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Effect of paroxetine on enhanced contextual fear induced by single prolonged stress in rats

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Abstract

Rationale

Single prolonged stress (SPS) is an animal model of posttraumatic stress disorder (PTSD) that can reproduce enhanced hypothalamo-pituitary-adrenal negative feedback.

Objectives

We examined whether SPS can produce an enhanced psychophysiological reactivity to laboratory stressors unrelated to trauma and whether paroxetine (PRX) can alleviate the enhanced anxiety and fear response in rats subjected to SPS. Furthermore, the effect of PRX on pain sensitivity was examined in rats with and without SPS.

Methods

Rats were subjected to SPS (restraint for 2 h, forced swim for 20 min, and ether anesthesia) and then kept undisturbed for 14 days. After that, contextual fear response was assessed. Twenty-four hours after foot shock conditioning, freezing behavior was measured during reexposure to the shock environment for 3 min. Pain sensitivity was assessed by the flinch–jump test. PRX (0.01, 0.03, or 0.1 mg/mL) was chronically administered orally in drinking water.

Results

Rats subjected to SPS showed a significant increase in contextual freezing compared to rats without SPS. Chronic administration of PRX at concentrations of 0.03 and 0.1 mg/mL (which produced serum concentrations similar to those that are clinically relevant) caused significant suppression of the enhanced contextual freezing. Acute administration of PRX at a dose producing clinically relevant serum concentrations did not affect the enhanced freezing.

Conclusions

Our results suggest that SPS can reproduce behavioral alteration similar to that observed in patients with PTSD, and this elevated fear response can be alleviated by the chronic administration of PRX at doses producing clinically relevant serum concentrations.

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References

  • American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association, Washington, DC

    Google Scholar 

  • Aubel B, Kayser V, Mauborgne A, Farre A, Hamon M, Bourgoin S (2004) Antihyperalgesic effects of cizolirtine in diabetic rats: behavioral and biochemical studies. Pain 110:22–32

    Article  PubMed  CAS  Google Scholar 

  • Baker DG, West SA, Nicholson WE, Ekhator NN, Kasckow JW, Hill KK, Bruce AB, Orth DN, Geracioti TD Jr (1999) Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder. Am J Psychiatry 156:585–588. Erratum in: Am J Psychiatry 156:986

    Google Scholar 

  • Bhagwagar Z, Wylezinska M, Taylor M, Jezzard P, Matthews PM, Cowen PJ (2004) Increased Brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor. Am J Psychiatry 161:368–370

    Article  PubMed  Google Scholar 

  • Blanchard RJ, Blanchard DC (1969) Crouching as an index of fear. J Comp Physiol Psychol 67:370–375

    Article  PubMed  CAS  Google Scholar 

  • Bolles RC (1970) Species-specific defense reactions and avoidance learning. Psychol Rev 77:32–48

    Article  Google Scholar 

  • Bolles RC, Collier AC (1976) The effect of predictive cues on freezing in rats. Anim Learn Behav 4:6–8

    Google Scholar 

  • Bouton ME, Bolles RC (1980) Conditioned fear assessed by freezing and by the suppression of three different baselines. Anim Learn Behav 8:429–434

    Google Scholar 

  • Brady LS, Gold PW, Herkenham M, Lynn AB, Whitfield HJ Jr (1992) The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. Brain Res 572:117–125

    Article  Google Scholar 

  • Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM, Nemeroff CB, Charney DS (1997) Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 154:624–629

    PubMed  CAS  Google Scholar 

  • Calcagnetti DJ, Holtzman SG (1992) Potentiation of morphine analgesia in rats given a single exposure to restraint stress immobilization. Pharmacol Biochem Behav 41:449–453

    Article  PubMed  CAS  Google Scholar 

  • Carmody J, Cooper K (1987) Swim stress reduces chronic pain in mice through an opioid mechanism. Neurosci Lett 74:358–363

    Article  PubMed  CAS  Google Scholar 

  • Costa A, Smeraldi A, Tassorelli C, Greco R, Nappi G (2005) Effects of acute and chronic restraint stress on nitroglycerin-induced hyperalgesia in rats. Neurosci Lett 383:7–11

    Article  PubMed  CAS  Google Scholar 

  • De Souza EB, Grigoriadis DE (1995) Corticotropin-releasing factor: physiology, pharmacology, and role in central nervous system and immune disorders. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Philadelphia, Lippincott-Raven, pp 505–518

    Google Scholar 

  • Fanselow MS, Helmstetter FJ (1998) Conditional analgesia, defensive freezing, and benzodiazepines. Behav Neurosci 102:233–243

    Article  Google Scholar 

  • Friedman MJ, Charney DS, Deutch AY (1995) Neurobiological and clinical consequences of stress. Philadelphia, Lippincott-Raven

    Google Scholar 

  • Gamaro GD, Xavier MH, Denardin JD, Pilger JA, Ely DR, Ferreira MB, Dalmaz C (1998) The effects of acute and repeated restraint stress on the nociceptive response in rats. Physiol Behav 63:693–697

    Article  PubMed  CAS  Google Scholar 

  • Harvey BH, Oosthuizen F, Brand L, Wegener G, Stein DJ (2004) Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacology (Berl) 175:494–502

    CAS  Google Scholar 

  • Hashimoto S, Inoue T, Koyama T (1999) Effects of conditioned fear stress on serotonin neurotransmission and freezing behavior in rats. Eur J Pharmacol 28:23–30

    Article  Google Scholar 

  • Kalin NH, Sherman JE, Takahashi LK (1988) Antagonism of endogenous CRH systems attenuates stress-induced freezing behavior in rats. Brain Res 457:130–135

    Article  PubMed  CAS  Google Scholar 

  • Kaye CM, Haddock RE, Langley PF, Mellows G, Tasker TC, Zussman BD, Greb WH (1989) A review of the metabolism and pharmacokinetics of paroxetine in man. Acta Psychiatr Scand 350 (Suppl):60–75

    CAS  Google Scholar 

  • Khan S, Liberzon I (2004) Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD. Psychopharmacology (Berl) 172:225–229

    Article  CAS  Google Scholar 

  • Kim JJ, Fanselow MS (1992) Modality-specific retrograde amnesia of fear. Science 256:675–677

    Article  PubMed  CAS  Google Scholar 

  • Kohda K, Hoshino A, Kato K, Kato N (2002) Two phasic effects of behavioral stress on rat hippocampal synaptic plasticity. Abstr Soc Neurosci 27:751.12

    Google Scholar 

  • Liberzon I, Krstov M, Young EA (1997) Stress–restress: effects on ACTH and fast feedback. Psychoneuroendocrinology 22:443–453

    Article  PubMed  CAS  Google Scholar 

  • Liberzon I, Lopez JF, Flagel SB, Vazquez DM, Young EA (1999) Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder. J Neuroendocrinol 11:11–17

    Article  PubMed  CAS  Google Scholar 

  • Marshall RD, Beebe KL, Oldham M, Zaninelli R (2001) Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry 158:1982–1988

    Article  PubMed  CAS  Google Scholar 

  • Martinez-Turrillas R, Frechilla D, Del Rio J (2002) Chronic antidepressant treatment increases the membrane expression of AMPA receptors in rat hippocampus. Neuropharmacology 43:1230–1237

    Article  PubMed  CAS  Google Scholar 

  • Orr SP, Metzger LJ, Lasko NB, Macklin ML, Peri T, Pitman RK (2000) De novo conditioning in trauma-exposed individuals with and without posttraumatic stress disorder. J Abnorm Psychol 109:290–298

    Article  PubMed  CAS  Google Scholar 

  • Orr SP, Metzger LJ, Lasko NB, Macklin ML, Hu FB, Shalev AY, Pitman RK (2003) Physiologic responses to sudden, loud tones in monozygotic twins discordant for combat exposure: association with posttraumatic stress disorder. Arch Gen Psychiatry 60:283–288

    Article  PubMed  Google Scholar 

  • Owens MJ, Knight DL, Nemeroff CB (2000) Paroxetine binding to the rat norepinephrine transporter in vivo. Biol Psychiatry 47:842–845

    Article  PubMed  CAS  Google Scholar 

  • Phillips RG, LeDoux JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106:274–285

    Article  PubMed  CAS  Google Scholar 

  • Pitman RK, Orr SP, Shalev AY, Metzger LJ, Mellman TA (1999) Psychophysiological alterations in post-traumatic stress disorder. Semin Clin Neuropsychiatry 4:234–241

    PubMed  CAS  Google Scholar 

  • Pitman RK, van der Kolk BA, Orr SP, Greenberg MS (1990) Naloxone-reversible analgesic response to combat-related stimuli in posttraumatic stress disorder. A pilot study. Arch Gen Psychiatry 47:541–544

    PubMed  CAS  Google Scholar 

  • Sanacora G, Mason GF, Rothman DL, Krystal JH (2002) Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 159:663–665

    Article  PubMed  Google Scholar 

  • Save E, Poucet B, Foreman N, Buhot MC (1992) Object exploration and reactions to spatial and nonspatial changes in hooded rats following damage to parietal cortex or hippocampal formation. Behav Neurosci 106:447–456

    Article  PubMed  CAS  Google Scholar 

  • Sindrup SH, Gram LF, Brosen K, Eshoj O, Mogensen EF (1990) The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain 42:135–144

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, Geyer MA, Vale WW, Koob GF (1986) Corticotropin-releasing factor potentiates acoustic startle in rats: blockade by chlordiazepoxide. Psychopharmacology (Berl) 88:147–152

    Article  CAS  Google Scholar 

  • Tucker P, Zaninelli R, Yehuda R, Ruggiero L, Dillingham K, Pitts CD (2001) Paroxetine in the treatment of chronic posttraumatic stress disorder: results of a placebo-controlled, flexible-dosage trial. J Clin Psychiatry 62:860–868

    Article  PubMed  CAS  Google Scholar 

  • Vaccarino AL, Marek P, Sternberg W, Liebeskind JC (1992) NMDA receptor antagonist MK-801 blocks non-opioid stress-induced analgesia in the formalin test. Pain 50:119–123

    Article  PubMed  CAS  Google Scholar 

  • Vendruscolo LF, Takahashi RN (2004) Synergistic interaction between mazindol, an anorectic drug, and swim-stress on analgesic responses in the formalin test in mice. Neurosci Lett 355:13–16

    Article  PubMed  CAS  Google Scholar 

  • Wegener G, Volke V, Harvey BH, Rosenberg R (2003) Local, but not systemic, administration of serotonergic antidepressants decreases hippocampal nitric oxide synthase activity. Brain Res 959:128–134

    Article  PubMed  CAS  Google Scholar 

  • Yehuda R, Antelman SM (1993) Criteria for rationally evaluating animal models of posttraumatic stress disorder. Biol Psychiatry 33:479–486

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank GlaxoSmithKline K.K. for providing paroxetine. This study was supported by a Grant-in-Aid for general scientific research from the Ministry of Education, Science, Culture of Japan, by Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology (JST).

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Authors and Affiliations

  1. Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Terumichi Takahashi, Shigeru Morinobu, Yasuyuki Iwamoto & Shigeto Yamawaki

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  1. Terumichi Takahashi
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  2. Shigeru Morinobu
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  3. Yasuyuki Iwamoto
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  4. Shigeto Yamawaki
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Correspondence to Shigeto Yamawaki.

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Takahashi, T., Morinobu, S., Iwamoto, Y. et al. Effect of paroxetine on enhanced contextual fear induced by single prolonged stress in rats. Psychopharmacology 189, 165–173 (2006). https://doi.org/10.1007/s00213-006-0545-6

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  • DOI: https://doi.org/10.1007/s00213-006-0545-6

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