Effects of combined escitalopram and aripiprazole in rats: role of the 5-HT1a receptor
- 248 Downloads
Pre-clinical and clinical studies have suggested that the antidepressant efficacy of escitalopram (ESC) can be augmented by co-administration of aripiprazole (ARI).
To establish if the effects of ESC + ARI can be altered by modulating the 5-HT1a receptor.
Sprague-Dawley male rats received ESC + ARI (10 and 2 mg/kg/day, respectively, via osmotic or by cumulative injections), as well as the 5-HT1a antagonist WAY-100635 (WAY; 0.01–1 mg/kg) and the 5-HT1a agonist 8-OH-DPAT (DPAT; 0.3–1 mg/kg) prior to testing in locomotion chambers and in the forced swim test (FST). Expression of the 5-HT1a receptor mRNA in the dorsal raphe nucleus, hippocampus, septum, and entorhinal cortex was also assessed.
WAY generally synergized, while DPAT antagonized, the effect of ESC + ARI on motor activity. All groups showed significantly lower 5-HT1a mRNA in the dorsal raphe nucleus. In the hippocampus, ESC + ARI and WAY + ESC + ARI groups displayed equivalent elevations of 5-HT1a mRNA, but this was not observed in groups that received DPAT + ESC + ARI. Finally, the addition of ARI to ESC augmented the effect that ESC alone had on reducing immobility in the FST. Importantly, WAY antagonized this effect, while DPAT had no consequences.
Taken together, these results in rats indicate that the 5-HT1a receptor is involved in the behavioral and brain region-specific mRNA effects of ESC + ARI.
KeywordsEscitalopram Aripiprazole 5-HT1a receptor mRNA Psychomotor Forced swim Augmentation Antidepressant SSRI Depression
This study was part of the Canadian Biomarker Integration Network in Depression (CAN-BIND) program (www.canbind.ca). CAN-BIND is an Integrated Discovery Program carried out in partnership with, and financial support from, the Ontario Brain Institute, an independent non-profit corporation, funded partially by the Ontario government. The opinions, results, and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred.
Compliance with ethical standards
All experiments were approved by the Animal Care Committee of the University of Guelph and were carried out in accordance with recommendations provided by the Canadian Council on Animal Care.
Conflict of interest
The authors declare that they have no conflict of interest.
- Berman RM, Marcus RN, Swanink R et al (2007) The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry 68:843–853. https://doi.org/10.1093/acprof:oso/9780199641819.001.0001 CrossRefGoogle Scholar
- Berman RM, Fava M, Thase ME, Trivedi MH, Swanink R, McQuade RD, Carson WH, Adson D, Taylor L, Hazel J, Marcus RN (2009) Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants. CNS Spectr 14:197–206. https://doi.org/10.1017/S1092852900020216 CrossRefGoogle Scholar
- Branch AD, Unterwald EM, Lee SE, Kreek MJ (1992) Quantitation of preproenkephalin mRNA levels in brain regions from male fischer rats following chronic cocaine treatment using a recently developed solution hybridization assay. Mol Brain Res 14:231–238. https://doi.org/10.1016/0169-328X(92)90178-E CrossRefGoogle Scholar
- Carey RJ (2010) Serotonin and Basal Sensory–Motor Control In Muller, C & Jacobs, B (Ed.) Handbook of the Behavioral Neurobiology of Serotonin (pp 325-330). London, Elsevier Academic PressGoogle Scholar
- Carey RJ, Depalma G, Damianopoulos E et al (2004a) Dopaminergic and serotonergic autoreceptor stimulation effects are equivalent and additive in the suppression of spontaneous and cocaine induced locomotor activity. Brain Res 1019:134–143. https://doi.org/10.1016/j.brainres.2004.05.091 CrossRefGoogle Scholar
- El Mansari M, Sánchez C, Chouvet G et al (2005) Effects of acute and long-term administration of escitalopram and citalopram on serotonin neurotransmission: an in vivo electrophysiological study in rat brain. Neuropsychopharmacology 30:1269–1277. https://doi.org/10.1038/sj.npp.1300686 CrossRefGoogle Scholar
- Fabre V, Beaufour C, Evrard A, Rioux A, Hanoun N, Lesch KP, Murphy DL, Lanfumey L, Hamon M, Martres MP (2000) Altered expression and functions of serotonin 5-HT(1A) and 5-HT(1B) receptors in knock-out mice lacking the 5-HT transporter. Eur J Neurosci 12:2299–2310. https://doi.org/10.1046/j.1460-9568.2000.00126.x CrossRefGoogle Scholar
- Fava M, Mischoulon D, Losifescu D et al (2012) A double-blind, placebo-controlled study of aripiprazole adjunctive to antidepressant therapy among depressed outpatients with inadequate response to prior antidepressant therapy (ADAPT-A study). Psychother Psychosom 81:87–97. https://doi.org/10.1159/000332050 CrossRefGoogle Scholar
- Fletcher A, Forster EA, Bill DJ, Brown G, Cliffe IA, Hartley JE, Jones DE, McLenachan A, Stanhope KJ, Critchley DJP, Childs KJ, Middlefell VC, Lanfumey L, Corradetti R, Laporte AM, Gozlan H, Hamon M, Dourish CT (1995) Electrophysiological, biochemical, neurohormonal and behavioural studies with WAY-100635, a potent, selective and silent 5-HT1a receptor antagonist. Behav Brain Res 73:337–353. https://doi.org/10.1016/0166-4328(96)00118-0 CrossRefGoogle Scholar
- Hjorth S, Westlin D, Bengtsson HJ (1997) WAY100635-induced augmentation of the 5-HT-elevating action of citalopram: relative importance of the dose of the 5-HT(1A) autoreceptor blocker versus that of the 5-HT reuptake inhibitor. Neuropharmacology 36:461–465. https://doi.org/10.1016/S0028-3908(97)00050-6 CrossRefGoogle Scholar
- Kaminska K, Rogoz Z (2016) The antidepressant - and anxiolytic-like effects following co-treatment with escitalopram and risperidone in rats. J Physiol Pharmacol 67:471–480Google Scholar
- Marcus RN, McQuade RD, Carson WH et al (2008) The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol 28:156–165. https://doi.org/10.1097/JCP.0b013e31816774f9 CrossRefGoogle Scholar
- Müller CP, Carey RJ, De Souza Silva MA et al (2002) Cocaine increases serotonergic activity in the hippocampus and nucleus accumbens in vivo: 5-HT1a-receptor antagonism blocks behavioral but potentiates serotonergic activation. Synapse 45:67–77. https://doi.org/10.1002/syn.10083 CrossRefGoogle Scholar
- Nelson JC, Pikalov A, Berman RM (2008) Augmentation treatment in major depressive disorder: focus on aripiprazole. Neuropsychiatr Dis Treat 4:937–948Google Scholar
- Nelson JC, Thase ME, Bellocchio EE, Rollin LM, Eudicone JM, McQuade RD, Marcus RN, Berman RM, Baker RA (2012) Efficacy of adjunctive aripiprazole in patients with major depressive disorder who showed minimal response to initial antidepressant therapy. Int Clin Psychopharmacol 27:125–133. https://doi.org/10.1097/YIC.0b013e3283502791 CrossRefGoogle Scholar
- Ozaki N, Otsubo T, Kato M, Higuchi T, Ono H, Kamijima K, ADMIRE Study Group (2015) Efficacy of aripiprazole augmentation in Japanese patients with major depressive disorder: a subgroup analysis and Montgomery–Åsberg Depression Rating Scale and Hamilton Rating Scale for depression item analyses of the aripiprazole depression multicenter efficacy study. Psychiatry Clin Neurosci 69:34–42. https://doi.org/10.1111/pcn.12214 CrossRefGoogle Scholar
- Stark AD, Jordan S, Allers KA, Bertekap RL, Chen R, Mistry Kannan T, Molski TF, Yocca FD, Sharp T, Kikuchi T, Burris KD (2007) Interaction of the novel antipsychotic aripiprazole with 5-HT1a and 5-HT2a receptors: functional receptor-binding and in vivo electrophysiological studies. Psychopharmacology 190:373–382. https://doi.org/10.1007/s00213-006-0621-y CrossRefGoogle Scholar