Research Paper Article de recherche Return to September 5, 2000 Table of Contents Effects of sustained (±)pindolol administration on serotonin neurotransmission in rats Nasser Haddjeri, PhD; Pierre Blier, MD, PhD Haddjeri — Centre de recherche en sciences neurologiques, Université de Montréal, Montreal, Que.; Blier — Department of Psychiatry, Brain Institute, University of Florida, Gainesville, Fla. β Objective: Given reports that (±)pindolol, a -adrenergic–5-HT1A/1B receptor antagonist, accelerates the onset of the therapeutic effect of certain antidepressant drugs in major depression, the aim of this study was to assess the effect of sustained (±)pindolol administration on the sensitivity of pre- and postsynaptic 5-HT1A receptors, terminal 5-HT1B autoreceptors and on overall 5-HT neurotransmission. Design: Prospective animal study. Animals: Sprague-Dawley rats. Outcome measures: Modifications of the sen- sitivity of somatodendritic and postsynaptic 5-HT1A receptors using in vivo electrophysiological paradigms in animals treated with vehicle or (±)pindolol (20 mg/kg/day, subcutaneously) through osmotic minipumps for 2 weeks. Results: (±)Pindolol attenuated the suppressant effect of the 5-HT autoreceptor agonist lysergic acid diethylamide (LSD) on the firing activity of 5-HT neurons, suggesting that (±)pindolol antago- nized somatodendritic 5-HT1A autoreceptors in the dorsal raphe nucleus. However, following a 2-day washout period, the suppressant effect of LSD was still attenuated, indicating rather a desensitization of 5- HT1A autoreceptors had occurred. In the CA3 region of the dorsal hippocampus, (±)pindolol treatment did not modify the responsiveness of postsynaptic 5-HT1A receptors to microiontophoretic applications of 5- HT. Moreover, such a treatment modified neither the effectiveness of the electrical stimulation of 5-HT fibers nor the function of terminal 5-HT autoreceptors. Finally, the administration of the selective 5-HT1A receptor antagonist WAY 100635 (100 µg/kg, intravenously) did not increase the firing activity of dorsal hippocampus CA3 pyramidal neurons in rats treated with (±)pindolol, thus failing to reveal the enhanced tonic activation of postsynaptic 5-HT1A receptors associated with major classes of antidepressant treat- ments. Conclusion: Prolonged administration of (±)pindolol by itself is not sufficient to enhance overall 5-HT neurotransmission; pindolol should therefore not be endowed with intrinsic antidepressant activity. Although pindolol is capable of antagonizing the 5-HT1A autoreceptor upon the initiation of a 5-HT reup- take-blocker treatment, it also induces a desensitization of this 5-HT1A autoreceptor, which could explain why patients do not relapse upon its discontinuation when they continue taking a 5-HT reuptake blocker. Objectif : Des études cliniques ont récemment démontré que le (±)pindolol, un antagoniste des récep- β teurs -adrenergic/5-HT1A/1B, accélérait la réponse thérapeutique de certains médicaments antidépresseurs chez des patients atteints de dépression majeure. Le but de la présente étude était d’évaluer les effets d’une administration prolongée de (±)pindolol sur la sensibilité des récepteurs pré et postsynaptiques 5-HT1A, Correspondence to: Dr. Pierre Blier, Department of Psychiatry, Brain Institute, University of Florida, PO Box 100256, Gainesville FL 32610; fax 352 392-2579 Medical subject headings: antidepressant agents; depression; lysergic acid diethylamide; pindolol; rats, Sprague-Dawley; receptors, serotonin J Psychiatry Neurosci 2000;25(4):378-88. Submitted July 19, 1999 Accepted Apr. 5, 2000 © 2000 Canadian Medical Association 378 Revue de psychiatrie et de neuroscience Vol. 25, no 4, 2000 (±)Pindolol and 5-HT neurotransmission celle des autorécepteurs 5-HT1B terminaux ainsi que sur la neurotransmission serotoninèrgique du cerveau de rat. Conception : Étude prospective sur des animaux. Animaux : Rats males Sprague-Dawley. Mesures des résul- tats : Modifications de la sensibilité des récepteurs 5-HT1A somatodendritiques et postsynaptiques en utilisant des méthodes électrophysiologiques in vivo chez des rats contrôles et traités par le (±)pindolol pour une période de 2 semaines à une dose de 20 mg/kg/jour (s.c.) en utilisant des mini-pompes osmotiques. Résultats : Un traite- ment à long-terme avec du (±)pindolol a atténué l’effet inhibiteurs du LSD, un agoniste des autorecepteurs 5-HT, sur la fréquence de décharge des neurones 5-HT du noyau du raphé dorsal, ce qui suggère un antagonisme des autorécepteurs somatodendritiques 5-HT1A. Toutefois, après une période d’écimination de 2 jours, l’effet inhibi- teur du LSD était toujours atténué, ce qui indique plutôt une désensibilisation des autorécepteurs 5-HT1A. Dans la région CA3 de l’hippocampe dorsal, des applications microiontophorétiques de 5-HT ont révelé que le traite- ment au (±)pindolol ne modifiait pas les réponses des récepteurs postsynaptiques 5-HT1A. De plus, un tel traite- ment ne changeait ni l’efficacité des stimulations électriques des fibres 5-HT ni la fonction autorecepteurs 5-HT terminaux. Finalement, l’administration intraveineuse du WAY 100635 (100 µg/kg), un antagoniste sélectif des récepteurs 5-HT1A, n’augmentait pas la fréquence de décharge des neurones des neurones pyramidaux CA3 de l’hippocampe dorsal chez des traités par le (±)pindolol, ne dévoilant pas une augmentation de l’activation tonique des récepteurs postsynaptiques 5-HT1A, comme c’est le cas pour les traitements antidépresseurs. Conclusion : Ces résultats indiquent qu’une administration prolongée de (±)pindolol en soi n’est pas suffisante pour augmenter la neurotransmission 5-HT et que cet agent serait dépourvu d’activité antidépressive. Bien que le pindolol soit capable d’antagoniser les autorécepteurs 5-HT1A dès le début de l’administration soutenue d’un bloqueur de la recapture de 5-HT, il produit également leur désensibilisation. Ceci expliquerait le fait que les patients ne Introduction SSRIs on extracellular 5-HT concentration by prevent- ing the activation of somatodendritic 5-HT1A autore- Although the pathophysiology of major depression has ceptors.14,15 Paradoxically, however, the active enan- not been elucidated, there is a growing body of evi- tiomer, (–)pindolol, possesses some partial agonist 16 dence that supports the involvement of the serotonergic activity at human 5-HT1A receptors, and it has been (5-HT) system in the therapeutic effect of antidepres- shown that its intravenous administration can sant treatments.1,2 Various classes of antidepressant decrease the firing activity of dorsal raphe 5-HT neu- treatments enhance 5-HT neurotransmission with a rons in freely-moving cats and anesthetised rats.17–19 time course that is consistent with their delayed thera- These results appear incompatible with a potentiation peutic effect. This would be mediated via different of extracellular 5-HT levels in postsynaptic structures mechanisms such as postsynaptic sensitization to 5-HT, resulting from 5-HT1A autoreceptor blockade by pin- desensitization of the somatodendritic or terminal 5-HT dolol when given in combination with SSRIs.14 α autoreceptors, or both, or a desensitization of 2-adren- Nevertheless, a biphasic effect of pindolol on the firing ergic heteroreceptors located on 5-HT terminals.1,3 activity of 5-HT neurons has been reported recently. A novel strategy to accelerate the antidepressant At low doses, (±)pindolol acts as a somatodendritic 5- response of medications acting on 5-HT neurons is to HT1A autoreceptor antagonist, but at a higher dose, it combine the arylalkylamine (±)pindolol, a β-adrener- decreases the firing rate of 5-HT neurons, in part by gic–5-HT1A/1B receptor antagonist, with a selective sero- attenuating the tonic excitatory input from noradren- tonin reuptake inhibitor (SSRI), a monoamine oxidase ergic neurons to 5-HT neurons.19 inhibitor (MAOI) or a 5-HT1A receptor agonist from the To mimic as much as possible the clinical condition in beginning of a treatment to obtain a more rapid onset which pindolol has been given 3 times daily in double- of antidepressant action.4 Although negative results blind trials, we treated rats with (±)pindolol for 2 weeks have been reported by one group,5,6 there are now 7 and used in vivo electrophysiological paradigms in the placebo-controlled studies showing that this approach rat dorsal raphe and dorsal hippocampus to assess the can result in a rapid onset of action and, in some cases, effect of sustained treatment with a constant infusion of a greater efficacy in treating major depression.7–13 (±)pindolol on the sensitivity of pre- and postsynaptic Accordingly, preclinical studies have shown that 5-HT1A receptors and terminal 5-HT1B autoreceptors and (±)pindolol can potentiate the enhancing effect of on overall 5-HT neurotransmission. Vol. 25, no 4, 2000 Journal of Psychiatry & Neuroscience 379 Haddjeri and Blier Methods mean of firing rate of neurons from about 1 to 2 minutes before the intravenous administration of the drugs and Male Sprague-Dawley rats (Charles River Laboratories, a mean after, until a plateau was reached. A percentage St-Constant, Que.) weighing 250 to 300 g were kept under change was then calculated. standard laboratory conditions (12-hour light–dark cycle with free access to food and water). Groups of 12 to 22 rats Recordings from CA3 dorsal hippocampus were treated for 2 weeks with (±)pindolol (20 pyramidal neurons mg/kg/day) or vehicle (saline), delivered by osmotic minipumps (ALZA, Palo Alto, Calif.) inserted subcuta- Recording