Serotonin Receptors as Targets for Drugs Useful to Treat Psychosis and Cognitive Impairment in Schizophrenia

Abstract

The concept that the efficacy of all antipsychotic drugs (APDs) can be explained by their action on dopamine (DA) D2 receptors is most challenged by drugs such as clozapine which target serotonin (5-HT)2A receptors as an essential component of their efficacy and tolerability. The 5-HT2A receptor, along with 5-HT1A, 5-HT 2C, 5-HT 6 or 5-HT 7 receptors, all of which are components of the mechanism of action of clozapine, represent important targets for treating multiple aspects of schizophrenia, especially psychosis and cognitive impairment. The class of atypical antipsychotic drugs (APDs), of which clozapine is the prototype, share in common more effective 5-HT 2A receptor inverse agonism and weaker interference with D2 receptor stimulation, either through D2 receptor blockade or partial D2 receptor agonism. This has led to development of a selective 5-HT2A antagonist, ACP-103 (pimavanserin), which has been found to be effective as monotherapy in L-DOPA psychosis and has promise as an add-on agent for sub-effective doses of atypical APDs. We review here the extensive preclinical evidence to support the importance of 5-HT2A receptor inverse agonism to the action of clozapine and related atypical APDs, and evidence supporting the potential of selective 5-HT2A, 5-HT 6 , and 5-HT 7, antagonists, 5-HT1A partial agonists and 5-HT2C agonists for development of drugs which ameliorate psychosis or cognitive impairment.

A Novel Translational Assay of Response Inhibition and Impulsivity: Effects of Prefrontal Cortex Lesions, Drugs Used in ADHD, and Serotonin 2C Receptor Antagonism

“…We report that SSRTT performance can be successfully modeled in mice and that performance was influenced by medial prefrontal cortex (mPFC) dysfunction and systemic administrations of methylphenidate and atomoxetine in a qualitatively similar manner to humans and previous rat models. We also provide evidence for novel and highly selective effects of 5-HT 2C receptor antagonism in enhancing response control, findings of potential relevance to the increasing interest in 5-HT 2C receptors as drug targets in several disorders where inhibitory deficits are present (Meltzer et al, 2012).…”

“…To our knowledge, the finding that the specific 5-HT 2C antagonist SB242084 enhances response control in the SSRTT is the first published report of such an effect. Given the behavioral selectivity and potency of SB242084, comparable to methylphenidate and atomoxetine, these data add to current debate about the therapeutic potential of 5-HT 2C receptors in psychopathology (Meltzer et al, 2012;Reynolds et al, 2005), and suggest, in principle, that blockade of 5-HT 2C receptors may be useful in the treatment of disorders such as ADHD, where failures of behavioral inhibition are overt; but also other disorders, such as schizophrenia, where inhibitory deficits are present but comorbid with a complex mix of other symptoms (Bonelli and Cummings, 2007;Grant and Potenza, 2012;Robbins et al, 2012).…”

Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction

“…The transcriptional and behavioural deficits in H2BGFP mice also relate to negative symptoms in schizophrenia, such as prepulse inhibition and cognitive impairments, and reduce motivational drive. In fact, it has been proposed that alterations in serotonergic activity could be responsible for the dysregulation of dopaminergic function observed in schizophrenia, and some of the receptors downregulated in H2BGFP mice are found to be decreased in the prefrontal cortex of schizophrenia subjects as well 45 . We should, however, note that other relevant aspects of behaviour related to serotonin dysfunction, such as despair ( Supplementary Fig.…”

Functional Selectivity in Serotonin Receptor 2A (5-HT2A) Endocytosis, Recycling, and Phosphorylation

“…Several ligands bind to the serotonin 2A receptor (5-HT 2A ), including biogenic amines such as dopamine (DA) and tryptamine as well as recreational drugs such as psilocybin and lysergic acid diethylamide (LSD) and therapeutic (antipsychotic) drugs (Meltzer et al, 2003(Meltzer et al, , 2012Meltzer and Massey, 2011;Nichols, 2004). As seen with some GPCRs, ligands acting at the 5-HT 2A receptor differentially modulate intracellular transduction cascades, a phenomenon commonly called "functional selectivity" (Raote et al, 2007;Urban et al, 2007).…”