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-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.

Serotonin 5-HT2Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

“…Global 5-HT depletion increases the number of premature responses on the 5-CSRT task, an effect that is mimicked by the 5-HT 2C R antagonist SB242084 in rats (Winstanley et al, 2004). Wild-type mice treated with SB 242084 also showed diminished response inhibition in the 5-CSRT task (Pennanen et al, 2013). Importantly, the 5-HT 2C R agonist Ro 60-0175 and M100907 both attenuated cocaine-induced premature responding on the 5-CSRT task, showing similar functional effects on a measure of impulsivity (Fletcher et al, 2011).…”

“…i Fletcher et al, 2002Fletcher et al, , 2006Fletcher et al, , 2008Winstanely et al, 2003;Frankel and Cunningham, 2004;Neisewander and Acosta, 2007;Burbassi and Cervo, 2008;Manvich et al, 2012b;Pennanen et al, 2013. j Filip and Cunningham, 2003. 188 Howell and Cunningham experimental conditions before conclusions about their reinforcing strength and abuse liability are drawn.…”

Dissociable Deficits of Executive Function Caused by Gestational Adversity are Linked to Specific Transcriptional Changes in the Prefrontal Cortex

“…5-CSRTT has traditionally been employed in otherwise normal, adult animals that can be fully trained prior to acute adult pharmacological manipulations. However, this approach, which calls for performance assessments after months of 5-CSRTT training on the part of the animal, may be confounded by neurodevelopmental insults such as those employed here, or by genetic manipulations (Pennanen et al, 2013), which will impact the ability of animals to perform the task early in training, but which may be recoverable by overtraining. Indeed, repeated exposure to the continuous performance test with reinforcement in humans leads to an amelioration of performance deficits in patients with ADHD and a loss of the ability to distinguish the vulnerable population (Bubnik et al, 2014).…”

Interaction between CHL1 and serotonin receptor 2c regulates signal transduction and behavior in mice

“…CHL1-deficient mice showed reduced reactivity to novelty or external stimuli, but no anxiety-related behavior (Montag-Sallaz et al, 2002;Pratte et al, 2003;Morellini et al, 2007;Pratte and Jamon, 2009). Mice expressing only the non-edited or the fully-edited isoform of the 5-HT2c receptor display anxiety-or depression-like symptoms and 5-HT2c-receptor-deficient mice display reduced reactivity to a novel environment or external stimuli, as well as alterations in sleep, feeding and reward-associated behaviors (for review and references, see Heisler et al, 2007;Fletcher et al, 2009;Iwamoto et al, 2009;Mombereau et al, 2010;Pennanen et al, 2013). Alterations in sleep, feeding and reward-associated behaviors have so far not been reported for CHL1-deficient mice.…”

“…The non-edited isoform and the partially edited isoforms exhibit pronounced or intermediate constitutive activity, whereas the fully edited isoform is not constitutively active and requires binding of serotonin for activation (Burns et al, 1997;Herrick-Davis et al, 1999;Niswender et al, 1999). Reduced reactivity to a novel environment and sensitivity to locomotor stimulants, as well as alterations in sleep, feeding and reward-associated behaviors are observed in 5-HT2c-receptor-deficient mice, whereas mice expressing the non-edited or fully-edited isoforms show anxiety and depression-like symptoms, respectively (for a review and references, see Heisler et al, 2007;Iwamoto et al, 2009;Fletcher et al, 2009;Mombereau et al, 2010;Pennanen et al, 2013). In humans, the 5-HT2c receptor has been associated with obesity as well as neurological and psychiatric disorders, such as schizophrenia, major depression, addiction, epilepsy, anxiety, sleep disorders, motor dysfunction and bipolar disorder (Berg et al, 2008;Lee et al, 2010).…”