CSF Norepinephrine Concentrations in Posttraumatic Stress Disorder

Geracioti, Thomas D.; Baker, Dewleen G.; Ekhator, Nosa N.; West, Scott A.; Hill, Kelly; Bruce, Ann; Schmidt, Dennis E.; Rounds-Kugler, Barbara; Yehuda, Rachel; Keck, Paul E.; Kasckow, John

doi:10.1176/appi.ajp.158.8.1227

Cited by 413 publications

(275 citation statements)

References 31 publications

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“…In this regard, NPY has a reciprocal functional relationship with both norepinephrine (15) and corticotropin-releasing hormone (CRH) (16). Interestingly, our previous data showing elevated basal CRH and norepinephrine concentrations in the CSF of combat-related PTSD patients (17,18) are consistent with the current finding.…”

Section: Discussionsupporting

confidence: 92%

Low Cerebrospinal Fluid Neuropeptide Y Concentrations in Posttraumatic Stress Disorder

Sah

Ekhator

Strawn

et al. 2009

Biological Psychiatry

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132

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Section: Discussionsupporting

confidence: 92%

Low Cerebrospinal Fluid Neuropeptide Y Concentrations in Posttraumatic Stress Disorder

Sah

Ekhator

Strawn

et al. 2009

Biological Psychiatry

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132

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“…Elevated NE and metabolites have been found in the cerebrospinal fluid, plasma, or brain tissue of schizophrenia patients (Yamamoto and Hornykiewicz, 2004), the cerebrospinal fluid of Tourette's (Leckman et al, 1995) and PTSD patients (Geracioti et al, 2001), and abnormalities in the LC itself also have been reported in schizophrenia patients (Gay et al, 1989;Lohr and Jeste, 1988;Marner et al, 2005). Because the present findings indicate that pharmacological stimulation of the LC-NE pathway is sufficient to disrupt PPI and dysregulation of the LC-NE system has been implicated in all of these conditions (Boehnlein and Kinzie, 2007;Robbins and Arnsten, 2009;Yamamoto and Hornykiewicz, 2004), it may be that altered tonic LC activity is a mechanism for the deficient sensorimotor gating that is seen in a subset of patients, regardless of their nosological classification into various illnesses.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

Alsene

Bakshi

2011

Neuropsychopharmacol

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Surprisingly little is known about the modulation of core endophenotypes of psychiatric disease by discrete noradrenergic (NE) circuits. Prepulse inhibition (PPI), the diminution of startle responses when weak prestimuli precede the startling event, is a widely validated translational paradigm for information-processing deficits observed in several mental disorders including schizophrenia, Tourette's syndrome, and post-traumatic stress disorder (PTSD). Despite putative NE disturbances in these illnesses, NE regulation of PPI remains poorly understood. In these studies, regulation of PPI by the locus coeruleus (LC), the primary source of NE to forebrain, was evaluated in rats using well-established protocols to pharmacologically activate/inactivate this nucleus. The ability of drugs that treat deficient PPI in these illnesses to reverse LC-mediated PPI deficits was also tested. Stimulation of LC receptors produced an anatomically and behaviorally specific deficit in PPI that was blocked by clonidine (Cataprese, an a2 receptor agonist that reduces LC neuronal firing after peri-LC delivery), a postsynaptic a1 NE receptor antagonist (prazosin), and second-generation antipsychotics (olanzapine, seroquel), but not by drugs that antagonized dopamine-1 (SCH23390), dopamine-2 (the first-generation antipsychotic Haloperidol), or serotonin-2 receptors (ritanserin). These results indicate a novel substrate in the regulation of PPI and reveal a novel functional role for the LC. Hence, a hyperactive LC-NE system might underlie a deficient sensorimotor gating endophenotype in a subset of patients suffering from psychiatric illnesses including schizophrenia, Tourette's syndrome, and PTSD, and the ability to normalize LC-NE transmission could contribute to the clinical efficacy of certain drugs (Cataprese, prazosin, and second-generation antipsychotics) in these conditions.

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“…The reconsolidation process is particularly relevant for PTSD, in which persistent and recurring recall of the traumatic event may strengthen the traumatic memory over time, while also providing an opportunity for recall-based pharmacological intervention. Indeed, evidence from studies of rodents indicates that enhanced noradrenergic signaling, such as that observed in PTSD patients (Geracioti et al, 2001), is associated with enhancement of fear memory during reconsolidation and a subsequent increase in resistance to fear extinction (Debiec et al, 2011).…”

Section: Memory Erasurementioning

confidence: 99%

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

Zovkic

Sweatt

2012

Neuropsychopharmacol

172

111

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One of the most exciting discoveries in the learning and memory field in the past two decades is the observation that active regulation of gene expression is necessary for experience to trigger lasting functional and behavioral change, in a wide variety of species, including humans. Thus, as opposed to the traditional view of 'nature' (genes) being separate from 'nurture' (environment and experience), it is now clear that experience actively drives alterations in central nervous system (CNS) gene expression in an ongoing fashion, and that the resulting transcriptional changes are necessary for experience to trigger altered long-term behavior. In parallel over the past decade, epigenetic mechanisms, including regulation of chromatin structure and DNA methylation, have been shown to be potent regulators of gene transcription in the CNS. In this review, we describe data supporting the hypothesis that epigenetic molecular mechanisms, especially DNA methylation and demethylation, drive long-term behavioral change through active regulation of gene transcription in the CNS. Specifically, we propose that epigenetic molecular mechanisms underlie the formation and stabilization of context-and cue-triggered fear conditioning based in the hippocampus and amygdala, a conclusion reached in a wide variety of studies using laboratory animals. Given the relevance of cued and contextual fear conditioning to post-traumatic stress, by extension we propose that these mechanisms may contribute to post-traumatic stress disorder (PTSD) in humans. Moreover, we speculate that epigenetically based pharmacotherapy may provide a new avenue of drug treatment for PTSD-related cognitive and behavioral function.

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CSF Norepinephrine Concentrations in Posttraumatic Stress Disorder

Abstract: These findings reveal the presence of greater CNS noradrenergic activity under baseline conditions in patients with chronic PTSD than in healthy subjects and directly link this pathophysiologic observation with the severity of the clinical posttraumatic stress syndrome.

Cited by 413 publications

References 31 publications

Low Cerebrospinal Fluid Neuropeptide Y Concentrations in Posttraumatic Stress Disorder

Low Cerebrospinal Fluid Neuropeptide Y Concentrations in Posttraumatic Stress Disorder

Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

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