Opposing Roles for 5-HT2A and 5-HT2C Receptors in the Nucleus Accumbens on Inhibitory Response Control in the 5-Choice Serial Reaction Time Task

Robinson, Emma; Dalley, Jeffrey W.; Theobald, David E.; Glennon, Jeffrey; Pezze, Marie A.; Murphy, Emily R.; Robbins, Trevor W.

doi:10.1038/sj.npp.1301636

Cited by 128 publications

(122 citation statements)

References 49 publications

(79 reference statements)

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“…Whereas 2CKO mice exhibited marked and persistent increases in omitted trials on both tasks, SB242084 treatment decreased omission errors under standard, but not under increased ITI conditions in the 5-CSRTT. Previously, SB242084-mediated reductions of omission errors had been reported in some, but not all studies (Winstanley et al, 2004;Fletcher et al, 2007a;Boulougouris et al, 2008;Robinson et al, 2008;Nilsson et al, 2012). In our 5-CSRTT study, SB242084-mediated reductions of omission errors in WT mice were accompanied by increases in numbers of trials performed and decreases in correct response latencies.…”

Section: Discussionmentioning

confidence: 48%

“…Antagonists such as SB242084 have not been reported to reliably impair measures of attention, but instead they increase premature responding in this task (Winstanley et al, 2004;Fletcher et al, 2007a;Robinson et al, 2008). Moreover, this drug has been shown to facilitate initial reversal learning, but did not impact adaptation to repeated shifts in reward contingency, in contrast to the impairment of serial reversal learning observed in 2CKO mice (Boulougouris et al, 2008).…”

Section: Discussionmentioning

confidence: 62%

“…We did not observe abnormal premature responding in 2CKO mice during task acquisition or at baseline performance. In contrast, treatment with the selective 5-HT 2C receptor antagonist SB242084 has previously been reported to increase premature responding in the 5-CSRTT (Winstanley et al, 2004;Fletcher et al, 2007a;Robinson et al, 2008). We therefore assessed whether SB242084 mediates its intrinsic effects on impulsivity indeed through 5-HT 2C receptor signaling.…”

Section: -Csrttmentioning

confidence: 99%

“…Among the implicated receptors, the 5-HT 2C receptor subtype has been linked to neuropsychiatric disorders (Giorgetti and Tecott, 2004;Drago and Serretti, 2009) and has emerged as a possible contributor to the regulation of executive functions (Tsaltas and Boulougouris, 2011). Administration of the 5-HT 2C receptor antagonist SB242084 increased premature responding in the 5-choice serial reaction time task (5-CSRTT), a paradigm used to evaluate the features of behavioral control, including visuospatial attention, response inhibition, and reaction latencies in animal models (Winstanley et al, 2004;Fletcher et al, 2007a;Robinson et al, 2008). In contrast, administration of another 5-HT 2C receptor antagonist (SER-082) did not alter impulsive behavior in the same task (Koskinen et al, 2000;Talpos et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Next, we examined monoamine neurotransmitter dynamics during 5-CSRTT performance. We choose to target the ventral striatum, as (1) optimal function of this region is crucial for 5-CSRTT performance (Cole and Robbins, 1989), (2) it is a major target area of the mesolimbic dopamine pathway, and (3) pharmacological manipulation of 5-HT 2C receptor signaling in the NAc impacts both 5-CSRTT behavior and dopamine activity (Robinson et al, 2008;Navailles and De Deurwaerdère, 2011). The absolute monoamine concentrations are provided in Supplementary Table S3.…”

Section: -Csrttmentioning

confidence: 99%

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Impact of Serotonin (5-HT)2C Receptors On Executive Control Processes

Pennanen

Hart

et al. 2012

Neuropsychopharmacol

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Although the serotonin (5-hydroxytryptamine, 5-HT) neurotransmitter system has been implicated in modulating executive control processes such as attention, response inhibition, and behavioral flexibility, the contributions of particular serotonin receptors remain unclear. Here, using operant-based behavioral paradigms, we demonstrate that mice with genetically ablated 5-HT 2C receptors (2CKO mice) display deficits in executive functions. 2CKO mice were impaired in the acquisition of a visuospatial attention task as assessed in the 5-choice serial reaction time task (5-CSRTT). In this task, 2CKO mice exhibited marked impairment of attentional processes, with normal response inhibition. We assessed dynamic changes in neurotransmitter levels within the nucleus accumbens (NAc) by in vivo microdialysis in task-performing animals. Extracellular dopamine concentrations were elevated in the NAc of 2CKO mice during task performance, indicating that 5-HT 2C receptors impact dopamine homeostasis during a visuospatial attention task. These findings raise the possibility that disinhibition of mesolimbic dopamine pathways contributes to impaired attention and perturbed task performance in 2CKO mice. Additionally, in a spatial reversal learning task, 2CKO mice failed to improve their performance over a series of reversals, indicating that intact 5-HT 2C receptor signaling is required to accurately respond to repeated changes in reward contingencies. In contrast to the 2CKO phenotype in the 5-CSRTT, wild-type mice treated with the 5-HT 2C receptor antagonist SB242084 exhibited diminished response inhibition, suggesting differing effects of acute pharmacological blockade and constitutive loss of 5-HT 2C receptor activity. Altogether, these findings provide insights into the serotonergic regulation of executive control processes and suggest that impaired 5-HT 2C receptor signaling during development may predispose to executive function disorders.

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