yamauchi T. Trazodone and its active metabolite m-chlorophenylpiperazine as partial agonists at 5-HT1A receptors assessed by [35S]GTPγS binding. 2005; J Psychopharmacol. 19: 235–241. doi: 10.1177/0269881105051526 15888508

22. Ghanbari R, El Mansari M, Blier P. Electrophysiological impact of trazodone on the dopamine and norepinephrine systems in the rat brain. 2012; Eur Neuropsychopharmacol. 22: 518–526. doi: 10.1016/j.euroneuro.2011.11.005 22154666

23. Baraban JM, Aghajanian GK. Noradrenergic innervation of serotonergic neurons in the dorsal raphe: demonstration by electron microscopic autoradiography. 1981; Brain Res. 204: 1–11. doi: 10.1016/0006-8993(81)90646-6 6166350

24. Peyron C, Luppi PH, Fort P, Rampon C, Jouvet M. Lower brainstem catecholamine afferents to the rat dorsal raphe nucleus. 1996; J Comp Neurol. 364: 402–413. doi: 10.1002/(SICI)1096-9861(19960115)364:3<402::AID-CNE2>3.0.CO;2-8 8820873

25. Baraban JM, Aghajanian GK. Suppression of firing activity of 5-HT neurons in the dorsal raphe by alpha-adrenoceptor antagonists. 1980; Neuropharmacology 19:, 355–363. doi: 10.1016/0028-3908(80)90187-2 6104308

26. Araragi N, Mlinar B, Baccini G, Gutknecht L, Lesch KP, Corradetti R. Conservation of 5-HT1A receptor-mediated autoinhibition of serotonin (5-HT) neurons in mice with altered 5-HT homeostasis. 2013; Front Pharmacol. 4 (97). doi: 10.3389/fphar.2013.00097 23935583

27. Montalbano A, Corradetti R, Mlinar B. Pharmacological Characterization of 5-HT1A Autoreceptor-Coupled GIRK Channels in Rat Dorsal Raphe serotonergic neurons. 2015a; PLoS One 10, e0140369. doi: 10.1371/journal.pone.0140369 26460748

28. Montalbano A, Waider J, Barbieri M, Baytas O, Lesch KP, Corradetti R, et al. Cellular resilience: serotonergic neurons in Tph2-/- mice retain normal firing behavior despite the lack of brain 5-HT. 2015b; Eur Neuropsychopharmacol. 25: 2022–2035. doi: 10.1016/j.euroneuro.2015.08.021 26409296

29. Mlinar B, Montalbano A, Piszczek L, Gross C, Corradetti R. Firing Properties of Genetically Identified Dorsal Raphe Serotonergic Neurons in Brain Slices. 2016; Front Cell Neurosci 10: 195. doi: 10.3389/fncel.2016.00195 27536220

30. Waeber C, Moskowitz MA. Autoradiographic visualisation of [3H]5-carboxamidotryptamine binding sites in the guinea pig and rat brain. 1995; Eur J Pharmacol. 283: 31–46. doi: 10.1016/0014-2999(95)00275-p 7498319

31. Boess FG, Martin IL Molecular biology of 5-HT receptors. 1994; Neuropharmacology 33: 275–317. doi: 10.1016/0028-3908(94)90059-0 7984267

32. Sundaram H, Newman-Tancredi A, Strange PG. Characterization of recombinant human serotonin 5HT1A receptors expressed in Chinese hamster ovary cells. [3H]spiperone discriminates between the G-protein-coupled and -uncoupled forms. 1993; Biochem Pharmacol. 45: 1003–1009. doi: 10.1016/0006-2952(93)90243-p 8461029

33. Gutknecht L, Kriegebaum C, Waider J, Schmitt A, Lesch KP. Spatio-temporal expression of tryptophan hydroxylase isoforms in murine and human brain: convergent data from Tph2 knockout mice. 2009; Eur Neuropsychopharmacol. 19: 266–82. doi: 10.1016/j.euroneuro.2008.12.005 19181488

34. Mlinar B, Montalbano A, Waider J, Lesch KP, Corradetti R. Increased functional coupling of 5-HT(1A) autoreceptors to GIRK channels in Tph2(-/-) mice. 2017; Eur Neuropsychopharmacol. 27:1258–1267. doi: 10.1016/j.euroneuro.2017.10.033 29126768

35. Kenakin T, Williams M. Defining and characterizing drug/compound function. 2014; Biochem Pharmacol. 87: 40–63. doi: 10.1016/j.bcp.2013.07.033 23954707

36. Berridge CW, Schmeichel BE, España RA. Noradrenergic modulation of wakefulness/arousal. 2012; Sleep Med Rev. 16: 187–197. doi: 10.1016/j.smrv.2011.12.003 22296742

37. Andrade R, Huereca D, Lyons JG, Andrade EM, McGregor KM. 5-HT1A Receptor-Mediated Autoinhibition and the Control of Serotonergic Cell Firing. 2015; ACS Chem Neurosci 6: 1110–1115. doi: 10.1021/acschemneuro.5b00034 25913021

38. Mlinar B, Tatini F, Ballini C, Nencioni S, Della Corte L, Corradetti R. Differential autoinhibition of 5-hydroxytryptamine neurons by 5-hydroxytryptamine in the dorsal raphe nucleus. 2005; Neuroreport 16: 1351–1355. doi: 10.1097/01.wnr.0000175249.25535.bf 16056138

39. Commons KG, Linnros SE. Delayed Antidepressant Efficacy and the Desensitization Hypothesis. 2019; ACS Chem Neurosci. doi: 10.1021/acschemneuro.8b00698 30807103

40. Vandermaelen CP, Aghajanian GK. Electrophysiological and pharmacological characterization of serotonergic dorsal raphe neurons recorded extracellularly and intracellularly in rat brain slices. 1983; Brain Res. 289: 109–119. doi: 10.1016/0006-8993(83)90011-2 6140982

41. Settimo L, Taylor D. Evaluating the dose-dependent mechanism of action of trazodone by estimation of occupancies for different brain neurotransmitter targets. 2018; J Psychopharmacol. 32: 96–104. doi: 10.1177/0269881117742101 29332554

42. Blier P, de Montigny C. Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone: electrophysiological studies in the rat brain. 1987; Synapse 1: 470–480. doi: 10.1002/syn.890010511 2905533

43. Hervás I, Vilaró MT, Romero L, Scorza MC, Mengod G, Artigas F. Desensitization of 5-HT(1A) autoreceptors by a low chronic fluoxetine dose effect of the concurrent administration of WAY-100635. 2001; Neuropsychopharmacol. 24: 11–20.

44. Karhu D, Groenewoud G, Potgieter MA, Mould DR. Dose proportionality of oncedaily trazodone extended-release caplets under fasting conditions. 2010; J Clin Pharmacol. 50: 1438–1449. doi: 10.1177/0091270009360979 20173086

45. Crespi F, Martin KF, Marsden CA. Measurement of extracellular basal levels of serotonin in vivo using nafion-coated carbon fibre electrodes combined with differential pulse voltammetry. 1988; Neuroscience 27: 885–896. doi: 10.1016/0306-4522(88)90191-1 3252175

46. Pazzagli M, Giovannini MG, Pepeu G. Trazodone increases extracellular serotonin levels in the frontal cortex of rats. 1999; Eur J Pharmacol. 383: 249–257. doi: 10.1016/s0014-2999(99)00644-5 10594316

47. Ghanbari R, El Mansari M, Blier P. Electrophysiological effects of the co-administration of escitalopram and bupropion on rat serotonin and norepinephrine neurons. 2010b; J Psychopharmacol. 24: 39–50. doi: 10.1177/0269881108095714 18719044

48. Sheehan DV, Croft HA, Gossen ER, Levitt RJ, Brullè C, Bouchard S, et al. Extended-release trazodone in major depressive disorder: a randomized, double-blind, placebo controlled study. 2009; Psychiatry 6: 20–33. 19724732

49. Fagiolini A, Comandini A, Catena Dell'Osso M, Kasper S. Rediscovering trazodone for the treatment of major depressive disorder. 2012; CNS Drugs. 26: 1033–49. doi: 10.1007/s40263-012-0010-5 23192413

50. Trulson ME, Jacobs BL. Raphe unit activity in freely moving cats: correlation with level of behavioural arousal. 1979; Brain Res. 163: 135–150. doi: 10.1016/0006-8993(79)90157-4 218676

51. Sakai K, Crochet S. Serotonergic dorsal raphe neurons cease firing by disfacilitation during paradoxical sleep. 2000; Neuroreport. 11: 3237–3241. doi: 10.1097/00001756-200009280-00037 11043555

52. Jacobs BL. Single unit activity of locus coeruleus neurons in behaving animals. 1986; Prog Neurobiol. 27: 183–194. 3529238

53. Fornal CA, Litto WJ, Metzler CW, Marrosu F, Tada K, Jacobs BL. Single-unit responses of serotonergic dorsal raphe neurons to 5-HT1A agonist and antagonist drug administration in behaving cats. 1994; J Pharmacol Exp Ther 270: 1345–1358. 7932189

54. Feige B, Baglioni C, Spiegelhalder K, Hirscher V, Nissen C, Riemann D. The microstructure of sleep in primary insomnia: an overview and extension. 2013; Int J Psychophysiol. 89: 171–180. doi: 10.1016/j.ijpsycho.2013.04.002 23583625


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