Role of the Serotonin 5-HT_2A Receptor in Learning

Abstract

This study reviews the role of the serotonin 5-HT 2A receptor in learning as measured by the acquisition of the rabbit's classically conditioning nictitating membrane response, a component of the eyeblink response. Agonists at the 5-HT 2A receptor including LSD (d-lysergic acid diethylamide) enhanced associative learning at doses that produce cognitive effects in humans. Some antagonists such as BOL (d-bromolysergic acid diethylamide), LY53,857, and ketanserin acted as neutral antagonists in that they had no effect on learning, whereas others (MDL11,939, ritanserin, and mianserin) acted as inverse agonists in that they retarded learning through an action at the 5-HT 2A receptor. These results were placed in the context of what is known concerning the anatomical distribution and electrophysiological effects of 5-HT 2A receptor activation in frontal cortex and hippocampus, as well as the role of cortical 5-HT 2A receptors in schizophrenia. It was concluded that the 5-HT 2A receptor demonstrates constitutive activity, and that variations in this activity can produce profound alterations in cognitive states.The past few decades have brought an increasing awareness of serotonin's role in behavior. The development of drugs acting on the serotonergic system of brain that allow for the treatment of depression, anxiety, appetite regulation, and post-traumatic stress disorders has focused a great deal of attention on the role of serotonin in processes involving emotional states. Commensurate with our increasing understanding of the role of serotonin in behavioral processes has been the identification of at least seven serotonin (5-hydroxytryptamine; 5-HT) receptor sub-types. More recently, investigators have focused on the role of serotonin in cognitive functions, including learning and memory (Harvey 1996;Barnes and Sharp 1999;Meneses 1999Meneses , 2002Williams et al. 2002) and in the deficits in attention and associative processes seen in schizophrenia (Meltzer 1999). Serotonin receptor subtypes that have been demonstrated to occur in brain regions capable of playing a role in learning and memory include the 5-HT 1 , 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 6 , and 5-HT 7 class of receptors (Barnes and Sharp 1999;Meneses 2002). Table 1 summarizes studies that have examined the effects of serotonin agonists on learning. It can be seen that agonists at the 5-HT 1A receptor subtype had either no effect (n = 2) or impaired learning (n = 3), whereas both 5-HT 2A/2C and 5-HT 4 receptor agonists primarily improved learning. The majority of serotonin antagonists are reported to have no effect on learning (Table 2). Thus, all of the 5-HT 1A (n = 4) and 5-HT 3 (n = 4) antagonists that have been examined were found to have no effect on learning. However, two of the six 5-HT 2A/2C antagonists impaired learning, as did one of the two 5-HT 4 antagonists.Although the data cited above indicate that activation of serotonin receptors or their blockade can produce alterations in learning, these data do not provide the consistent outcomes that woul...

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