Elevated Tyrosine Hydroxylase in the Locus Coeruleus of Suicide Victims

Ordway, Gregory A.; Smith, Kristin L.; Haycock, John W.

doi:10.1046/j.1471-4159.1994.62020680.x

Cited by 136 publications

(73 citation statements)

References 22 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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“…Levels of monoamine neurotransmitters and metabolites (HPLC with electrochemical detection; Wilson et al 1994 (Ordway et al 1994;Zhong et al 1995), VMAT2 protein by quantitative blot immunolabeling using an affinity-purified antibody (Chemicon) raised against a previously described peptide (Erickson et al 1996), and ERK1/2 protein by quantitative blot immunolabeling (Ortiz et al 1995) were conducted as previously described.…”

Section: Brain Dissection and Neurochemical Analysesmentioning

confidence: 99%

Striatal Dopaminergic and Serotonergic Markers in Human Heroin Users

Kish

Kalasinsky

Derkach

et al. 2001

Neuropsychopharmacology

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To establish whether chronic opiate exposure might impair brain dopaminergic or serotonergic function in humans, we assessed biochemical indices of monoaminergic neurotransmitter activity and integrity in post mortem striatum of nine chronic heroin users and 14 control subjects. Striatal levels of the vesicular monoamine transporter were normal, suggesting that the density of dopamine nerve terminals is not reduced in heroin users. In nucleus accumbens, levels of tyrosine hydroxylase protein (-25%) and those of the dopamine metabolite homovanillic acid (-33%) were reduced significantly together with a trend for decreased dopamine (-32%) An important feature of psychostimulant and opiate drugs of abuse is their ability, upon acute administration, to activate brain dopaminergic neurons as evidenced by increased striatal synaptic concentrations of dopamine (DiChiara 1995). Chronic dopaminergic overactivity caused by drugs of abuse leads to a variety of compensatory changes that could influence behavior of the drug user. Synaptic levels of dopamine are decreased in experimental animals withdrawn from chronic psychostimulants (cf. DiChiara 1995) whereas striatal tissue dopamine levels are reduced in human chronic psychostimulant users: moderately for methamphetamine users (Wilson et al. 1996a) or slightly for cocaine users (Wilson et al. 1996b). These changes could explain the dysphoric anhedonic motivational state during withdrawal to psychostimulant drugs. Both experimental animals and humans (cf. Wilson et al. 1996a,b) exposed to psychostimulants also demonstrate altered striatal levels of the dopamine transporter (DAT), a 24 , NO . 5 component of the dopamine nerve terminal critically involved in regulation of synaptic dopamine levels.Relatively less attention has been focused on longterm effects of opiate drugs of abuse on the dopamine system. In fact, it has been assumed that opiates do not produce "enduring changes" in dopaminergic transmission or cellularity (Rogers et al. 1999). Chronic administration of morphine or heroin to rodents, however, causes decreased striatal concentrations of synaptic dopamine (Acquas et al. 1991;Crippens and Robinson 1994), its biosynthetic enzyme tyrosine hydroxylase (Self et al. 1995) and those of DAT (Simantov 1993). Chronic morphine appears to damage dopaminergic neurons as indicated by impaired axonal transport from the dopamine cell body area of the ventral tegmental area (VTA) to nucleus accumbens, decreased size of dopaminergic cell bodies, and by increased expression in VTA of a marker of injury, glial fibrillary acidic protein (Beitner-Johnson et al. 1992;1993;Self et al. 1995; SklairTavron et al. 1996). As these animal data suggest that opiates might impair, reversibly or irreversibly, brain dopaminergic function in humans, we determined whether concentrations of biochemical markers of dopamine nerve terminal function and integrity are decreased in post mortem striatum (caudate, putamen, nucleus accumbens) of human chronic heroin users. The markers included ...

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“…Left side nuclei were used for other experiments. We have previously found no differences in right and left side biochemical or cellular data (37,41,42). Tissue blocks were then sectioned sequentially using a cryostat microtome (− 16°C ) in a transverse plane perpendicular to the floor of the fourth ventricle throughout the entire length of the LC beginning near its rostral end, collecting all tissue sections.…”

Section: Dissectionmentioning

confidence: 99%

“…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 Tyrosine Hydroxylase in the Locus Coeruleus of Suicide Victims

Cited by 136 publications

References 22 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

Striatal Dopaminergic and Serotonergic Markers in Human Heroin Users

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

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