Establishing operant conflict tests for the translational study of anxiety in mice
- 27 Downloads
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.
KeywordsAnxiety Reward-aversion conflict Translational test Mouse Operant choice Response latency Response vigour Anxiolytic
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).
Compliance with ethical standards
Conflict of interest
ES is an employee of TSE Systems, Germany. All remaining authors declare no competing interests.
- 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 85:328–341CrossRefGoogle Scholar
- Dawson GR, Tricklebank MD (1995) Use of the elevated plus maze in the search for novel anxiolytic agents. TiPS 16:33–36Google Scholar
- File SE, Lippa AS, Beer B, Lippa MT (2004) Animal tests of anxiety. In: Current protocols in neuroscience Chapter 8, Unit 8.3Google Scholar
- Gray JA, McNaughton N (2000) The neuropsychology of anxiety: an enquiry into the functions of the septo-hippocampal system, 2nd edn. Oxford University Press, OxfordGoogle Scholar
- 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 188:41–55CrossRefGoogle Scholar
- 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 661:63–71CrossRefGoogle Scholar
- 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 182:132–143CrossRefGoogle Scholar