Abstract
The increase of extracellular 5-HT in brain terminal regions produced by the acute administration of 5-HT reuptake inhibitors (SSRI's) is hampered by the activation of somatodendritic 5-HT1A autoreceptors in the raphe nuclei. The present in vivo electrophysiological studies were undertaken, in the rat, to assess the effects of the coadministration of venlafaxine, a dual 5-HT/NE reuptake inhibitor, and (-)pindolol on pre- and postsynaptic 5-HT1A receptor function. The acute administration of venlafaxine and of the SSRI paroxetine (5 mg/kg, i.v.) induced a suppression of the firing activity of dorsal hippocampus CA3 pyramidal neurons. This effect of venlafaxine was markedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective β-adrenoceptor antagonist metoprolol (15 mg/kg, i.p.). That this effect of venlafaxine was mediated by an activation of postsynaptic 5-HT1A receptors was suggested by its complete reversal by the 5-HT1A antagonist WAY 100635 (100 μg/kg, i.v.). A short-term treatment with VLX (20 mg/kg/day × 2 days) resulted in a ca. 90% suppression of the firing activity of 5-HT neurons in the dorsal raphe nucleus. This was prevented by the coadministration of (-)pindolol (15 mg/kg/day × 2 days). Taken together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HT1A receptors resulting from 5-HT reuptake inhibition probably by blocking the somatodendritic 5-HT1A autoreceptor, but not its postsynaptic congener. These results support and extend previous findings providing a biological substratum for the efficacy of pindolol as an accelerating strategy in major depression.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Ablad B, Carlsson E, Ek L . (1973): Pharmacological studies of two new cardioselective adrenergic beta-receptor antagonists. Life Sci 12: 107–119
Adell A, Artigas F . (1991): Differential effects of clomipramine given locally or systemically on extracellular 5-hydroxytryptamine in raphe nuclei and frontal cortex. An in vivo brain microdialysis study. Naunyn-Schmiedeberg's Arch Pharmacol 343: 237–244
Aghajanian GK . (1978): Feedback regulation of central monoaminergic neurons: Evidence from single cell recording studies. In Youdim MBH, Lovenberg W, Sharman DF, Lagnado JR (eds), Essays in Neurochemistry and Neuropharmacology. New-York, John Wiley and Sons, pp 1–32
Andrade R, Malenka RC, Nicoll RA . (1986): A G protein couples serotonin and GABAB receptors to the same channels in hippocampus. Science 234: 1261–1265
Artigas F . (1993): 5-HT and antidepressants: New views from microdialysis studies. Trends Pharmacol Sci 14: 262
Assié MB, Koek W . (1996): (−)-Pindolol and (±)-tertatolol affect rat hippocampal 5-HT levels through mechanisms involving not only 5-HT1A, but also 5-HT1B receptors. Neuropharmacology 35: 213–222
Bel N, Artigas F . (1993): Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei. Synapse 15: 243–245
Berman RM, Darnell AM, Miller HL, Anand A, Charney DS . (1997): Effect of pindolol in hastening response to fluoxetine in the treatment of major depression: A double-blind, placebo-controlled trial. Am J Psychiatry 154: 37–43
Béïque JC, de Montigny C, Blier P, Debonnel G . (1998a): Blockade of 5-Hydroxytryptamine and noradrenaline uptake by venlafaxine: A comparative study with paroxetine and desipramine. Br J Pharmacol 125: 526–532
Béïque JC, de Montigny C, Blier P, Debonnel G . (1999): Venlafaxine: Discrepancy between in vivo 5-HT and NE reuptake blockade and affinity for reuptake sites. Synapse 32: 198–211
Béïque JC, Lavoie N, de Montigny C, Debonnel G . (1998b): Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters. Eur J Pharmacol 349: 129–132
Blier P, de Montigny C . (1994): Current advances and trends in the treatment of depression. Trends Pharmacol Sci 15: 220–226
Blier P, de Montigny C, Tardif D . (1984): Effects of the two antidepressant drugs mianserin and indalpine on the serotoninergic system: Single cell studies in the rat. Psychopharmacology 84: 242–249
Bordet R, Thomas P, Dupuis B . (1998): Effect of pindolol on onset of action of paroxetine in the treatment of major depression: Intermediate analysis of a double-blind, placebo-controlled trial. Am J Psychiatry 155: 1346–1351
Chaput Y, de Montigny C, Blier P . (1986): Effects of a selective 5-HT reuptake blocker, citalopram, on the sensitivity of 5-HT autoreceptors: Electrophysiological studies in the rat. Naunyn-Schmiedeberg's Arch Pharmacol 33: 342–349
Clifford EM, Gartside SE, Umbers V, Cowen PJ, Hajós M, Sharp T . (1998): Electrophysiological and neurochemical evidence that pindolol has agonist properties at the 5-HT1A autoreceptor in vivo. Br J Pharmacol 124: 206–212
Corradetti R, Laaris N, Hanoun N, Laporte AM, Le Poul E, Hamon M, Lanfumey L . (1998): Antagonist properties of (-)-pindolol and WAY 100635 at somatodendritic and postsynaptic 5-HT1A receptors in the rat brain. Br J Pharmacol 123: 449–462
Curet O, de Montigny C, Blier P . (1992): Effect of desipramine and amphetamine on noradrenergic neurotransmission: Electrophysiological studies in the rat brain. Eur J Pharmacol 221: 59–70
de Montigny C, Blier P . (1992): Electrophysiological properties of 5-HT1A receptors and of 5- HT1A agonists. In Stahl SM, Gastpar M, Keppel Hesselink JM, Traber J (eds), Serotonin 1A receptors in Depression and Anxiety. New York, Raven Press, pp 83–98
de Montigny C, Blier P, Caillé G, Kouassi E . (1981): Pre- and postsynaptic effect of zimelidine and norzimelidine on the serotonergic system: single cell studies in the rat. Acta Psychiatr Scand 63: S79–S80
de Montigny C, Chaput Y, Blier P . (1992): Classical and novel targets for antidepressant drugs. In Mendlewicz J, Brunello N, Langer SZ, Racagni G (eds), New pharmacological approach to the therapy of depressive disorders. Basel, S. Karger, pp 8–17
de Montigny C, Silverstone P.H, Bakish D, Blier P, Debonnel G . (1999): Venlafaxine in treatment-resistant major depression: A Canadian multicentre open-label trial. J Clin Psychopharmacol 19: 401–406
Derivan A, Entsuah AR, Kikta D . (1995): Venlafaxine: Measuring the onset of antidepressant action. Psychopharmacol Bull 31: 439–447
Dreshfield LJ, Wong DT, Perry KW, Engleman EA . (1996): Enhancement of fluoxetine-dependent increase of extracellular serotonin (5-HT) levels by (-)-pindolol, an antagonist at 5-HT1A receptors. Neurochem Res 21: 557–562
Engel G, Göthert M, Hoyer D, Schlicker E, Hillenbrand K . (1986): Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT1B binding sites. Naunyn- Schmiedebergs Arch Pharmacol 332: 1–7
Fink K, Zentner J, Göthert M . (1995): Subclassification of presynaptic 5-HT autoreceptors in the human cerebral cortex as 5-HT1D receptors. Naunyn-Schmiedeberg's Arch Pharmacol 352: 451–454
Fletcher A, Forster EA, Brown G, Cliffe IA, Hartley JE, Jones DE, McLenachan A, Stanhope KJ, Critchley DJP, Childs KJ, Middlefell VC, Lanfumey L, Corradeti R, Laporte A-M, Gozlan H, Hamon M, Dourish CT . (1996): Electrophysiological, biochemical, neurohormonal and behavioral studies with WAY 100635, a potent, selective and silent 5-HT1A receptor antagonist. Behav Brain Res 73: 337–353
Fornal CA, Martin FJ, Metzler CW, Jacobs BL . (1997): Pindolol suppressess serotonergic neuronal activity activity (by a WAY 100635-sensitive mechanism) and does not block the neuronal inhibition produced by 8-OH-DPAT in awake cats. Soc Neurosci Abstr 23: 973
Forster EA, Cliffe IA, Bill DJ, Dover GM, Jones D, Reilly Y, Fletcher A . (1995): A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635. Eur J Pharmacol 281: 81–88
Gartside SE, Umbers V, Hajos M, Sharp T . (1995): Interaction between a selective 5-HT1A receptor antagonist and an SSRI in vivo: Effects on 5-HT cell firing and extracellular 5- HT. Br J Pharmacol 115: 1064–1070
Gur E, Dremencov E, Lerer B, Newman ME . (1999): Venlafaxine: acute and chronic effects on 5-hydroxytryptamine levels in rat brain in vivo. Eur J Pharmacol 372: 17–24
Haddjeri N, Blier P, de Montigny C . (1998a): Long-term antidepressant treatments result in a tonic activation of forebrain 5-HT1A receptors. J Neurosci 18: 10150–10156
Haddjeri N, de Montigny C, Blier P . (1998b): Modulation of the firing activity of rat serotonin and noradrenaline neurons by (±)pindolol. Biol Psychiatry 45: 1163–1169
Hadrava V, Blier P, Dennis T, Ortemann C, de Montigny C . (1995): Characterization of 5-hydroxytryptamine1A properties of flesinoxan: In vivo electrophysiology and hypothermia study. Neuropharmacology 34: 1311–1326
Haigler HJ, Aghajanian GK . (1974): Lysergic acid diethylamide and serotonin: A comparison of effects on serotonergic neurons receiving a serotonergic input. J Pharmacol Exp Ther 168: 688–699
Hajós M, Gartside SE, Sharp T . (1995): Inhibition of median and dorsal raphe neurones following administration of the selective serotonin reuptake inhibitor paroxetine. Naunyn-Schmiedeberg's Arch Pharmacol 351: 624–629
Hartig PR, Branchek TA, Weinshank RL . (1992): A subfamily of 5-HT1D receptor genes. Trends Pharmacol Sci 13: 152–159
Hartig PR, Hoyer D, Humphrey PPA, Martin GR . (1996): Alignement of receptor nomenclature with the human genome: Classification of 5-HT1B and 5-HT1D receptor subtypes. Trends Pharmacol Sci 17: 103–105
Hjorth S . (1993): Serotonin 5-HT1A autoreceptor blockade potentiates the ability of the 5-HT reuptake inhibitor citalopram to increase nerve terminal output of 5-HT in vivo: A microdialysis study. J Neurochem 60: 776–779
Hjorth S, Bengtsson HJ, Milano S . (1996): Raphe 5-HT1A autoreceptors, but not postsynaptic 5-HT1A receptors or b-adrenoceptors, restrain the citalopram-induced increase in extracellular 5-hydroxytryptamine in vivo.. Eur J Pharmacol 316: 43–47
Hoyer D, Engel G, Kalkman HO . (1985): Characterization of the 5-HT1B recognition site in rat brain: Binding studies with (-)[125I]iodocyanopindolol. Eur J Pharmacol 118: 1–12
Invernizzi R, Bramante M, Samanin R . (1995): Extracellular concentrations of serotonin in the dorsal hippocampus after acute and chronic treatment with citalopram. Brain Res 696: 62–66
Kandel ER, Spencer WA . (1961): Electrophysiology of hippocampal neurons. II. After potentials and repetitive firing. J Neurophysiol 24: 243–259
Kreiss DS, Lucki I . (1995): Effects of acute and repeated administration of antidepressant drugs on extracellular levels of 5-hydroxytryptamine measured in vivo.. J Pharmacol Exp Ther 274: 866–876
Kurtz N . (1992): Efficacy of azapirones in depression. In Stahl SM, Gastpar M, Keppel Hesselink JM, Traber J (eds), Serotonin 1A receptors in Depression and Anxiety. New York, Raven Press, pp 163–170
Lacroix D, Blier P, Curet O, de Montigny C . (1991): Effects of long-term desipramine administration on noradrenergic neurotransmission: Electrophysiological studies in the rat brain. J Pharmacol Exp Ther 257: 1081–1090
Maes M, Vandoolaeghe E, Desnyder R . (1996): Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. J Aff Dis 41: 201–210
Malagie I, Trillat AC, Jacquot C, Gardier AM . (1995): Effects of acute fluoxetine on extracellular serotonin levels in the raphe: An in vivo microdialysis study. Eur J Pharmacol 286: 213–217
Muth EA, Haskins JT, Moyer JA, Husbands GE, Nielsen ST, Sigg EB . (1986): Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative. Biochem Pharmacol 35: 4493–4497
Newman-Tancredi A, Chaput C, Gavaudan S, Verrièle L, Millan MJ . (1998): Agonist and antagonist actions of (-)pindolol at recombinant, human serotonin1A (5-HT1A) receptors. Neuropsychopharmacology 18: 395–398
Nierenberg AA, Feighner JP, Rudolph R, Cole JO, Sullivan J . (1994): Venlafaxine for treatment-resistant unipolar depression. J Clin Psychopharmacol 14: 419–423
Parker EM, Grisel DA, Iben LG, Shapiro RA . (1993): A single amino acid difference accounts for the pharmacological distinctions between the rat and human 5-hydroxytryptamine1B receptors. J Neurochem 60: 380–383
Pérez V, Gilaberte I, Faries D, Alvarez E, Artigas F . (1997): Randomised, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet 349: 1594–1597
Piñeyro G, Blier P, Dennis T, de Montigny C . (1994): Desensitization of the neuronal 5-HT carrier following its long-term blockade. J Neurosci 14: 3036–3047
Ranck JB . (1973): Studies of single neurons in dorsal hippocampal formation and septum in unrestrained rats. I. Behavioral and firing repertoires. Exp Neurol 41: 461–531
Romero L, Artigas F . (1997): Preferential potentiation of the effects of serotonin uptake inhibitors by 5-HT1A receptor antagonist in the dorsal raphe pathway: Role of somatodendritic autoreceptors. J Neurochem 68: 2593–2603
Romero L, Bel N, Artigas F, de Montigny C, Blier P . (1996): Effect of pindolol on the function of pre- and postsynaptic 5-HT1A receptors: In vivo microdialysis and electrophysiological studies in the rat brain. Neuropsychopharmacology 15: 349–360
Rueter LE, de Montigny C, Blier P . (1998): In vivo electrophysiological assessment of the agonistic properties of flibanserin at pre- and postsynaptic 5-HT1A receptors in the rat brain. Synapse 29: 392–405
Rutter JJ, Gundlah C, Auerbach SB . (1995): Systemic uptake inhibition decreases serotonin release via somatodendritic autoreceptor activation. Synapse 20: 225–233
Schoeffter P, Hoyer D . (1989): 5-Hydroxytryptamine 5-HT1B and 5-HT1D receptors mediating inhibition of adenylate cyclase activity. Naunyn-Schmiedeberg's Arch Pharmacol 340: 285–292
Sharp T, Umbers V, Gartside SE . (1997): Effect of a selective 5-HT reuptake inhibitor in combination with 5-HT1A and 5-HT1B receptor antagonists on extracellular 5-HT in rat frontal cortex in vivo.. Br J Pharmacol 121: 941–946
Tome MB, Isaac MT, Harte R, Holland C . (1997): Paroxetine and pindolol: A randomized trial of serotonergic autoreceptor blockade in the reduction of antidepressant latency. Int Clin Psychopharmacol 12: 81–89
Voigt JP, Laurie DJ, Seeburg PH, Bach A . (1991): Molecular cloning and characterization of a rat brain cDNA encoding a 5-hydroxytryptamine1B receptor. EMBO J 10: 4017–4023
Wang RY, de Montigny C, Gold BI, Roth RH, Aghajanian GK . (1979): Denervation supersensitivity to serotonin in rat forebrain: Single cell studies. Brain Res 178: 479–497
Weinshank RL, Zgombick JM, Macchi MJ, Branchek TA, Hartig PR . (1992): Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT1Da and 5-HT1Db . Proc Natl Acad Sci USA 89: 3630–3634
Zanardi R, Artigas F, Franchini L, Sforzini L, Gasperini M, Smeraldi E, Perez J . (1997): How long should pindolol be associated with paroxetine to improve the antidepressant response? J Clin Psychopharmacol 17: 446–450
Zanardi R, Franchini L, Gasperini M, Lucca A, Smeraldi E, Perez J . (1998): Faster onset of action of fluvoxamine in combination with pindolol in the treatment of delusional depression: A controlled study. J Clin Psychopharmacol 18: 441–446
Acknowledgements
This work was supported by the Medical Research Council of Canada (MRC; grants MA 6444 and MT 11014) and by Wyeth-Ayerst Research. J.C.B. is in receipt of a fellowship from the Fonds de la Recherche en Santé du Québec (FRSQ); P.B. is recipient of a MRC Scientist award; and G.D. is recipient of a Scholarship from the FRSQ.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Béïque, JC., Blier, P., de Montigny, C. et al. Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine. Neuropsychopharmacol 23, 294–306 (2000). https://doi.org/10.1016/S0893-133X(00)00112-3
Received:
Revised:
Accepted:
Issue date:
DOI: https://doi.org/10.1016/S0893-133X(00)00112-3
Keywords
This article is cited by
-
Psychopharmacological properties and therapeutic profile of the antidepressant venlafaxine
Psychopharmacology (2022)
-
Catecholaminergic and opioidergic system mediated effects of reboxetine on diabetic neuropathic pain
Psychopharmacology (2020)
-
In vivo electrophysiological recordings of the effects of antidepressant drugs
Experimental Brain Research (2019)
-
Pharmacogenetics of antidepressive treatment
European Archives of Psychiatry and Clinical Neuroscience (2010)
-
Differential role of 5-HT1A and 5-HT1B receptors on the antinociceptive and antidepressant effect of tramadol in mice
Psychopharmacology (2006)
