The Implication of 5-HT Receptor Family Members in Aggression, Depression and Suicide: Similarity and Difference

Abstract

Being different multifactorial forms of psychopathology, aggression, depression and suicidal behavior, which is considered to be violent aggression directed against the self, have principal neurobiological links: preclinical and clinical evidence associates depression, aggression and suicidal behavior with dysregulation in central serotonergic (5-HT) neurotransmission. The implication of different types of 5-HT receptors in the genetic and epigenetic mechanisms of aggression, depression and suicidality has been well recognized. In this review, we consider and compare the orchestra of 5-HT receptors involved in these severe psychopathologies. Specifically, it concentrates on the role of 5-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT₃ and 5-HT₇ receptors in the mechanisms underlying the predisposition to aggression, depression and suicidal behavior. The review provides converging lines of evidence that: (1) depression-related 5-HT receptors include those receptors with pro-depressive properties (5-HT_2A, 5-HT₃ and 5-HT₇) as well as those providing an antidepressant effect (5-HT_1A, 5-HT_1B, 5-HT_2C subtypes). (2) Aggression-related 5-HT receptors are identical to depression-related 5-HT receptors with the exception of 5-HT₇ receptors. Activation of 5-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2C receptors attenuate aggressiveness, whereas agonists of 5-HT₃ intensify aggressive behavior.

Keywords: aggression; behavior; brain serotonin system; depression; serotonin receptors; suicide.

Figure 1

Hypothetical mechanism of 5-HT_2B receptors implicated in the mechanisms of depression. Under physiological conditions, 5-HT_2B receptors directly modulate serotonergic neurotransmission as well as astrocytic functions; under stressful conditions, the 5-HT_2B receptors are downregulated which may lead to both serotonergic and astrocytic dysfunctions.

Figure 2

Schematic representation of mechanisms of 5-HT_2A and 5-HT_2C receptor involvement in the pathogenesis of depression. Under physiological conditions, postsynaptic 5-HT_2A and 5-HT_2C receptors regulate glutamate and/or GABA release; upon stress-induced serotonin depletion, 5-HT_2A and 5-HT_2C receptors are upregulated and sensitized. Sensitized 5-HT_2A and 5-HT_2C receptors indirectly inhibit serotonergic neurotransmission, aggravate serotonin deficit and provoke depressive-like behavior.

Figure 3

Hypothetical mechanism of the role of 5-HT_1A/5-HT₇ receptor heterodimerization in the mechanism of depression. Under physiological conditions, the amount of 5-HT_1A/5-HT₇ heterodimers in presynaptic neurons is higher than in postsynaptic neurons; under depression, the 5-HT_1A/5-HT_1A homo- and 5-HT_1A/5-HT₇ heterodimers ratio in presynaptic neurons shifts towards 5-HT_1A/5-HT_1A homodimers which decreases the amount of 5-HT in the synaptic cleft.