The role of 5-HT2C receptors in touchscreen visual reversal learning in the rat: a cross-site study

Abstract

Rationale: Reversal learning requires associative learning and executive functioning to suppress non-adaptive responding. Reversal-learning deficits are observed in e.g. schizophrenia and obsessive-compulsive disorder and implicate neural circuitry including the orbitofrontal cortex (OFC). Serotonergic function has been strongly linked to visual reversal learning in humans and experimental animals but less is known about which receptor subtypes are involved.

Objectives: The objectives of the study were to test the effects of systemic and intra-OFC 5-HT2C-receptor antagonism on visual reversal learning in rats and assess the psychological mechanisms underlying these effects within novel touchscreen paradigms.

Methods: In experiments 1-2, we used a novel 3-stimulus task to investigate the effects of 5-HT2C-receptor antagonism through SB 242084 (0.1, 0.5 and 1.0 mg/kg i.p.) cross-site. Experiment 3 assessed the effects of SB 242084 in 2-choice reversal learning. In experiment 4, we validated a novel touchscreen serial visual reversal task suitable for neuropharmacological microinfusions by baclofen-/muscimol-induced OFC inactivation. In experiment 5, we tested the effect of intra-OFC SB 242084 (1.0 or 3.0 μg/side) on performance in this task.

Results: In experiments 1-3, SB 242084 reduced early errors but increased late errors to criterion. In experiment 5, intra-OFC SB 242084 reduced early errors without increasing late errors in a reversal paradigm validated as OFC dependent (experiment 4).

Conclusion: Intra-OFC 5-HT2C-receptor antagonism decreases perseveration in novel touchscreen reversal-learning paradigms for the rat. Systemic 5-HT2C-receptor antagonism additionally impairs late learning-a robust effect observed cross-site and potentially linked to impulsivity. These conclusions are discussed in terms of neural mechanisms underlying reversal learning and their relevance to psychiatric disorders.

Keywords: 5-HT2C receptor; Orbitofrontal cortex; Rat; Reversal learning; SB 242084.

Fig. 1

Effects of SB 242084 on 3-stimulus visual discrimination and reversal learning in the rat at the academic (experiment 1; a–d) and industrial (experiment 2; e–h) partners. In reversal learning, SB 242084 increased trials (a, e), incorrect responses (b, f) ‘previous CS+’ errors (c, g) and ‘constant CS−’ errors (d, h) to criterion at both the academic and industrial sites. Stimulus-reward contingencies were not counterbalanced in experiment 2 but counterbalanced in experiment 1. Asterisks denote p < 0.05 vs. vehicle (*p < 0.05; **p < 0.01)

Fig. 2

Effects of SB 242084 on early errors and late errors in 3-stimulus reversal learning at the academic (experiment 1; a, b) and the industrial (experiment 2; c, d) partners. SB 242084 increased late errors in both laboratories (a, c). SB 242084 decreased early errors but the effect reached significance only at the industrial site (b, d). Stimulus-reward contingencies were not counterbalanced in experiment 2 but counterbalanced in experiment 1. Asterisks denote p < 0.05 vs. vehicle (*p < 0.05; **p < 0.01)

Fig. 3

Dose-dependent effects of SB 242084 on 2-stimulus reversal learning in the rat. a Trials to criterion. No effect of dose but a significant dose-linear effect. b Incorrect responses. No effect of dose. c Early errors. No effect of dose but a significant dose linear effect. d Late errors. Significant effect of dose as well as a dose linear effect. Broken line represents mean discrimination learning performance. Asterisks denote p < 0.05 vs. vehicle (*p < 0.05)

Fig. 4

Effects of pharmacological inactivation and intracerebral SB 242084 infusions on the touchscreen serial visual reversal task. a Histological validation of baclofen/muscimol cohort. A total of six rats had cannulae targeting the lateral OFC and received all infusions. b Effect of pharmacological inactivation on total trials. c Effect of pharmacological inactivation on omissions. Note that omissions are only possible after the rats have initiated a trial by responding at the ‘start box’ (see Supplementary Fig. 1). d Effect of pharmacological inactivation on percent correct responses during the first reversal session (e) histological validation of OFC SB 242084 cohort. A total of 10 rats had cannulae targeting the lateral OFC and received all infusions. f Effect of intra-OFC SB 242084 infusions on total trials across phases. g Effect of intra-OFC SB 242084 infusions on omissions. h Effect of intra-OFC SB 242084 on percent correct during the first reversal session. Asterisks denote p < 0.05 vs. vehicle (*p < 0.05; ***p < 0.001)