Hostname: page-component-78c5997874-ndw9j Total loading time: 0 Render date: 2024-11-17T06:14:32.179Z Has data issue: false hasContentIssue false
  • English
  • Français

Serotonin depletion reduces both acquisition and expression of context-conditioned fear

Published online by Cambridge University Press:  17 February 2021

S. Melker Hagsäter Open the ORCID record for S. Melker Hagsäter [Opens in a new window] ,
Robert Pettersson ,
Axel Holmäng  and
Elias Eriksson
Get access Rights & Permissions [Opens in a new window]

Abstract

Objective:

Whereas numerous experimental and clinical studies suggest a complex involvement of serotonin in the regulation of anxiety, it remains to be clarified if the dominating impact of this transmitter is best described as anxiety-reducing or anxiety-promoting. The aim of this study was to assess the impact of serotonin depletion on acquisition, consolidation, and expression of conditioned fear.

Methods:

Male Sprague–Dawley rats were exposed to foot shocks as unconditioned stimulus and assessed with respect to freezing behaviour when re-subjected to context. Serotonin depletion was achieved by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) (300 mg/kg daily × 3), (i) throughout the period from (and including) acquisition to (and including) expression, (ii) during acquisition but not expression, (iii) after acquisition only, and (iv) during expression only.

Results:

The time spent freezing was significantly reduced in animals that were serotonin-depleted during the entire period from (and including) acquisition to (and including) expression, as well as in those being serotonin-depleted during either acquisition only or expression only. In contrast, PCPA administrated immediately after acquisition, that is during memory consolidation, did not impact the expression of conditioned fear.

Conclusion:

Intact serotonergic neurotransmission is important for both acquisition and expression of context-conditioned fear.

Keywords

anxietyserotoninpsychopharmacology
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 33 , Issue 3 , June 2021 , pp. 148 - 155
Check for updates
Copyright
© The Author(s), 2021. Published by Cambridge University Press on behalf of Scandinavian College of Neuropsychopharmacology

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Amat, J, Matus-Amat, P, Watkins, LR and Maier, SF (1998). Escapable and inescapable stress differentially and selectively alter extracellular levels of 5-HT in the ventral hippocampus and dorsal periaqueductal gray of the rat. Brain Research 797, 12–22.CrossRefGoogle ScholarPubMed
Anagnostaras, SG, Wood, SC, Shuman, T, Cai, DJ, Leduc, AD, Zurn, KR, Zurn, JB, Sage, JR and Herrera, GM (2010). Automated assessment of pavlovian conditioned freezing and shock reactivity in mice using the video freeze system. Frontiers in Behavioral Neuroscience 4, 158.CrossRefGoogle ScholarPubMed
Angrini, M, Leslie, JC and Shephard, RA (1998). Effects of propranolol, buspirone, pCPA, reserpine, and chlordiazepoxide on open-field behavior. Pharmacology Biochemistry & Behavior 59, 387–397.CrossRefGoogle ScholarPubMed
Bauer, EP (2015). Serotonin in fear conditioning processes. Behavioural Brain Research 277, 68–77.CrossRefGoogle ScholarPubMed
Blanchard, RJ and Blanchard, DC (1969). Crouching as an index of fear. Journal of Comparative and Physiological Psychology 67, 370–375.CrossRefGoogle Scholar
Bocchio, M, McHugh, SB, Bannerman, DM, Sharp, T and Capogna, M (2016). Serotonin, Amygdala and fear: assembling the puzzle. Frontiers in Neural Circuits 10, 24.CrossRefGoogle ScholarPubMed
Bodnar, RJ, Kordower, JH, Wallace, MM and Tamir, H (1981). Stress and morphine analgesia: alterations following p-chlorophenylalanine. Pharmacology Biochemistry and Behavior 14, 645–651.CrossRefGoogle ScholarPubMed
Borelli, KG, Gargaro, AC, dos Santos, JM and Brandao, ML (2005). Effects of inactivation of serotonergic neurons of the median raphe nucleus on learning and performance of contextual fear conditioning. Neuroscience Letters 387, 105–110.CrossRefGoogle Scholar
Brauer, LH, Johanson, CE, Schuster, CR, Rothman, RB and de Wit, H (1996). Evaluation of phentermine and fenfluramine, alone and in combination, in normal, healthy volunteers. Neuropsychopharmacology 14, 233–241.CrossRefGoogle ScholarPubMed
Buhot, MC, Martin, S and Segu, L (2000). Role of serotonin in memory impairment. Annals of Medicine 32, 210–221.CrossRefGoogle ScholarPubMed
Coplan, JD, Gorman, JM and Klein, DF (1992). Serotonin related functions in panic-anxiety: a critical overview. Neuropsychopharmacology 6, 189–200.Google ScholarPubMed
Dai, JX, Han, HL, Tian, M, Cao, J, Xiu, JB, Song, NN, Huang, Y, Xu, TL, Ding, YQ and Xu, L (2008). Enhanced contextual fear memory in central serotonin-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 105, 11981–11986.CrossRefGoogle ScholarPubMed
Dazzi, L, Seu, E, Cherchi, G and Biggio, G (2005). Chronic administration of the SSRI fluvoxamine markedly and selectively reduces the sensitivity of cortical serotonergic neurons to footshock stress. European Neuropsychopharmacology 15, 283–290.CrossRefGoogle ScholarPubMed
Dringenberg, HC, Hargreaves, EL, Baker, GB, Cooley, RK and Vanderwolf, CH (1995). p-chlorophenylalanine-induced serotonin depletion: reduction in exploratory locomotion but no obvious sensory-motor deficits. Behavioural Brain Research 68, 229–237.CrossRefGoogle Scholar
Dudai, Y (2004). The neurobiology of consolidations, or, how stable is the engram? Annual Review of Psychology 55, 51–86.CrossRefGoogle ScholarPubMed
Eden, S, Bolle, P and Modigh, K (1979). Monoaminergic control of episodic growth hormone secretion in the rat: effects of reserpine, alpha-methyl-p-tyrosine, p-chlorophenylalanine, and haloperidol. Endocrinology 105, 523–529.CrossRefGoogle ScholarPubMed
Eriksson, E and Humble, M (1990). Serotonin in psychiatric pathophysiology. Biological Basis of Psychiatric Treatment 3, 66–119.Google Scholar
Esler, M, Lambert, E, Alvarenga, M, Socratous, F, Richards, J, Barton, D, Pier, C, Brenchley, C, Dawood, T, Hastings, J, Guo, L, Haikerwal, D, Kaye, D, Jennings, G, Kalff, V, Kelly, M, Wiesner, G and Lambert, G (2007). Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: reduction by a selective serotonin reuptake inhibitor. Stress 10, 295–304.CrossRefGoogle ScholarPubMed
Fanselow, MS (2000). Contextual fear, gestalt memories, and the hippocampus. Behavioural Brain Research 110, 73–81.CrossRefGoogle ScholarPubMed
Ferguson, J, Henriksen, S, Cohen, H, Mitchell, G, Barchas, J and Dement, W (1970). “Hypersexuality” and behavioral changes in cats caused by administration of p-chlorophenylalanine. Science 168, 499–501.CrossRefGoogle ScholarPubMed
Fibiger, HC, Mertz, PH and Campbell, BA (1972). The effect of para-chlorophenylalanine on aversion thresholds and reactivity to foot shock. Physiology & Behavior 8, 259–263.CrossRefGoogle ScholarPubMed
Fulford, AJ and Marsden, CA (2007). An intact dopaminergic system is required for context-conditioned release of 5-HT in the nucleus accumbens of postweaning isolation-reared rats. Neuroscience 149, 392–400.CrossRefGoogle ScholarPubMed
Furmark, T, Tillfors, M, Garpenstrand, H, Marteinsdottir, I, Langstrom, B, Oreland, L and Fredrikson, M (2004). Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia. Neuroscience Letters 362, 189–192.CrossRefGoogle ScholarPubMed
Graeff, FG (1994). Neuroanatomy and neurotransmitter regulation of defensive behaviors and related emotions in mammals. Brazilan Journal of Medical and Biological Research 27, 811–829.Google ScholarPubMed
Graeff, FG and Zangrossi, H Jr. (2010). The dual role of serotonin in defense and the mode of action of antidepressants on generalized anxiety and panic disorders. Central Nervous System Agents in Medical Chemistry 10, 207–217.CrossRefGoogle ScholarPubMed
Gutknecht, L, Popp, S, Waider, J, Sommerlandt, FM, Goppner, C, Post, A, Reif, A, van den Hove, D, Strekalova, T, Schmitt, A, Colavarsigmao, MB, Sommer, C, Palme, R and Lesch, KP (2015). Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice. Psychopharmacology (Berl) 232, 2429–2441.CrossRefGoogle Scholar
Hagsater, SM, Thoren, J, Pettersson, R and Eriksson, E (2019). Selective serotonin reuptake inhibition increases noise burst-induced unconditioned and context-conditioned freezing. Acta Neuropsychiatrica 31, 46–51.CrossRefGoogle ScholarPubMed
Hajos-Korcsok, E, Robinson, DD, Yu, JH, Fitch, CS, Walker, E and Merchant, KM (2003). Rapid habituation of hippocampal serotonin and norepinephrine release and anxiety-related behaviors, but not plasma corticosterone levels, to repeated footshock stress in rats. Pharmacology Biochemistry and Behavior 74, 609–616.CrossRefGoogle Scholar
Hashimoto, S, Inoue, T and Koyama, T (1999). Effects of conditioned fear stress on serotonin neurotransmission and freezing behavior in rats. European Journal of Pharmacology 378, 23–30.CrossRefGoogle ScholarPubMed
Hassell, JE Jr., Collins, VE, Li, H, Rogers, JT, Austin, RC, Visceau, C, Nguyen, KT, Orchinik, M, Lowry, CA and Renner, KJ (2019). Local inhibition of uptake2 transporters augments stress-induced increases in serotonin in the rat central amygdala. Neuroscience Letters 701, 119–124.CrossRefGoogle ScholarPubMed
Hindi Attar, C, Finckh, B and Buchel, C (2012). The influence of serotonin on fear learning. PLoS One 7, e42397.CrossRefGoogle ScholarPubMed
Hritcu, L, Clicinschi, M and Nabeshima, T (2007). Brain serotonin depletion impairs short-term memory, but not long-term memory in rats. Physiology & Behavior 91, 652–657.CrossRefGoogle Scholar
Inoue, T, Kitaichi, Y and Koyama, T (2011). SSRIs and conditioned fear. Progress in Neuropsychopharmacol and Biology Psychiatry 35, 1810–1819.CrossRefGoogle ScholarPubMed
Inoue, T, Tsuchiya, K and Koyama, T (1996). Serotonergic activation reduces defensive freezing in the conditioned fear paradigm. Pharmacology Biochemistry and Behavior 53, 825–831.CrossRefGoogle ScholarPubMed
Isosaka, T, Matsuo, T, Yamaguchi, T, Funabiki, K, Nakanishi, S, Kobayakawa, R and Kobayakawa, K (2015). Htr2a-expressing cells in the central Amygdala control the hierarchy between innate and learned fear. Cell 163, 1153–1164.CrossRefGoogle ScholarPubMed
Izumi, T, Ohmura, Y, Futami, Y, Matsuzaki, H, Kubo, Y, Yoshida, T and Yoshioka, M (2012). Effects of serotonergic terminal lesion in the amygdala on conditioned fear and innate fear in rats. European Journal of Pharmacology 696, 89–95.CrossRefGoogle ScholarPubMed
Johnson, PL, Lightman, SL and Lowry, CA (2004). A functional subset of serotonergic neurons in the rat ventrolateral periaqueductal gray implicated in the inhibition of sympathoexcitation and panic. Annals of the New York Academy of Sciences 1018, 58–64.CrossRefGoogle ScholarPubMed
Johnson, PL, Molosh, A, Fitz, SD, Arendt, D, Deehan, GA, Federici, LM, Bernabe, C, Engleman, EA, Rodd, ZA, Lowry, CA and Shekhar, A (2015). Pharmacological depletion of serotonin in the basolateral amygdala complex reduces anxiety and disrupts fear conditioning. Pharmacology Biochemistry and Behavior 138, 174–179.CrossRefGoogle ScholarPubMed
Kiyasova, V, Fernandez, SP, Laine, J, Stankovski, L, Muzerelle, A, Doly, S and Gaspar, P (2011). A genetically defined morphologically and functionally unique subset of 5-HT neurons in the mouse raphe nuclei. Journal of Neuroscience 31, 2756–2768.CrossRefGoogle ScholarPubMed
Koe, BK and Weissman, A (1966). p-Chlorophenylalanine: a specific depletor of brain serotonin. Journal of Pharmacology and Experimental Therapeutics 154, 499–516.Google Scholar
Kohler, C and Lorens, SA (1978). Open field activity and avoidance behavior following serotonin depletion: a comparison of the effects of parachlorophenylalanine and electrolytic midbrain raphe lesions. Pharmacology Biochemistry and Behavior 8, 223–233.CrossRefGoogle ScholarPubMed
Kubala, KH, McGinnis, MY, Anderson, GM and Lumia, AR (2008). The effects of an anabolic androgenic steroid and low serotonin on social and non-social behaviors in male rats. Brain Research 1232, 21–29.CrossRefGoogle ScholarPubMed
Landen, M, Erlandsson, H, Bengtsson, F, Andersch, B and Eriksson, E (2009). Short onset of action of a serotonin reuptake inhibitor when used to reduce premenstrual irritability. Neuropsychopharmacology 34, 585–592.CrossRefGoogle ScholarPubMed
Liu, Y, Jiang, Y, Si, Y, Kim, JY, Chen, ZF and Rao, Y (2011). Molecular regulation of sexual preference revealed by genetic studies of 5-HT in the brains of male mice. Nature 472, 95–99.CrossRefGoogle ScholarPubMed
Luyten, L, Schroyens, N, Hermans, D and Beckers, T (2014). Parameter optimization for automated behavior assessment: plug-and-play or trial-and-error? Frontiers in Behavioral Neuroscience 8, 28.CrossRefGoogle ScholarPubMed
Magierek, V, Ramos, PL, da Silveira-Filho, NG, Nogueira, RL and Landeira-Fernandez, J (2003). Context fear conditioning inhibits panic-like behavior elicited by electrical stimulation of dorsal periaqueductal gray. Neuroreport 14, 1641–1644.CrossRefGoogle ScholarPubMed
Marsden, CA and Curzon, G (1976). Studies on the behavioural effects of tryptophan and rho-chlorophenylalanine. Neuropharmacology 15, 165–171.CrossRefGoogle ScholarPubMed
Masuda, T, Nishikawa, H, Inoue, T, Toda, H, Nakagawa, S, Boku, S and Koyama, T (2013). 5-HT depletion, but not 5-HT1A antagonist, prevents the anxiolytic-like effect of citalopram in rat contextual conditioned fear stress model. Acta Neuropsychiatrica 25, 77–84.CrossRefGoogle Scholar
McGaugh, JL (2000). Memory--a century of consolidation. Science 287, 248–251.CrossRefGoogle ScholarPubMed
Melik, E, Babar-Melik, E, Ozgunen, T and Binokay, S (2000). Median raphe nucleus mediates forming long-term but not short-term contextual fear conditioning in rats. Behavioural Brain Research 112, 145–150.CrossRefGoogle Scholar
Miczek, KA, Altman, JL, Appel, JB and Boggan, WO (1975). Para-chlorophenylalanine, serotonin and killing behavior. Pharmacology Biochemistry and Behavior 3, 355–361.CrossRefGoogle Scholar
Mitsushima, D, Yamada, K, Takase, K, Funabashi, T and Kimura, F (2006). Sex differences in the basolateral amygdala: the extracellular levels of serotonin and dopamine, and their responses to restraint stress in rats. European Journal of Neuroscience 24, 3245–3254.CrossRefGoogle ScholarPubMed
Miyata, S, Shimoi, T, Hirano, S, Yamada, N, Hata, Y, Yoshikawa, N, Ohsawa, M and Kamei, J (2007). Effects of serotonergic anxiolytics on the freezing behavior in the elevated open-platform test in mice. Journal of Pharmacological Sciences 105, 272–278.CrossRefGoogle ScholarPubMed
Naslund, J, Studer, E, Nilsson, K, Westberg, L and Eriksson, E (2013). Serotonin depletion counteracts sex differences in anxiety-related behaviour in rat. Psychopharmacology (Berl) 230, 29–35.CrossRefGoogle ScholarPubMed
Naslund, J, Studer, E, Pettersson, R, Hagsater, M, Nilsson, S, Nissbrandt, H and Eriksson, E (2015). Differences in anxiety-like behavior within a batch of Wistar rats are associated with differences in serotonergic transmission, enhanced by acute SRI administration, and abolished by serotonin depletion. The International Journal of Neuropsychopharmacology 18, pyv018.CrossRefGoogle ScholarPubMed
Nikaido, Y, Yamada, J, Migita, K, Shiba, Y, Furukawa, T, Nakashima, T and Ueno, S (2016). cis-3-Hexenol and trans-2-hexenal mixture prevents development of PTSD-like phenotype in rats. Behavioural Brain Research 297, 251–258.CrossRefGoogle Scholar
Ogren, SO (1985). Evidence for a role of brain serotonergic neurotransmission in avoidance learning. Acta Physiologica Scandinavica, Supplementum 544, 1–71.Google ScholarPubMed
Ogren, SO and Berge, OG (1984). Test-dependent variations in the antinociceptive effect of p-chloroamphetamine-induced release of 5-hydroxytryptamine. Neuropharmacology 23, 915–924.CrossRefGoogle Scholar
Pettersson, R, Hagsater, SM and Eriksson, E (2016). Serotonin depletion eliminates sex differences with respect to context-conditioned immobility in rat. Psychopharmacology (Berlin) 233, 1513–1521.CrossRefGoogle ScholarPubMed
Ramirez, F, Moscarello, JM, LeDoux, JE and Sears, RM (2015). Active avoidance requires a serial basal amygdala to nucleus accumbens shell circuit. Journal of Neuroscience 35, 3470–3477.CrossRefGoogle ScholarPubMed
Rammsayer, T and Netter, P (1990). Personality related differences in response to 5-HT uptake inhibition. International Journal of Neuroscience 55, 99–106.CrossRefGoogle ScholarPubMed
Riess, BF (1945). A possible explanation of “Freezing” behavior in rats. Science 102, 570.CrossRefGoogle ScholarPubMed
Rok-Bujko, P, Krzascik, P, Szyndler, J, Kostowski, W and Stefanski, R (2012). The influence of neonatal serotonin depletion on emotional and exploratory behaviours in rats. Behavioural Brain Research 226, 87–95.CrossRefGoogle ScholarPubMed
Santucci, AC, Knott, PJ and Haroutunian, V (1996). Excessive serotonin release, not depletion, leads to memory impairments in rats. European Journal of Pharmacology 295, 7–17.CrossRefGoogle Scholar
Sinclair, LI, Christmas, DM, Hood, SD, Potokar, JP, Robertson, A, Isaac, A, Srivastava, S, Nutt, DJ and Davies, SJ (2009). Antidepressant-induced jitteriness/anxiety syndrome: systematic review. British Journal of Psychiatry 194, 483–490.CrossRefGoogle ScholarPubMed
Sorge, RE, Martin, LJ, Isbester, KA, Sotocinal, SG, Rosen, S, Tuttle, AH, Wieskopf, JS, Acland, EL, Dokova, A, Kadoura, B, Leger, P, Mapplebeck, JC, McPhail, M, Delaney, A, Wigerblad, G, Schumann, AP, Quinn, T, Frasnelli, J, Svensson, CI, Sternberg, WF and Mogil, JS (2014). Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nature Methods 11, 629–632.CrossRefGoogle ScholarPubMed
Tagliamonte, A, Tagliamonte, P, Gessa, GL and Brodie, BB (1969). Compulsive sexual activity induced by p-chlorophenylalanine in normal and pinealectomized male rats. Science 166, 1433–1435.CrossRefGoogle ScholarPubMed
Targum, SD and Marshall, LE (1989). Fenfluramine provocation of anxiety in patients with panic disorder. Psychiatry Research 28, 295–306.CrossRefGoogle ScholarPubMed
Tenen, SS (1967). The effects of p-chlorophenylalanine, a serotonin depletor, on avoidance acquisition, pain sensitivity and related behavior in the rat. Psychopharmacologia 10, 204–219.CrossRefGoogle ScholarPubMed
Voigt, JP, Rex, A, Sohr, R and Fink, H (1999). Hippocampal 5-HT and NE release in the transgenic rat TGR(mREN2)27 related to behavior on the elevated plus maze. European Neuropsychopharmacology 9, 279–285.CrossRefGoogle Scholar
Waider, J, Popp, S, Mlinar, B, Montalbano, A, Bonfiglio, F, Aboagye, B, Thuy, E, Kern, R, Thiel, C, Araragi, N, Svirin, E, Schmitt-Bohrer, AG, Corradetti, R, Lowry, CA and Lesch, KP (2019). Serotonin deficiency increases context-dependent fear learning through modulation of Hippocampal activity. Frontiers in Neuroscience 13, 245.CrossRefGoogle ScholarPubMed
Yokoyama, M, Suzuki, E, Sato, T, Maruta, S, Watanabe, S and Miyaoka, H (2005). Amygdalic levels of dopamine and serotonin rise upon exposure to conditioned fear stress without elevation of glutamate. Neuroscience Letters 379, 37–41.CrossRefGoogle ScholarPubMed
Yoshioka, M, Matsumoto, M, Togashi, H and Saito, H (1995). Effects of conditioned fear stress on 5-HT release in the rat prefrontal cortex. Pharmacology Biochemistry and Behavior 51, 515–519.CrossRefGoogle ScholarPubMed
Zanoveli, JM, Carvalho, MC, Cunha, JM and Brandao, ML (2009). Extracellular serotonin level in the basolateral nucleus of the amygdala and dorsal periaqueductal gray under unconditioned and conditioned fear states: an in vivo Microdialysis study. Brain Research 1294, 106–115.CrossRefGoogle Scholar
Zohar, J & Westenberg, HG (2000). Anxiety disorders: a review of tricyclic antidepressants and selective serotonin reuptake inhibitors. Acta Psychiatrica Scandinavica, Supplementum 403, 39–49.CrossRefGoogle ScholarPubMed