Role of the Serotonin 5-HT2A Receptor in Learning
John A. Harvey
Learning & Memory, 2003, 355-362
This study reviews the role of the serotonin 5-HT2A 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-HT2A 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-HT2A receptor. These results were placed in the context of what is known concerning the anatomical distribution and electrophysiological effects of 5-HT2A receptor activation in frontal cortex and hippocampus, as well as the role of cortical 5-HT2A receptors in schizophrenia. It was concluded that the 5-HT2A 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 1999, 2002; Williams 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-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 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-HT1A receptor subtype had either no effect (n = 2) or impaired learning (n = 3), whereas both 5-HT2A/2C and 5-HT4 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-HT1A (n = 4) and 5-HT3 (n = 4) antagonists that have been examined were found to have no effect on learning. However, two of the six 5-HT2A/2C antagonists impaired learning, as did one of the two 5-HT4 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 would allow for definite conclusions concerning the precise role of the various receptor subtypes in learning. However, this is not surprising, as different behavioral paradigms invoke differen forms of learning that are mediated by differently distribute neuronal networks. In this regard, it is important to note that, even within a particular paradigm, alterations in the precise manner by which stimuli are presented can produce systematic differences in the brain regions undergoing learning-dependent changes. For example, it is well known that contextual fear conditioning requires hippocampal mediation, whereas signaled fear conditioning does not (Phillips and LeDoux 1994). Consequently, activation of serotonin receptors in different brain regions would be expected to have different effects, depending on the behavioral paradigm used, as well as on the precise role of the different classes of serotonin receptors in mediating activity within particular neuronal networks. On the basis of these considerations, our laboratory chose to use a single behavioral paradigm (classical eyeblink conditioning) and to restrict our studies to an examination of the role of the serotonin 5-HT2A receptor in learning. This chapter details the results of studies providing evidence that the serotonin 5-HT2A receptor demonstrates intrinsic activity that determines the rate of associative learning.
Serotonin 5-HT2A receptors in frontal cortex and hippocampus modulate local circuitry. In contrast to the limited experimental data on other serotonin receptor subtypes, a great deal of systematic data has been collected to indicate an important role for 5-HT2A receptors in modulating neuronal circuitry in medial prefrontal cortex and hippocampus. Both of these brain areas are known to be involved importantly in associative learning across a number of species and learning paradigms, including the classically conditioned eyeblink response in rabbits (Buchanan and Powell 1982; Port et al. 1985; Solomon et al. 1986; Kronforst- Collins and Disterhoft 1998; Weible et al. 2000) and humans (Clark and Squire 1998). The 5-HT2A receptors are located in both the medial prefrontal cortex and hippocampus of the rat (Pazos et al. 1985), rabbit (Aloyo and Harvey 2000), primate (Jakab and Goldman-Rakic 1998), and human (Hoyer et al. 1986; López- Giménez, et al. 1998; Barnes and Sharp 1999). The 5-HT2A receptors found in the rabbit frontal cortex are pharmacologically similar to human receptors (Aloyo and Harvey 2000). Electrophysiological studies in the rat (Sheldon and Aghajanian 1991; Marek and Aghajanian 1994) and primate (Williams et al. 2002) indicate that 5-HT2A receptors can modulate cortical neuronal- excitability, and thus, may be expected to play an important role in modulating learning. The 5-HT2A receptors have been shown to be located on both the dendrites of cortical pyramidal cells as well as on interneurons (Jakab and Goldman-Rakic 1998), and mediate excitation in both neuronal types (Tanaka and North 1993; Aghajanian and Marek 1997). Thus, activation of 5-HT2A receptors in cortex can produce both a direct excitation and a feed-forward inhibition of cortical pyramidal cells. In addition, the location of 5-HT2A receptors in cortex and hippocampus on cholinergic (Quirion et al. 1985) and glutamatergic (Aghajanian and Marek 2000; Lambe et al. 2000; Hasuo et al. 2002) axon terminals can serve to regulate the release of these transmitters. On the basis of studies that have used intrahippocampal injections of drugs that alter glutamatergic and cholinergic transmission
during trace conditioning of the rabbit’s eyeblink response (Thompson et al. 1992; Weiss et al. 2000), the increased release of acetylcholine and glutamate in hippocampus would also be expected to enhance learning. Thus, activation of 5-HT2A receptor would be expected to increase learning through post-synaptic actions on cortical pyramidal cells (Williams et al. 2002) as well as through heteroceptors located on presynaptic terminals of cortical cholinergic and glutamatergic neurons.