Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases

Abstract

The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.

Dopamine and Dopamine-Related Ligands Can Bind Not Only to Dopamine Receptors

“…These triads can contain both dopamine and serotonin or adrenergic terminals. The first point on how the interaction between DRs and 5-HT receptors can occur is the formation of the heteroreceptor complexes of D 2 DR and 5-HT 2A receptors [ 125 ]. The heterocomplexes could explain the effects of atypical antipsychotic drugs [ 125 ].…”

“…The first point on how the interaction between DRs and 5-HT receptors can occur is the formation of the heteroreceptor complexes of D 2 DR and 5-HT 2A receptors [ 125 ]. The heterocomplexes could explain the effects of atypical antipsychotic drugs [ 125 ]. One of the possible mechanisms is based on blocking the allosteric enhancement of D 2 DR protomer signaling by 5-HT 2A receptor protomer activation.…”

Comparisons of Serum Interleukin-8 Levels in Major Depressive Patients With Drug-Free Versus SSRIs Versus Healthy Controls

“…This result suggested that the SSRIs might modulate increased serum IL-8 levels in patients with MDD. The SSRIs have been reported to modulate microglia and astrocytes in hippocampus to produce the inflammatory cytokines including IL-8 ( 69 – 73 ). Moreover, MDD has been considered a neuroinflammatory disorder that was implicated in the abnormal activities of brain microglia and astrocytes ( 24 – 26 ).…”

Dysfunctional Heteroreceptor Complexes as Novel Targets for the Treatment of Major Depressive and Anxiety Disorders

“…In addition to the above, it has been observed that Gal (1–15) but not Gal (1–29) can modulate in an antagonistic way 5-HT1AR in the dorsal hippocampus. It was proposed that GalR1-GalR2-5-HT1AR receptor mosaics can exist in the hippocampus, on dorsal raphe cells, and other limbic neurons where galanin fragment 1–15 is also able to exert allosteric interactions via modulation of the GalR1-GalR2 component of the trimeric hetero receptor complex to enhance 5-HT1AR protomer function in the basal state of this heterocomplex [ 138 ].…”

“…It is of special interest that ketamine can have direct effects on the 5-HT2R and D2R, as observed in 2002 [ 385 ]. It will be of special interest to understand if the D2R-5-HT2A heterocomplex is especially vulnerable to ketamine treatment [ 131 , 135 , 138 ]. Presently the relevance of the high affinities of ketamine for D2R and 5-HT2R is not clear regarding the role of ketamine in mental disorders.…”