Serotonin–glutamate and serotonin–dopamine reciprocal interactions as putative molecular targets for novel antipsychotic treatments: from receptor heterodimers to postsynaptic scaffolding and effector proteins

Abstract

The physical and functional interactions between serotonin-glutamate and serotonin-dopamine signaling have been suggested to be involved in psychosis pathophysiology and are supposed to be relevant for antipsychotic treatment. Type II metabotropic glutamate receptors (mGluRs) and serotonin 5-HT(2A) receptors have been reported to form heterodimers that modulate G-protein-mediated intracellular signaling differentially compared to mGluR2 and 5-HT(2A) homomers. Additionally, direct evidence has been provided that D(2) and 5-HT(2A) receptors form physical heterocomplexes which exert a functional cross-talk, as demonstrated by studies on hallucinogen-induced signaling. Moving from receptors to postsynaptic density (PSD) scenario, the scaffolding protein PSD-95 is known to interact with N-methyl-D-aspartate (NMDA), D(2) and 5-HT(2) receptors, regulating their activation state. Homer1a, the inducible member of the Homer family of PSD proteins that is implicated in glutamatergic signal transduction, is induced in striatum by antipsychotics with high dopamine receptor affinity and in the cortex by antipsychotics with mixed serotonergic/dopaminergic profile. Signaling molecules, such as Akt and glycogen-synthase-kinase-3 (GSK-3), could be involved in the mechanism of action of antipsychotics, targeting dopamine, serotonin, and glutamate neurotransmission. Altogether, these proteins stand at the crossroad of glutamate-dopamine-serotonin signaling pathways and may be considered as valuable molecular targets for current and new antipsychotics. The aim of this review is to provide a critical appraisal on serotonin-glutamate and serotonin-dopamine interplay to support the idea that next generation schizophrenia pharmacotherapy should not exclusively rely on receptor targeting strategies.

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

“…In general, a complex link between 5-HT2A and dopamine tone appears to modulate brain activity (Di Pietro and Seamans, 2007;Lieberman et al, 1998). Consistently, 5-HT2A and D2 receptors are both located on prefrontal pyramidal and nonpyramidal neurons (Fink and Gothert, 2007;Goldman-Rakic, 1998, 2000;Seamans and Yang, 2004), and their signaling is also transmitted through the common intraneuronal pathways (Beaulieu, 2012;de Bartolomeis et al, 2013). Overall, these findings suggest that the relationship between D2 and 5-HT2A modulates neuronal function through multiple mechanisms, and that their balanced stimulation is crucial.…”

“…Thus, genetically induced levels of 5-HT2A receptors may in turn interact with lower or greater expression of D2L postsynaptic receptors as a function of DRD2 variation in determining differential levels of stimulation of prefrontal pyramidal neurons or interneurons of relevance for cognitive processing. Another synergistic or alternative mechanism of the combined effect of rs1076560 and rs6314 on working memory processing is that stimulation of D2 and 5-HT2A receptors implicates intraneuronal adjustments that modulate common pathways including molecules such as AKT1 and GSK3beta (Beaulieu, 2012;de Bartolomeis et al, 2013), whose expression and related genetic variation have been associated with schizophrenia (Blasi et al, 2011(Blasi et al, , 2013bTan et al, 2008). In line with the relevance of common signaling cascades, current evidence also suggests that the cross-talk between D2 and 5-HT2A may be facilitated by the assembly of heteromers (Albizu et al, 2011;de Bartolomeis et al, 2013;Fuxe et al, 2014).…”

Roles of PTEN/PI3K/AKT/GSK3? Pathway in Neuron Signaling Involved in Autism

“…Then, AKT phosphorylates a diverse set of substrates including GSK3β [46]. 5-HT promotes interactions with a scaffolding and regulatory molecule, which results in the activation of PI3K/AKT [47]. Therefore, the PTEN may be a significant regulator of this pathway in mediating the ASD phenotype.…”

Clozapine augmentation with amisulpride

“…It could be hypothesized that patients with SRS have a more complex pathophysiology than patients who respond to FGAs or SGAs 12 ; thus, they may benefit from a multisite receptor effect (like the effect of amisulpride) rather than a stronger antidopaminergic effect. 13 Systems other than the dopaminergic one are likely involved in the pathophysiology of SRS and may represent the target of augmentation strategies.…”