Activation of 5-HT2A/C Receptors Counteracts 5-HT1A Regulation of N-Methyl-D-aspartate Receptor Channels in Pyramidal Neurons of Prefrontal Cortex

Abstract

Abnormal serotonin-glutamate interaction in prefrontal cortex (PFC) is implicated in the pathophysiology of many mental disorders, including schizophrenia and depression. However, the mechanisms by which this interaction occurs remain unclear. Our previous study has shown that activation of 5-HT 1A Serotonin (5-HT)2 is a key neuromodulator mediating diverse cognitive and emotional functions in the central nervous system (1). The pleiotropic functions of serotonin are afforded by the concerted actions of multiple 5-HT receptor subtypes, 5-HT 1 -to 5-HT 7 (2, 3). Mice lacking 5-HT receptors exhibit phenotypes ranging from increased anxiety (4), to elevated aggression (5), to antidepressant-like behaviors (6). One of the major targets of serotonin is prefrontal cortex (PFC), a crucial brain region controlling emotion and cognition (7,8). Several lines of evidence have shown that 5-HT 1A and 5-HT 2A receptors, which are abundantly co-expressed in most of PFC pyramidal neurons (9), often have opposing actions on common substrates. For instance, activation of 5-HT 1A receptors results in neuronal inhibition by increasing potassium currents (10) and decreasing calcium currents (11). In contrast, 5-HT 2A receptor stimulation leads to neuronal excitation by suppressing potassium currents (2) and enhancing pre-synaptic glutamate release (12). Moreover, elevated 5-HT 1A receptors and reduced 5-HT 2A receptors are found in PFC of schizophrenia patients (13,14), suggesting that the levels of 5-HT 1A and 5-HT 2A receptors are differentially altered in diseased states.One of the potential cellular targets of 5-HT receptors involved in cognitive and emotional control is the NMDA-type glutamate receptor, a ligand-gated ion channel that has been implicated in the pathophysiology of mental disorders (15). NMDAR hypofunction caused by systemic administration of non-competitive NMDAR antagonists or knockdown of NMDAR expression produces schizophrenia-like behavioral symptoms (16 -18). Moreover, it has been found that the expression of NMDARs is reduced in postmortem brains of depressed patients (19), and chronic antidepressant treatment enhances NMDAR levels in mouse brains (20). Our previous study has shown that activation of 5-HT 1A receptors suppresses NMDAR channel function in PFC pyramidal neurons (21). It remains unknown whether 5-HT 2A receptor activation has any impact on the 5-HT 1A -NMDAR interaction.

Antipsychotic activity of standardizedBacopaextract against ketamine-induced experimental psychosis in mice: Evidence for the involvement of dopaminergic, serotonergic, and cholinergic systems

“…In order to evaluate the role of serotonergic system, the receptor subtypes 5HT-1A, 5HT-2A, and 5HT-2C were specifically selected for gene analysis. The selection was based on the role that those receptors play in regulating the 5HT firing and their involvement in the pathophysiology of schizophrenia (Jensen et al, 2010;Simpson et al, 1996;Yasuno et al, 2003;Yuen et al, 2008). Our results indicate that the expression of 5HT-1A receptor was induced by about twofold in response to the chronic ketamine treatment in the cortex tissues (Figure 10).…”

Attenuation of Phencyclidine-Induced Object Recognition Deficits by the Combination of Atypical Antipsychotic Drugs and Pimavanserin (ACP 103), a 5-Hydroxytryptamine2A Receptor Inverse Agonist

“…It is noteworthy that M100907 and pimavanserin effectively block the effects of acute PCP stimulation of locomotor activity, considered a model of psychosis (Maurel-Remy et al, 1995;Vanover et al, 2006;Gardell et al, 2007) as well as their ability to block NMDA antagonist effects on the firing rate of pyramidal neurons (Wang and Liang 1998). The 5-HT 2A receptor has been shown to play a key role in the transport and dynamic regulation of NMDA receptors in cortical pyramidal neurons (Yuen et al, 2008). 5-HT 2A agonists which are hallucinogens modulate NMDA receptor-mediated neurotransmission in the prefrontal cortex, effects that are blocked by M100907 (Arvanov et al, 1999).…”

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

“…They observed that although Met-enkephalin, etorphine, and methadone result in the robust desensitization of Metenkephalin-induced hyperpolarization and internalization of the receptor in locus ceruleus neurons expressing FLAG-tagged ORs, oxycodone is unable to promote either event, whereas the agonists morphine and oxymorphine both induce receptor desensitization without detectable internalization. Although desensitization and internalization may be interrelated, particularly because receptor sequestration into intracellular vesicles can disrupt further coupling between the receptor and certain downstream effectors, internalization has been shown to facilitate receptor signaling to additional signaling cascades for other GPCRs (Luttrell et al, 1997;Daaka et al, 1998;Lin et al, 1998;Yuen et al, 2008). Therefore, internalization and desensitization cannot reliably be considered as synchronous events.…”