Increased tryptophan hydroxylase immunoreactivity in the dorsal raphe nucleus of alcohol-dependent, depressed suicide subjects is restricted to the dorsal subnucleus

Abstract

Considerable evidence suggests that alcoholics with co-occurring depressive disorder are at greater risk for developing psychosocial problems particularly suicidal behavior. Moreover, dysfunction in serotonin (5-HT) neurotransmission has been implicated in depression, suicide and alcoholism. In the present study, we measured the levels of tryptophan hydroxylase (TPH), the main synthetic enzyme of 5-HT synthesis, in specific nuclei of the dorsal raphe (DR) in depressed suicide victims with alcohol dependence and matched psychiatrically normal controls. TPH immunoreactivity (IR) was quantified in frozen tissue sections containing the DR from 8 suicide victims with a diagnosis of major depression and alcohol dependence, and 8 psychiatrically normal control subjects by using immunoautoradiographic methods. We found that the levels of TPH-IR were significantly increased by 46% in the dorsal subnucleus of the DR in depressed suicide victims with alcohol dependence when compared with controls. In contrast, TPH-IR levels did not significantly differ in the other DR subnuclei between depressed, alcoholic suicide subjects, and controls. Our results indicate that abnormalities in 5-HT biosynthesis in the brain of depressed alcoholic suicide subjects are restricted within distinct regions of the DR.

Chemical neuroanatomy of the dorsal raphe nucleus and adjacent structures of the mouse brain

“…In fact, several neuropeptides have been discussed in relation to depression and its treatment based on animal experiments (Fuxe et al, 1990(Fuxe et al, , 1998Weiss et al, 1998;Reul and Holsboer, 2002;Holmes et al, 2003;Owens, 2004;Sajdyk et al, 2004;Nemeroff and Vale, 2005;Nestler and Carlezon, 2006;Ogren et al, 2006;Lu et al, 2007). There are already histochemical studies reporting changes in markers for 5-HT in human postmortem tissue, including increased levels of TPH2 protein and transcript in depressed versus control patients (Underwood et al, 1999;Boldrini et al, 2005;Bach-Mizrachi et al, 2006;Bonkale et al, 2006). However, changes in 5-HTT or 5-HT1A receptor could not be detected in suicide victims with major depression (Bligh-Glover et al, 2000;Anisman et al, 2008), or in the number of 5-HT neurons (Hendricksen et al, 2004).…”

Chronic low dose ovine corticotropin releasing factor or urocortin II into the rostral dorsal raphe alters exploratory behavior and serotonergic gene expression in specific subregions of the dorsal raphe

“…Furthermore, a recent study suggests that in a group of ethanol abusing depressed suicide victims, TPH immunoreactivity was increased in the dorsomedial DRN at the mid-rostral level. While the study quantified immunoreactivity in the dorsomedial DRN as a whole, the figures presented suggest that TPH was increased markedly in the core dorsomedial DRN (Bonkale et al, 2006). Taken collectively, these data suggest that changes in the relative level of Tph2 expression in the ventromedial and dorsomedial DRN might well play a role in modulating behavior.…”

Elevated expression of tryptophan hydroxylase-2 mRNA at the neuronal level in the dorsal and median raphe nuclei of depressed suicides

“…13 At the protein level, we found higher density and number of TPH immunoreactive (IR) neurons in the DRN of depressed suicides by immunocytochemistry, 14 a finding replicated in a second cohort using immunoautoradiography. 15 Another group reported higher TPH protein expression restricted to the dorsal subnucleus of the DRN in alcohol-dependent depressed suicides 16 but found no change in non-alcoholic depressed suicides, 17 demonstrating the anatomically restricted contributions of individual DRN subnuclei in regulating serotonin.…”