Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression

Zhu, Meng; Klimek, Violetta; Dilley, Ginny E.; Haycock, John W.; Stockmeier, Craig A.; Overholser, James C.; Meltzer, Herbert Y.; Ordway, Gregory A.

doi:10.1016/s0006-3223(99)00135-3

Cited by 127 publications

(84 citation statements)

References 67 publications

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“…Abnormalities that have been observed in the LC from human depressives (Klimek et al, 1997;Ordway et al, 1994aOrdway et al, , 1994bOrdway et al, , 2003Zhu et al, 1999) can be reproduced, in part, by chronic stress or pharmacological depletion of norepinephrine in rats (Cubells et al, 1995;Lee et al, 1983;Melia et al, 1992;Torda et al, 1985;U'Prichard et al, 1979;Wang et al, 1998;Zafar et al, 1997). Given that stress activates the LC in laboratory animals (Pavcovich et al, 1990), that chronic stress depletes norepinephrine in the LC (Weiss and Simson, 1986), and that stress is a common precipitator of depression in humans, it seems possible that depression may be associated with elevated excitatory input to the LC.…”

Section: Role Of Glutamatergic Signaling In Depressionmentioning

confidence: 99%

“…Previous observations reveal that depression is associated with altered concentrations of several noradrenergic proteins in the LC. For example, elevated levels of tyrosine hydroxylase (TH) (Ordway et al, 1994a;Zhu et al, 1999), increased agonist binding to a 2 -adrenergic receptors (Ordway et al, 1994b(Ordway et al, , 2003, and reduced levels of norepinephrine transporters (Klimek et al, 1997) were previously reported in the LC from major depression and in suicide victims. Interestingly, depletion of norepinephrine or repeated stress in rats can increase TH expression, increase binding to a 2 -adrenergic receptors, and/or decrease binding to the norepinephrine transporter (Cubells et al, 1995;Lee et al, 1983;Melia et al, 1992;Torda et al, 1985;U'Prichard et al, 1979;Wang et al, 1998;Zafar et al, 1997).…”

Section: Introductionmentioning

confidence: 96%

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Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Karolewicz

Stockmeier

Ordway

2005

Neuropsychopharmacol

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Low levels of the intracellular mediator of glutamate receptor activation, neuronal nitric oxide synthase (nNOS) were previously observed in locus coeruleus (LC) from subjects diagnosed with major depression. This finding implicates abnormalities in glutamate signaling in depression. Receptors responding to glutamate in the LC include ionotropic N-methyl-D-aspartate receptors (NMDARs). The functional NMDAR is a hetero-oligomeric structure composed of NR1 and NR2 (A-D) subunits. Tissue containing the LC and a nonlimbic LC projection area (cerebellum) was obtained from 13 and 9 matched pairs, respectively, of depressed subjects and control subjects lacking major psychiatric diagnoses. NMDAR subunit composition in the LC was evaluated in a psychiatrically normal subject. NR1 and NR2C subunit immunoreactivities in LC homogenates showed prominent bands at 120 and 135 kDa, respectively. In contrast to NR1 and NR2C, very weak immunoreactivity of NR2A and NR2B subunits was observed in the LC. Possible changes in concentrations of NR1 and NR2C that might occur in depression were assessed in the LC and cerebellum. The overall amount of NR1 immunoreactivity was normal in the LC and cerebellum in depressed subjects. Amounts of NR2C protein were significantly higher ( þ 61%, p ¼ 0.003) in the LC and modestly, but not significantly, elevated in the cerebellum ( þ 35%) of depressives as compared to matched controls. Higher levels of NR2C subunit implicate altered glutamatergic input to the LC in depressive disorders.

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Section: Role Of Glutamatergic Signaling In Depressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Karolewicz

Stockmeier

Ordway

2005

Neuropsychopharmacol

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“…As noted above, various lines of evidence, both preclinical and clinical, indicate that therapeutically-effective AD treatments result in a decrease in the activity of LC neurons (see Grant and Weiss, 2001; Nestler et al , 1990; Ordway et al , 1994; West et al , 2009; Zhu et al , 1999). For PAR, the time-course data for adult rats in the present study indicate that this effect develops over treatment time, perhaps determined by gradual changes in brain receptor function and/or other trophic processes triggered by the drug treatment.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously observed that many symptoms of depression appear in conjunction with increase in activity of the principal noradrenergic cell group in the brain, the locus coeruleus (LC) (Simson and Weiss, 1988; Weiss et al , 1996, 1998, 2005). Evidence of LC hyperactivity in depression has been obtained from clinical observations, such as higher cerebrospinal fluid levels of norepinephrine and its primary metabolite 3-methoxy-6-hydroxyphenylglycol (MHPG) in depressives (Ehnvall et al , 2003, Wong et al , 2000) and higher levels of tyrosine hydroxylase, the rate-limiting enzyme for norepinephrine synthesis, in LC of suicide victims (Ordway et al , 1994, Zhu et al , 1999). …”

Section: Introductionmentioning

confidence: 99%

Paroxetine-Induced Increase in Activity of Locus Coeruleus Neurons in Adolescent Rats: Implication of a Countertherapeutic Effect of an Antidepressant

West

Ritchie

Weiss

2010

Neuropsychopharmacol

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Concern that antidepressant (AD) drugs, especially selective serotonin reuptake inhibitors and paroxetine (PAR) in particular, can increase suicidality during the early treatment of juvenile patients (children and adolescents) has created a dilemma for clinicians treating depressives. Though preclinical research cannot resolve controversy in this area, our present findings may provide insight into how AD drugs might, under certain conditions, exacerbate rather than ameliorate the depressive state. Both clinical and preclinical evidence indicates that the principle noradrenergic cell group in the brain, the locus coeruleus (LC), is over-active in depressives and that, conversely, effective AD treatments decrease activity of LC neurons. We report here that short-term (2 and 4 day) administration of PAR produces an increase in the activity of LC neurons (spontaneous firing rate and sensory-evoked responses) in young rats, contrary to the “therapeutic” decrease in activity typically observed in adult rats. Blood levels of PAR were lower in young rats than in adult rats, though similar low blood levels produced by a lower dose of PAR in adult rats failed to produce an increase in LC activity. Additionally, activity of young rats in the swim test was determined to assess depressive-like responses. The same dose/durations of PAR which produced the largest increases in LC activity in young rats produced decreases in swim-test activity, indicating that brief administration of PAR in young rats can promote, rather than reduce, the depressive state. These results offer a model which may help screen potential adjunctive treatments to avoid early adverse effects of ADs.

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“…Converging evidence from studies of the LC from postmortem depressed subjects and from catecholamine-depletion studies in living depressed subjects has provided compelling evidence that depression is associated with a deficit in noradrenergic transmission [12,36,39] Previous observations from postmortem studies have revealed that major depressive disorder (MDD) and suicide are associated with altered concentrations of several noradrenergic proteins in the LC. For example, elevated levels of tyrosine hydroxylase [42,69], increased agonist binding to α 2 -adrenergic receptors [40,43] and reduced levels of norepinephrine transporters [20] have been reported in the LC from MDD subjects and/or from suicide victims. Studies utilizing laboratory animals provide interesting insights into the possible basis for these postmortem findings.…”

Section: Introductionmentioning

confidence: 99%

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

Zhu¹,

Karolewicz²,

Nail³

et al. 2006

Brain Research

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Major depression and suicide are associated with altered concentrations of specific noradrenergic proteins in the human locus coeruleus (LC). Based on experimental studies that can reproduce these LC abnormalities in laboratory animals, we hypothesized that noradrenergic pathobiology in depression is a result of over-activity of the LC. LC activity is under the control of both excitatory and inhibitory inputs. A major inhibitory input to the LC is GABAergic, arising from the nucleus prepositus hypoglossi. Numerous studies demonstrating low levels of GABA in the CSF and plasma of subjects with major depressive disorder (MDD) raise the possibility that LC over-activity in depression may be secondary to reduced GABAergic input to the LC. Here, GABAergic input to the LC in depression was evaluated by studying the binding of [ 3 H]flunitrazepam to GABA A receptors at three anatomically-defined levels of the human postmortem LC. LC tissues were collected from subjects with MDD, subjects with depressive disorders including MDD that died as a result of suicide, and psychiatrically normal control subjects. A modest rostral-caudal gradient of GABA A receptor binding density was observed amongst all subjects. No significant differences in the amount of binding to GABA A receptors were observed between control subjects (n=21) and MDD subjects (n=9) or depressed suicide victims (n=17). These results demonstrate that GABA A receptor binding in the LC measured with [ 3 H]flunitrazepam is not altered in subjects with depressive illnesses.

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Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression

Cited by 127 publications

References 67 publications

Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Paroxetine-Induced Increase in Activity of Locus Coeruleus Neurons in Adolescent Rats: Implication of a Countertherapeutic Effect of an Antidepressant

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

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