Impact of serotonin (5-HT)2C receptors on executive control processes

Abstract

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-HT2C 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-HT2C 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-HT2C 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-HT2C receptor antagonist SB242084 exhibited diminished response inhibition, suggesting differing effects of acute pharmacological blockade and constitutive loss of 5-HT2C receptor activity. Altogether, these findings provide insights into the serotonergic regulation of executive control processes and suggest that impaired 5-HT2C receptor signaling during development may predispose to executive function disorders.

Figure 1

5-CSRTT acquisition performance. (a) The number of sessions required to reach the criterion on the one-choice version of the task did not differ between genotypes (WT, N=22; 2CKO, N=14). (b) Cumulative percentage of mice in each group acquiring baseline criterion. (c) The mean number of sessions required to reach stable baseline performance was significantly higher in the 2CKO group. *p⩽0.05. Data shown represent mean±SEM (WT, N=20; 2CKO, N=8).

Figure 2

Detailed analysis of 5-CSRTT acquisition performance. (a) The percentage of omission errors was significantly enhanced in 2CKO mice. (b) In addition, the percentage of training sessions that did not meet the omission criterion was significantly higher in 2CKO mice. (c) A significant reduction in average reward latency, the main motivation index of the task, was detected in 2CKO mice. Only animals that reached the criterion on an individual training stage were used for calculations. Data shown represent mean±SEM.

Figure 3

Effect of SB242084 on impulse control in the 5-CSRTT. (a) Under standard conditions (ITI=5 s), SB242084 at the higher dose (0.5 mg/kg) significantly increased premature responding in WT but not in 2CKO mice (WT, N=17; 2CKO, N=6). (b) By increasing the ITI duration to 7 s, thereby provoking more premature responding, SB242084 again augmented impulsive responding only in WT mice (WT, N=16; 2CKO, N=6). Data shown represent mean±SEM. *p⩽0.05, **p⩽0.01.

Figure 4

Changes in neurotransmitter activity in the NAc during 5-CSRTT performance. Temporal patterns of (a) dopamine (DA) and (b) serotonin (5-HT) release are shown as percentage of baseline in 10-min sampling intervals. The time of 5-CSRTT task on-set is indicated with an arrow. (c, d) Bar graphs representing AUC (area under the curve) values for DA and 5-HT at baseline, during and after (post) task performance, showing (c) selective DA release upon task onset in 2CKO mice and (d) slightly reduced extracellular 5-HT levels independent of genotype. Data shown represent mean±SEM (WT, N=10; 2CKO, N=6). *p⩽0.05, **p⩽0.01.

Figure 5

Serial spatial SD/SR task performance. (a) The number of trials required to complete each stage of the serial SD/SR task. (b) The number of incorrect responses (errors) to the criterion across all three successive reversals, showing that 2CKO mice in contrast to WT mice did not improve their performance across reversals. SD, simple discrimination; SR, simple reversal; Ret, retention of a previously acquired stimulus–reward contingency. Data shown represent mean±SEM (WT, N=12; 2CKO, N=12). *p⩽0.05; **p⩽0.01.