In conflict-based anxiety tests, rodents decide between actions with simultaneous rewarding and aversive outcomes. In humans, computerised operant conflict tests have identified response choice, latency, and vigour as distinct behavioural components. Animal operant conflict tests for measurement of these components would facilitate translational study.
In C57BL/6 mice, two operant conflict tests for measurement of response choice, latency, and vigour were established, and effects of chlordiazepoxide (CDZ) thereon investigated.
Mice were moderately diet-restricted to increase sucrose reward salience. A 1-lever test required responding under medium-effort reward/threat conditions of variable ratio 2–10 resulting in sucrose at p = 0.7 and footshock at p = 0.3. A 2-lever test mandated a choice between low-effort reward/threat with a fixed-ratio (FR) 2 lever yielding sucrose at p = 0.7 and footshock at p = 0.3 versus high-effort reward/no threat with a FR 20 lever yielding sucrose at p = 1.
In the 1-lever test, CDZ (7.5 or 15 mg/kg i.p.) reduced post-trial pause (response latency) following either sucrose or footshock and reduced inter-response interval (increased response vigour) after footshock. In the 2-lever test, mice favoured the FR2 lever and particularly at post-reward trials. CDZ increased choice of FR2 and FR20 responding after footshock, reduced response latency overall, and increased response vigour at the FR2 lever and after footshock specifically.
Mouse operant conflict tests, especially 2-lever choice, allow for the translational study of distinct anxiety components. CDZ influences each component by ameliorating the impact of both previous punishment and potential future punishment.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Amemori K, Amemori S, Graybiel AM (2015) Motivation and affective judgments differentially recruit neurons in the primate dorsolateral prefrontal and anterior cingulate cortex. J Neurosci 35:1939–1953
Azzinnari D, Sigrist H, Staehli S, Palme R, Hildebrandt T, Leparc G, Hengerer B, Seifritz E, Pryce CR (2014) Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function. Neuropharmacology 85:328–341
Bach DR (2015) Anxiety-like behavioural inhibition is normative under environmental threat-reward correlations. PLoS Comput Biol 11:e1004646
Bach DR, Dayan P (2017) Algorithms for survival: a comparative perspective on emotions. Nat Rev Neurosci 18:311–319
Bach DR, Guitart-Masip M, Packard PA, Miro J, Falip M, Fuentemilla L, Dolan RJ (2014) Human hippocampus arbitrates approach-avoidance conflict. Curr Biol 24:541–547
Bach DR, Korn CW, Vunder J, Bantel A (2018) Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial. Transl Psychiatry 8:157
Britton KT, Morgan J, Rivier J, Vale W, Koob GF (1985) Chlordiazepoxide attenuates response suppression induced by corticotropin-releasing factor in the conflict test. Psychopharmacology 86:170–174
Calhoon GG, Tye KM (2015) Resolving the neural circuits of anxiety. Nat Neurosci 18:1394–1404
Coutinho CB, Cheripko JA, Carbone JJ (1969) Relationship between the duration of anticonvulsant activity of chlordiazepoxide and systemic levels of the parent compound and its major metabolites in mice. Biochem Pharmacol 18:303–316
Dawson GR, Tricklebank MD (1995) Use of the elevated plus maze in the search for novel anxiolytic agents. TiPS 16:33–36
Evenden J, Ross L, Jonak G, Zhou J (2009) A novel operant conflict procedure conflict procedure using incrementing shock intensities to assess the anxiolytic and anxiogeneic effects of drugs. Behav Pharmacol 20:226–236
File SE, Lippa AS, Beer B, Lippa MT (2004) Animal tests of anxiety. In: Current protocols in neuroscience Chapter 8, Unit 8.3
Gray JA, McNaughton N (2000) The neuropsychology of anxiety: an enquiry into the functions of the septo-hippocampal system, 2nd edn. Oxford University Press, Oxford
Gray JA, Davis N, Feldon J, Rawlins NP, Owen SR (1981) Animal models of anxiety. Prog Neuro-Psychopharmacol 5:143–157
Griebel G, Holmes A (2013) 50 years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov 12:667–687
Ito R, Lee AC (2016) The role of the hippocampus in approach-avoidance conflict decision-making: evidence from rodent and human studies. Behav Brain Res 313:345–357
Jean-Richard-Dit-Bressel P, McNally GP (2015) The role of the basolateral amygdala in punishment. Learn Mem 22:128–137
Jean-Richard-Dit-Bressel P, Killcross S, McNally GP (2018) Behavioral and neurobiological mechanisms of punishment: implications for psychiatric disorders. Neuropsychopharmacology 43:1639–1650
Khemka S, Barnes G, Dolan RJ, Bach DR (2017) Dissecting the function of hippocampal oscillations in a human anxiety model. J Neurosci 37:6869–6876
Kirlic N, Young J, Aupperle RL (2017) Animal to human translational paradigms relevant for approach avoidance conflict decision making. Behav Res Ther 96:14–29
Korn CW, Vunder J, Miro J, Fuentemilla L, Hurlemann R, Bach DR (2017) Amygdala lesions reduce anxiety-like behavior in a human benzodiazepine-sensitive approach-avoidance conflict test. Biol Psychiatry 82:522–531
Lopez-Aumatell R, Guitart-Masip M, Vicens-Costa E, Gimenez-Llort L, Valdar W, Johannesson M, Flint J, Tobena A, Fernandez-Teruel A (2008) Fearfulness in a large N/Nih genetically heterogeneous rat stock: differential profiles of timidity and defensive flight in males and females. Behav Brain Res 188:41–55
Lu SX, Higgins GA, Hodgson RA, Hyde LA, Del Vecchio RA, Guthrie DH, Kazdoba T, McCool MF, Morgan CA, Bercovici A, Ho GD, Tulshian D, Parker EM, Hunter JC, Varty GB (2011) The anxiolytic-like profile of the nociceptin receptor agonist, endo-8-[bis(2-chlorophenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octane-3-carboxami de (SCH 655842): comparison of efficacy and side effects across rodent species. Eur J Pharmacol 661:63–71
Rodgers RJ, Johnson NJ (1995) Factor analysis of spatiotemporal and ethological measures in the murine elevated plus-maze test of anxiety. Pharmacol Biochem Behav 52:297–303
Rodgers RJ, Cao BJ, Dalvi A, Holmes A (1997) Animal models of anxiety: an ethological perspective. Braz J Med Biol Res 30:289–304
Shimp KG, Mitchell MR, Beas BS, Bizon JL, Setlow B (2015) Affective and cognitive mechanisms of risky decision making. Neurobiol Learn Mem 117:60–70
Simon NW, Setlow B (2012) Modeling risky decision making in rodents. Methods Mol Biol 829:165–175
Tajima S, Drugowitsch J, Pouget A (2016) Optimal policy for value-based decision-making. Nat Commun 7:12400
Tovote P, Fadok JP, Luthi A (2015) Neuronal circuits for fear and anxiety. Nat Rev Neurosci 16:317–331
Varty GB, Hyde LA, Hodgson RA, Lu SX, McCool MF, Kazdoba TM, Del Vecchio RA, Guthrie DH, Pond AJ, Grzelak ME, Xu X, Korfmacher WA, Tulshian D, Parker EM, Higgins GA (2005) Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species. Psychopharmacology 182:132–143
Vogel JR, Beer B, Clody DE (1971) A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmacologia 21:1–7
We are grateful to Björn Henz and Alex Osei for animal care. The experiments comply with the current laws of Switzerland.
This research was funded by the Swiss National Science Foundation (grant 31003A-160147 to CRP).
Conflict of interest
ES is an employee of TSE Systems, Germany. All remaining authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article belongs to a Special Issue on Translational Computational Psychopharmacology
About this article
Cite this article
Oberrauch, S., Sigrist, H., Sautter, E. et al. Establishing operant conflict tests for the translational study of anxiety in mice. Psychopharmacology 236, 2527–2541 (2019). https://doi.org/10.1007/s00213-019-05315-y
- Reward-aversion conflict
- Translational test
- Operant choice
- Response latency
- Response vigour