Normal [3H]flunitrazepam binding to GABAA receptors in the locus coeruleus in major depression and suicide

Zhu, He; Karolewicz, Beata; Nail, Emily; Stockmeier, Craig A.; Szebeni, Katalin; Ordway, Gregory A.

doi:10.1016/j.brainres.2006.09.082

Cited by 16 publications

(10 citation statements)

References 63 publications

(78 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…If there is a deficit in GABA neurotransmission in depression, then adaptive changes in the density of GABA receptors might be predicted. Studies of GABA-A receptor binding in post-mortem tissues from depressed and suicide subjects have not demonstrated consistent alterations as increases, decreases or no change were found in the benzodiazepine binding sites (Pandey et al, 1997; Cheetham et al, 1988; Rochet et al, 1992; Kugaya et al, 2003; Zhu et al, 2006). Moreover, gene expression studies report reduced (Merali et al, 2004) or up-regulated (Choudary et al, 2005) transcripts encoding specific subunits of the GABA-A receptor in depression and suicide.…”

Section: Discussionmentioning

confidence: 97%

Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression

Karolewicz

Maciąg

O'Dwyer

et al. 2009

Int. J. Neuropsychopharm.

Self Cite

157

View full text Add to dashboard Cite

Accumulating evidence suggests dysfunction of the gamma-aminobutyric acid (GABA) system in major depressive disorder (MDD). Neuroimaging studies consistently report reductions of cortical GABA in depressed patients. Our post-mortem analyses demonstrate a reduction in the density and size of GABAergic interneurons in the dorsolateral prefrontal cortex (PFC) in MDD. The goal of this study was to test whether the level of glutamic acid decarboxylase (GAD), the GABA synthesizing enzyme, will also be reduced in the same cortical region in MDD. Levels of GAD-65 and GAD-67 proteins were investigated by Western blotting in samples from the dorsolateral PFC (BA9) in 13 medication-free subjects with MDD, and 13 psychiatrically healthy controls. The overall amount of GAD-67 was significantly reduced (−34 %) in depressed subjects as compared to matched controls. Since recent neuroimaging studies demonstrate that antidepressants modulate GABA levels, additional experiments were performed to examine the levels of GAD in 8 depressed subjects treated with antidepressant medications. Levels of GAD-67 were unchanged in these depressed subjects as compared to their respective controls (n=8). The overall amounts of GAD-65 were similar in depressed subjects compared to matched controls, regardless of antidepressant medication. Reduced levels of GAD-67, which is localized to somata of GABA neurons, further support our observation of a decreased density of GABAergic neurons in the PFC in depression. It is likely that a decrease in GAD-67 accounts for the reduction in GABA levels revealed by neuroimaging studies. Moreover, our data support previous neuroimaging observations that antidepressant medication normalizes GABA deficits in depression.

show abstract

Section: Discussionmentioning

confidence: 97%

Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression

Karolewicz

Maciąg

O'Dwyer

et al. 2009

Int. J. Neuropsychopharm.

Self Cite

157

View full text Add to dashboard Cite

show abstract

“…Of interest, a gene expression study compared nonpsychiatric comparison subjects and both depressed and nondepressed suicide victims and found no differences between nondepressed suicide victims and comparison subjects in GABA receptors, subunits, or receptor-linked protein genes across several brain regions (139, 143). However, greater gene expression or binding in the hippocampus and prefrontal cortex of the depressed group (139, 141) suggests a potential role of GABA in depression. Two neuroreceptor binding studies did not confirm abnormalities in GABA A or GABA B in either suicide or depression compared with nonpsychiatric comparison subjects (141, 144).…”

Section: Neurotransmitter Systems Implicated In Suicidementioning

confidence: 99%

“…However, greater gene expression or binding in the hippocampus and prefrontal cortex of the depressed group (139, 141) suggests a potential role of GABA in depression. Two neuroreceptor binding studies did not confirm abnormalities in GABA A or GABA B in either suicide or depression compared with nonpsychiatric comparison subjects (141, 144). Together, these findings do not suggest GABA-ergic dysfunction in suicide.…”

Section: Neurotransmitter Systems Implicated In Suicidementioning

confidence: 99%

“…Few suicide studies have focused on GABA A receptors (13, 139-141). One study comparing GABA A α1, α2, α3, α4, α5, δ, and γ2 subunit mRNA expression in the frontopolar cortex of suicide victims and comparison subjects found decreased expression of α1, α3, α4, and δ mRNA in suicide victims (13), possibly linked to methylation patterns (142).…”

Section: Neurotransmitter Systems Implicated In Suicidementioning

confidence: 99%

See 1 more Smart Citation

Toward a Biosignature for Suicide

Oquendo¹,

Sullivan

Sudol

et al. 2014

AJP

253

210

View full text Add to dashboard Cite

Objective Suicide, a major cause of death worldwide, has distinct biological underpinnings. The authors review and synthesize the research literature on biomarkers of suicide, with the aim of using the findings of these studies to develop a coherent model for the biological diathesis for suicide. Method The authors examined studies covering a large range of neurobiological systems implicated in suicide. They provide succinct descriptions of each system to provide a context for interpreting the meaning of findings in suicide. Results Several lines of evidence implicate dysregulation in stress response systems, especially the hypothalamic-pituitary-adrenal axis, as a diathesis for suicide. Additional findings related to neuroinflammatory indices, glutamatergic function, and neuronal plasticity at the cellular and circuitry level may reflect downstream effects of such dysregulation. Whether serotonergic abnormalities observed in individuals who have died by suicide are independent of stress response abnormalities is an unresolved question. Conclusions The most compelling biomarkers for suicide are linked to altered stress responses and their downstream effects, and to abnormalities in the serotonergic system. Studying these systems in parallel and in the same populations may elucidate the role of each and their interplay, possibly leading to identification of new treatment targets and biological predictors.

show abstract

“…When used as an anesthetic in humans, midazolam suppresses glucose utilization in the LC [70]. Radiolabeled flunitrazepam binds to benzodiazepine receptors in the LC of human brains, and LC neurons are inhibited by activation of GABA A receptors [71, 72]. The benzodiazepines chlordiazepoxide and diazepam decrease stress-induced releases of NE [73, 74].…”

Section: Sleep-promoting Medicationsmentioning

confidence: 99%

Good night and good luck: Norepinephrine in sleep pharmacology

Mitchell

Weinshenker

2010

Biochemical Pharmacology

141

View full text Add to dashboard Cite

Sleep is a crucial biological process is regulated through complex interactions between multiple brain regions and neuromodulators. As sleep disorders can have deleterious impacts on health and quality of life, a wide variety of pharmacotherapies have been developed to treat conditions of excessive wakefulness and excessive sleepiness. The neurotransmitter norepinephrine (NE), through its involvement in the ascending arousal system, impacts the efficacy of many wake-and sleeppromoting medications. Wake-promoting drugs such as amphetamine and modafinil increase extracellular levels of NE, enhancing transmission along the wake-promoting pathway. GABAergic sleep-promoting medications like benzodiazepines and benzodiazepine-like drugs that act more specifically on benzodiazepine receptors increase the activity of GABA, which inhibits NE and the wake-promoting pathway. Melatonin and related compounds increase sleep by suppressing the activity of the neurons in the brain's circadian clock, and NE influences the synthesis of melatonin. Antihistamines block the wake-promoting effects of histamine, which shares reciprocal signaling with NE. Many antidepressants that affect the signaling of NE are also used for treatment of insomnia. Finally, adrenergic antagonists that are used to treat cardiovascular disorders have considerable sedative effects. Therefore, NE, long known for its role in maintaining general arousal, is also a crucial player in sleep pharmacology. The purpose of this review is to consider the role of NE in the actions of wake-and sleep-promoting drugs within the framework of the brain arousal systems.

show abstract

Normal [3H]flunitrazepam binding to GABAA receptors in the locus coeruleus in major depression and suicide

Cited by 16 publications

References 63 publications

Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression

Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression

Toward a Biosignature for Suicide

Good night and good luck: Norepinephrine in sleep pharmacology

Contact Info

Product

Resources

About