Previous human postmortem brain tissue research has implicated abnormalities of 5-HT receptor availability in depression and suicide. Although altered abundance of 5-HT 1A, 5-HT 2A, and 5-HT 2C receptors (5-HT(1A), 5-HT(2A), and 5-HT(2C)) has been reported, the causes remain obscure. This study evaluated the availability of these three receptor subtypes in postmortem brain tissue specimens from persons with a history of major depression (MDD) and normal controls and tested the relationships to protein kinases A and C (PKA, PKC). Samples were obtained from postmortem brain tissue (Brodmann area 10) from 20 persons with a history of MDD and 20 matched controls as determined by a retrospective diagnostic evaluation obtained from family members. Levels of 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptor were quantitated via Western blot analyses. Basal and stimulated PKA and PKC activity were also determined. The depressed samples showed significantly increased 5-HT(2A) receptor abundance relative to controls, but no differences in 5-HT(1A) or 5-HT(2C) receptors. Basal and cyclic AMP-stimulated PKA activity was also reduced in the depressed sample; PKC activity was not different between groups. 5-HT(2A) receptor availability was significantly inversely correlated with PKC activity in controls, but with PKA activity in the depressed sample. Increased 5-HT(2A) receptor abundance and decreased PKA activity in the depressed sample are consistent with prior reports. The correlation of 5-HT(2A) receptor levels with PKA activity in the depressed group suggests that abnormalities of 5-HT(2A) receptor abundance may depend on receptor uncoupling and heterologous regulation by PKA.
"One problem that affects the interpretation of post-mortem studies on this topic is the occurrence of suicide in many of the depression cohorts reported in literature. For instance, postmortem studies that claimed to have determined molecular alterations in relation to depression had in fact selected, in the diagnosis group, depressed patients who (nearly) all committed suicide, and compared them with control subjects without any psychiatric disorder and who did not commit suicide (Bernard et al., 2011; Cotter et al., 2001; Dwivedi et al., 2006b; Martins-de-Souza et al., 2012; Rajkowska et al., 1999; Shelton et al., 2009). Vice versa, the studies focused on suicide appeared to compare suicide cases to matched controls without any psychiatric disorder (Dwivedi et al., 2006a, 2006b; Poulter et al., 2008; Thalmeier et al., 2008). "
"Other elements of the serotonergic system have also been related to the pathology of depression, including the 5-HT reuptake transporter, 5-HT synthesis pathway, and several 5- HT receptor subtypes, among others the 5-HT 2A receptor (5-HT 2A R). Postmortem studies indicate increased levels of 5- HT 2A R in frontal cortex (FC) of subjects with major depressive disorder and suicide victims (Hrdina and Du, 2001; Hrdina et al., 1993; Pandey et al., 2002; Shelton et al., 2009). These results are supported by imaging studies showing an increase in 5-HT 2A R binding in cortical regions of euthymic and "
"Notably, induction of learned helplessness in rats is associated with 5-HT 2A upregulation in cortical areas [Dwivedi et al. 2005]. Moreover, increased 5-HT 2A receptor densities in post-mortem PFCs of depressed patients are associated with decreased activity of protein kinase A, but not PKC [Shelton et al. 2009]. Although the psychedelic effects of classical hallucinogens appear likely to be due to agonist action on the 5-HT 2A receptor, binding to 5-HT 2C and 5-HT 1A receptors [Nichols, 2004] have also been implicated in depressive and anxiety disorders and treatment thereof. "
[Show abstract][Hide abstract] ABSTRACT: Hallucinogens have been part of spiritual practice for millennia, but controversy surrounding their mind-manifesting effects led to their proscription by the mid-20th century, largely without evidence of harm or toxicity and despite nascent data suggesting therapeutic utility in treating depressive illnesses. This review explores their pharmacodynamic actions and the current limited data on their clinic effectiveness. These drugs appear to exert their psychedelic effects through their agonist or partial agonist activity at the serotonergic 5-HT2A receptor, though they also have affinity for other metabotropic serotonin receptors. Hallucinogen binding affects a wide range of intracellular signalling pathways, the precise nature of which remains incompletely understood. They alter the serotonergic tone of brainstem raphe nuclei that project through the brain; they interact with receptors in the prefrontal cortex altering connectivity patterns and intracellular functioning; and they disrupt inhibitory contro
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