Serotonin-1A autoreceptor binding in the dorsal raphe nucleus of depressed suicides

Abstract

Serotonergic dysfunction is present in mood disorders and suicide. Brainstem 5-HT1A somatodendritic autoreceptors regulate serotonin neuron firing but studies of autoreceptor binding in the dorsal raphe nucleus (DRN) in depressed suicides report conflicting results. We sought to determine: (1) the anatomical distribution of 5-HT1A receptor binding in the DRN in depressed suicides and psychiatrically normal controls; and (2) whether sex differences in 5-HT1A binding in the DRN contribute to differences between depressed suicides and controls. Previously collected quantitative receptor autoradiograms of [3H]8-hydroxy-2-(di-n-propyl)aminotetralin (3H-8-OH-DPAT) in postmortem tissue sections containing the DRN from drug-free suicide victims (n=10) and matched controls (n=10) were analyzed. Less total receptor binding (fmol/mg tissuexmm3) was observed in the entire DRN in depressed suicides compared with controls (p<0.05). Group differences along the rostrocaudal extent of the DRN were observed for cross-sectional 5-HT(1A) binding (fmol/mg tissue) and receptor binding (fmol/mgxmm3, p<0.05). Cross-sectional 5-HT1A DRN binding in depressed suicides compared with controls was higher rostrally and lower caudally. The differences between depressed suicides and controls were present in males and females, although females had more binding than males. Less autoreceptor binding in the DRN of depressed suicides may represent a homeostatic response to less serotonin release, increasing serotonin neuron firing. More autoreceptor binding in rostral DRN might contribute to deficient serotonin release in ventromedial prefrontal cortex by lower neuronal firing.

Increased Serotonin-1A (5-HT1A) Autoreceptor Expression and Reduced Raphe Serotonin Levels in Deformed Epidermal Autoregulatory Factor-1 (Deaf-1) Gene Knock-out Mice

“…Based on promoter studies, the G-allele should increase 5-HT1A autoreceptor levels to reduce 5-HT neuron firing and decrease postsynaptic 5-HT1A receptors to synergistically reduce serotonin neurotransmission. In depressed subjects, the homozygous 5-HT1A G/G(Ϫ1019) genotype was associated with increased 5-HT1A autoreceptor binding potential (20 -22), consistent with increased 5-HT1A autoreceptors in postmortem studies of depressed suicides (23,24). Thus, the 5-HT1A G(Ϫ1019) allele may alter 5-HT1A receptor expression in vivo because of its inability to bind Deaf-1.…”

Disconnect Between Brainstem Serotonin Neurons And Prefrontal Cortex Serotonin Receptors In Suicide

“…The upregulation in tryptophan hydroxylase and 5-HT synthesis may be offset by local 5-HT release acting on inhibitory autoreceptors to reduce serotonergic neurotransmission in the prefrontal cortex in suicide. We find more 5-HT 1A receptors in the rostral DRN in depressed suicides [35], as well as more 5-HT [34]. If so, the decrease in 5-HT 1A receptors in the caudal DRN [35] indicates local plasticity and less autoinhibition from locally released 5-HT.…”

“…We find more 5-HT 1A receptors in the rostral DRN in depressed suicides [35], as well as more 5-HT [34]. If so, the decrease in 5-HT 1A receptors in the caudal DRN [35] indicates local plasticity and less autoinhibition from locally released 5-HT. Alternatively, local release of 5-HT might be sufficient to shut down 5-HT neuron firing despite the abundant 5-HT DRN neurons.…”

“…It is not only an increase in the capacity of the DRN neurons to synthesize 5-HT, we measure more 5-HT and more of the metabolite 5-HIAA [34]. In contrast, there are fewer 5-HT 1A inhibitory autoreceptors that would functionally result in less autoinhibition of 5-HT neuron firing in caudal DRN, while in rostral DRN there are more autoreceptors which could reduce DRN firing [20,35].…”

Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior

“…A reduction in 5-HT neurotransmission implicated in anxiety and depression (Mann, 1999;Jans et al, 2007) has been associated with increased 5-HT1A autoreceptor expression in depressed subjects (Parsey et al, 2010) and depressed suicides (Stockmeier et al, 1998;Boldrini et al, 2008). Thus, the transcriptional "set point" of 5-HT1A autoreceptor expression may be elevated in depression, suggesting altered function of transcription factors (Albert et al, 2011).…”