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Biphasic effects of 5-HT1A agonism on impulsive responding are dissociable from effects on anxiety in the variable consecutive number task

  • Miranda L. Groft
  • Marigny C. Normann
  • Paige R. Nicklas
  • Julia E. Jagielo-Miller
  • Peter J. McLaughlinEmail author
Original Article

Abstract

The serotonergic 5-HT1A receptor is known to be involved in both impulsivity and anxiety-related behavior. Although anxiety and impulsivity are different constructs, it has been shown that anxiogenesis can result in impulsiveness. It is therefore important to determine if the 5-HT1A receptor is involved in the commission of impulsive actions independent of its effects on anxiety. The 5-HT1A agonist 8-OH-DPAT (0.0125–0.1 mg/kg subcutaneous) increased impulsive action at low doses, but decreased it at higher doses, on the novel paced variable consecutive number with discriminative stimulus task (VCN). Neither the 5-HT1A antagonist WAY 100,635 (0.2–1.2 mg/kg subcutaneous), nor the noradrenergic antagonist and pharmacological stressor yohimbine (1–2 mg/kg intraperitoneal) altered measures of impulsivity. Stress induced by yohimbine was sufficient to produce anxiety-like behavior in the elevated zero maze, confirming that the VCN task is a selective assay of impulsive action that is not affected by anxiety. We hypothesize that the biphasic effect of 8-OH-DPAT is due to actions on presynaptic raphe 5-HT1A autoreceptors, and also postsynaptic 5-HT1A receptors. These results suggest that this receptor mediates impulsive action and that this is not secondary to its role in anxiety.

Keywords

5-HT1A receptors Anxiety Norepinephrine Operant Serotonin Stress 

Notes

Acknowledgments

The authors thank Rachel Hardy, Nathan Pistory, Maeve Stewart, Taylor Proper, and Mikaela Whalen for assistance in conducting the studies.

Authors’ contributions

MN, JJM, and PM conceived the design, MG, MN, PN, JJM, and PM conducted the research, MG, MN, PN analyzed the data, and MG, PN, and PM wrote the paper. All authors read and approved the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted (Edinboro University IACUC protocol #2017-0101). This article does not contain any studies with human participants performed by any of the authors.

References

  1. Adamec R, Shallow T (2000) Effects of baseline anxiety on response to kindling of the right medial amygdala. Physiol Behav 70:67–80.  https://doi.org/10.1016/S0031-9384(00)00247-X Google Scholar
  2. Adamec R, Shallow T, Burton P (2005) Anxiolytic and anxiogenic effects of kindling—role of baseline anxiety and anatomical location of the kindling electrode in response to kindling of the right and left basolateral amygdala. Behav Brain Res 159:73–88.  https://doi.org/10.1016/j.bbr.2004.10.004 Google Scholar
  3. Albert PR, Vahid-Ansari F, Luckhart C (2014) Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression. Front Behav Neurosci 8.  https://doi.org/10.3389/fnbeh.2014.00199
  4. Andrews N, Hogg S, Gonzalez LE, File SE (1994) 5-HT1A receptors in the median raphe nucleus and dorsal hippocampus may mediate anxiolytic and anxiogenic behaviours respectively. Eur J Pharmacol 264:259–264.  https://doi.org/10.1016/0014-2999(94)00473-0 Google Scholar
  5. Audero E, Mlinar B, Baccini G, Skachokova ZK, Corradetti R, Gross C (2013) Suppression of serotonin neuron firing increases aggression in mice. J Neurosci 33:8678–8688.  https://doi.org/10.1523/JNEUROSCI.2067-12.2013 Google Scholar
  6. Barlow RL, Dalley JW, Pekcec A (2018) Differences in trait impulsivity do not bias the response to pharmacological drug challenge in the rat five-choice serial reaction time task. Psychopharmacology 235:1199–1209.  https://doi.org/10.1007/s00213-018-4836-5 Google Scholar
  7. Bhagwagar Z, Rabiner E, Sargent P et al (2004) Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol Psychiatry 9:386–392.  https://doi.org/10.1038/sj.mp.4001401 Google Scholar
  8. Bizot J, Le Bihan C, Puech AJ et al (1999) Serotonin and tolerance to delay of reward in rats. Psychopharmacology 146:400–412Google Scholar
  9. Braun AA, Skelton MR, Vorhees CV, Williams MT (2011) Comparison of the elevated plus and elevated zero mazes in treated and untreated male Sprague–Dawley rats: effects of anxiolytic and anxiogenic agents. Pharmacol Biochem Behav 97:406–415.  https://doi.org/10.1016/j.pbb.2010.09.013 Google Scholar
  10. Broos N, van Mourik Y, Schetters D, de Vries TJ, Pattij T (2017) Dissociable effects of cocaine and yohimbine on impulsive action and relapse to cocaine seeking. Psychopharmacology 234:3343–3351.  https://doi.org/10.1007/s00213-017-4711-9 Google Scholar
  11. Carey RJ, DePalma G, Damianopoulos E, Müller CP, Huston JP (2004) The 5-HT1A receptor and behavioral stimulation in the rat: effects of 8-OHDPAT on spontaneous and cocaine-induced behavior. Psychopharmacology 177:46–54.  https://doi.org/10.1007/s00213-004-1917-4 Google Scholar
  12. Carli M, Samanin R (2000) The 5-HT1(A) receptor agonist 8-OH-DPAT reduces rats’ accuracy of attentional performance and enhances impulsive responding in a five-choice serial reaction time task: role of presynaptic 5-HT1(A) receptors. Psychopharmacology 149:259–268.  https://doi.org/10.1007/s002139900368 Google Scholar
  13. Celada P, Bortolozzi A, Artigas F (2013) Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research. CNS Drugs 27:703–716.  https://doi.org/10.1007/s40263-013-0071-0 Google Scholar
  14. Dekeyne A, Brocco M, Adhumeau A, Gobert A, Millan MJ (2000) The selective serotonin (5-HT)1A receptor ligand, S15535, displays anxiolytic-like effects in the social interaction and Vogel models and suppresses dialysate levels of 5-HT in the dorsal hippocampus of freely-moving rats. Psychopharmacology 152:55–66.  https://doi.org/10.1007/s002130000449 Google Scholar
  15. Del Carlo A, Benvenuti M, Fornaro M et al (2012) Different measures of impulsivity in patients with anxiety disorders: a case control study. Psychiatry Res 197:231–236.  https://doi.org/10.1016/j.psychres.2011.09.020 Google Scholar
  16. Eagle DM, Lehmann O, Theobald DE et al (2009) Serotonin depletion impairs waiting but not stop-signal reaction time in rats: implications for theories of the role of 5-HT in behavioral inhibition. Neuropsychopharmacology 34:1311–1321.  https://doi.org/10.1038/npp.2008.202 Google Scholar
  17. Evenden JL (1998) The pharmacology of impulsive behaviour in rats IV: the effects of selective serotonergic agents on a paced fixed consecutive number schedule. Psychopharmacology 140:319–330.  https://doi.org/10.1007/s002130050773 Google Scholar
  18. Evenden J, Meyerson B (1999) The behavior of spontaneously hypertensive and Wistar Kyoto rats under a paced fixed consecutive number schedule of reinforcement. Pharmacol Biochem Behav 63:71–82.  https://doi.org/10.1016/S0091-3057(98)00222-6 Google Scholar
  19. File SE, Gonzalez LE, Andrews N (1996) Comparative study of pre- and postsynaptic 5-HT1A receptor modulation of anxiety in two ethological animal tests. J Neurosci 16:4810–4815Google Scholar
  20. Garcia-Garcia AL, Newman-Tancredi A, Leonardo ED (2014) P5-HT1A receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function. Psychopharmacology 231:623–636.  https://doi.org/10.1007/s00213-013-3389-x Google Scholar
  21. Groenink L, van Bogaert MJV, van der Gugten J et al (2003) 5-HT1A receptor and 5-HT1B receptor knockout mice in stress and anxiety paradigms. Behav Pharmacol 14:369–383.  https://doi.org/10.1097/01.fbp.0000087737.21047.75 Google Scholar
  22. Hsiung SC, Adlersberg M, Arango V, Mann JJ, Tamir H, Liu KP (2003) Attenuated 5-HT1A receptor signaling in brains of suicide victims: involvement of adenylyl cyclase, phosphatidylinositol 3-kinase, Akt and mitogen-activated protein kinase. J Neurochem 87:182–194.  https://doi.org/10.1046/j.1471-4159.2003.01987.x Google Scholar
  23. Keppel G, Wickens TD (2004) Design and analysis: a Researcher’s handbook, 4th edn. Prentice Hall, Englewood CliffsGoogle Scholar
  24. Kumar JR, Rajkumar R, Lee LC, Dawe GS (2016) Nucleus incertus contributes to an anxiogenic effect of buspirone in rats: involvement of 5-HT 1A receptors. Neuropharmacology 110:1–14.  https://doi.org/10.1016/j.neuropharm.2016.07.019 Google Scholar
  25. Lane SD, Tcheremissine OV, Lieving LM, Nouvion S, Cherek DR (2005) Acute effects of alprazolam on risky decision making in humans. Psychopharmacology 181:364–373.  https://doi.org/10.1007/s00213-005-2265-8 Google Scholar
  26. Lane SD, Cherek DR, Nouvion SO (2008) Modulation of human risky decision making by flunitrazepam. Psychopharmacology 196:177–188.  https://doi.org/10.1007/s00213-007-0951-4 Google Scholar
  27. Laraway S, Snycerski S, Baker LE, Poling A (2008) Gamma-hydroxybutyrate (GHB) reduces operant behavior without impairing working memory in rats responding under fixed-consecutive-number schedules. Pharmacol Biochem Behav 88:205–212.  https://doi.org/10.1016/j.pbb.2007.08.002 Google Scholar
  28. Lemonde S, Turecki G, Bakish D et al (2003) Impaired repression at a 5-Hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 23:8788 LP–8788799Google Scholar
  29. Mahoney MK, Barnes JH, Wiercigroch D, Olmstead MC (2016) Pharmacological investigations of a yohimbine–impulsivity interaction in rats. Behav Pharmacol 27:585–595.  https://doi.org/10.1097/FBP.0000000000000251 Google Scholar
  30. McKenzie-Quirk SD, Miczek KA (2003) 5-HT1A agonists: alcohol drinking in rats and squirrel monkeys. Psychopharmacology 167:145–152.  https://doi.org/10.1007/s00213-003-1395-0 Google Scholar
  31. McLaughlin PJ, Jagielo-Miller JE, Plyler ES et al (2017) Differential effects of cannabinoid CB1 inverse agonists and antagonists on impulsivity in male Sprague Dawley rats: identification of a possibly clinically relevant vulnerability involving the serotonin 5HT1A receptor. Psychopharmacology 234:1029–1043.  https://doi.org/10.1007/s00213-017-4548-2 Google Scholar
  32. Minzenberg MJ, Grossman R, New AS, Mitropoulou V, Yehuda R, Goodman M, Reynolds DA, Silverman JM, Coccaro EF, Marcus S, Siever LJ (2005) Blunted hormone responses to ipsapirone are associated with trait impulsivity in personality disorder patients. Neuropsychopharmacology 2:197–203.  https://doi.org/10.1038/sj.npp.1300853 Google Scholar
  33. Moreira FA, Crippa JAS (2009) The psychiatric side-effects of rimonabant. Rev Bras Psiquiatr 31:145–153.  https://doi.org/10.1590/S1516-44462009000200012 Google Scholar
  34. National Research Council (2011) Guide for the care and use of laboratory animals, 8th edn. National Academies Press, Washington, D.C.Google Scholar
  35. Ohmura Y, Kumamoto H, Tsutsui-Kimura I, Minami M, Izumi T, Yoshida T, Yoshioka M (2013) Tandospirone suppresses impulsive action by possible blockade of the 5-HT1A receptor. J Pharmacol Sci 122:84–92.  https://doi.org/10.1254/jphs.12264FP Google Scholar
  36. Pattij T, Schoffelmeer ANM (2015) Serotonin and inhibitory response control: focusing on the role of 5-HT1A receptors. Eur J Pharmacol 753:140–145.  https://doi.org/10.1016/j.ejphar.2014.05.064 Google Scholar
  37. Poulos CX, Parker JL, Le AD (1996) Dexfenfluramine and 8-OH-DPAT modulate impulsivity in a delay-of-reward paradigm: implications for a correspondence with alcohol consumption. Behav Pharmacol 7:395–399Google Scholar
  38. Rivalan M, Grégoire S, Dellu-Hagedorn F (2007) Reduction of impulsivity with amphetamine in an appetitive fixed consecutive number schedule with cue for optimal performance in rats. Psychopharmacology 192:171–182.  https://doi.org/10.1007/s00213-007-0702-6 Google Scholar
  39. Schippers MC, Schetters D, De Vries TJ, Pattij T (2016) Differential effects of the pharmacological stressor yohimbine on impulsive decision making and response inhibition. Psychopharmacology 233:2775–2785.  https://doi.org/10.1007/s00213-016-4337-3 Google Scholar
  40. Schreiber R, De Vry J (1993) 5-HT1A receptor ligands in amimal models of anxiety, impulsivity and depression: multiple mechanisms of action? Prog Neuro-Psychopharmacol Biol Psychiatry 17:87–104Google Scholar
  41. Soubrié P (1986) Reconciling the role of central serotonin neurons in human and animal behavior. Behav Brain Sci 9:319–335.  https://doi.org/10.1017/S0140525X00022871 Google Scholar
  42. Sprouse J, Reynolds L, Li X, Braselton J, Schmidt A (2004) 8-OH-DPAT as a 5-HT7 agonist: phase shifts of the circadian biological clock through increases in cAMP production. Neuropharmacology 46:52–62.  https://doi.org/10.1016/j.neuropharm.2003.08.007 Google Scholar
  43. Swann AC, Lijffijt M, Lane SD, Cox B, Steinberg JL, Moeller FG (2013) Norepinephrine and impulsivity: effects of acute yohimbine. Psychopharmacology 229:83–94.  https://doi.org/10.1007/s00213-013-3088-7 Google Scholar
  44. Thompson PM, Cruz DA, Olukotun DY, Delgado PL (2012) Serotonin receptor, SERT mRNA and correlations with symptoms in males with alcohol dependence and suicide. Acta Psychiatr Scand 126:165–174.  https://doi.org/10.1111/j.1600-0447.2011.01816.x Google Scholar
  45. Zaretsky DV, Zaretskaia MV, DiMicco JA, Rusyniak DE (2015) Yohimbine is a 5-HT1A agonist in rats in doses exceeding 1mg/kg. Neurosci Lett 606:215–219.  https://doi.org/10.1016/j.neulet.2015.09.008 Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PsychologyEdinboro University of PennsylvaniaEdinboroUSA
  2. 2.Department of PsychologyNorthern Illinois UniversityDeKalbUSA
  3. 3.Department of PsychologyUniversity of KentuckyLexingtonUSA

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