5-HT_2A:Its Role in Frontally Mediated Executive Function and Related Psychopathology

Abstract

Serotonin (5-HT)2A receptors are widely distributed, with high levels in the frontal cortex, where postsynaptic activation may increase activity in pyramidal glutamatergic neurons and mediate various executive functions. More specifically, reciprocal cortical-raphe pathways may allow the ventral prefrontal cortex to inhibit stress-induced neural activity in the brainstem when stressors are perceived as controllable. However, early adversity and negative attitudes may be associated with higher frontal 5-HT2A receptor levels and greater risk for stress-induced psychopathology, and certain 5-HT2A gene variants have been associated with increased risk for impulsive behavior. Conversely, many antidepressants result in decreased levels of 5-HT2A receptor levels, and blockade of 5-HT2A receptors has proven useful in the treatment of a number of psychiatric disorders.

Prefrontal Serotonergic Denervation Induces Increase in the Density of 5-HT2A Receptors in Adult Rat Prefrontal Cortex

“…These play a crucial role in higher brain functions such as working memory [5]. From the 5-HT receptor subtypes found in cortex, 5-HT 2A receptor has received extensive attention in both physiology and pharmacology; little is known of the influence of this 5-HT receptor subtype in the cognitive process [32].…”

“…Both in vitro [37] and in vivo [1,29] studies have revealed that 5-HT 2A receptors mediate the direct depolarizing action of 5-HT on prefrontal pyramidal neurons, whereas the activation of 5-HT 2A receptors in GABAergic interneurons leads to inhibition of these cells, facilitating in turn the excitatory activity of pyramidal cells [8,37]. 5-HT 2A receptors in the central nervous system have been implicated in a variety of psychoneural functions, due in part to their high affinity for psychoactive [12] and various antidepressants drugs [10,32]. Particularly, 5-HT 2A receptors have been strongly related to working memory process in primates performing, which involves the interaction between the excitatory and inhibitory elements within local circuits [35].…”

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

“…First, executive dysfunction is not limited to schizophrenia, and is prominent in affective disorders such as major depression (Taylor Tavares et al, 2007). Second, 5-HT2A-Rs localized in the mPFC have been found to be important modulators of executive functions that are known to be impaired in affective as well as psychotic illness, such as working memory, cognitive flexibility and impulse control (Clarke et al, 2004;Stein et al, 2007;Williams et al, 2002;Winstanley et al, 2004). Third, exposure to stress causes dendritic retraction of mPFC pyramidal neurons and blunts 5-HT2A-R-mediated modulation of these neurons (Liu and Aghajanian, 2008), and produces associated deficits in PFC-mediated behaviors such as fear extinction and attentional set-shifting (Izquierdo et al, 2006;Liston et al, 2006).…”

Variations in5-HT2AInfluence Spatial Cognitive Abilities and Working Memory

“…5-hydroxytryptamine receptor 2A is expressed at high levels in cerebral cortical areas and at intermediate levels in the hippocampus, nucleus accumbens and the hypothalamus 4 . The postsynaptic activations of receptor in those brain structures may increase during the process of memory 5,6 . The 5-HT2A gene is located 13q14.2.…”