Noradrenergic function in generalized anxiety disorder: Effects of yohimbine in healthy subjects and patients with generalized anxiety disorder

doi:10.1016/0165-1781(89)90132-7

Psychiatry Research

Volume 27, Issue 2, February 1989, Pages 173-182

https://doi.org/10.1016/0165-1781(89)90132-7 Get rights and content

Abstract

There is extensive preclinical and clinical support for the hypothesis that hyperactivity of noradrenergic neuronal systems is related to the pathophysiology of some forms of human anxiety. In the present investigation, the behavioral, biochemical, and cardiovascular responses to the α₂-adrenergic receptor antagonist, yohimbine, was determined in 20 patients with generalized anxiety disorder (GAD) and 20 healthy subjects. The responses to yohimbine were generally similar in the two groups except there was a trend for the yohimbine-induced increase in plasma 3-methoxy-4-hydroxyphenylglycol to be less in the GAD patients. These findings contrast with previous studies of the effects of yohimbine in panic disorder patients and, thereby, support a neurobiological distinction between these two disorders.

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Cited by (84)

Yohimbine enhancement of exposure therapy for social anxiety disorder: A randomized controlled trial
2014, Biological Psychiatry
Citation Excerpt :
Our study also replicates both published studies of yohimbine augmentation of exposure therapy in finding that low doses of yohimbine HCl (ten 10.8 mg in these studies) are not associated with adverse events (20,21). These findings are inconsistent with studies documenting increased nervousness among healthy control subjects after administration of intravenous yohimbine (47) or 20 mg of oral yohimbine (48) but consistent with other reports on the safety of acute and chronic administration of lower doses of oral yohimbine in healthy individuals (11). In terms of mechanism of action, our study was designed to minimize the influence of enhanced autonomic symptoms and anxiety on exposure outcome.
Preclinical and clinical trials suggest that yohimbine may augment extinction learning without significant side effects. However, previous clinical trials have only examined adults with specific phobias. Yohimbine has not yet been investigated in the augmentation of exposure therapy for other anxiety disorders.
Adults (n = 40) with a DSM-IV diagnosis of social anxiety disorder were randomized to placebo or yohimbine HCl (10.8 mg) 1 hour before each of four exposure sessions. Outcome measures were collected at baseline, each treatment session, posttreatment, and 1-month follow-up.
Yohimbine was well tolerated. Yohimbine augmentation, relative to placebo augmentation, resulted in faster improvement and better outcomes on self-report measures of social anxiety disorder severity (Liebowitz Social Anxiety Scale, d = .53) and depressed mood severity (Beck Depression Inventory, d = .37) but not on the clinician-rated measures (Clinical Global Impressions-Severity Scale, d = .09; Clinical Global Impressions-Improvement Scale, d = .25). Between-group differences on the Liebowitz Social Anxiety Scale were moderated by the level of fear reported at the end of an exposure exercise (end fear), such that the advantage of yohimbine over placebo was only evident among patients who reported low end fear.
The results provide moderate support for yohimbine as a therapeutic augmentation strategy for exposure therapy in social anxiety disorder, one that may be especially effective when coupled with successful exposure experiences. Beneficial effects for yohimbine were readily evident for self-report measures but not for clinician-rated outcomes of social anxiety severity and improvement.
Alterations in ethanol seeking and self-administration following yohimbine in selectively bred alcohol-preferring (P) and high alcohol drinking (HAD-2) rats
2013, Behavioural Brain Research
Evidence suggests that stress increases alcohol drinking and promotes relapse in humans. Animal models that assess related behaviors include the sipper tube ethanol self-administration and the stress-induced reinstatement paradigms. While selectively bred for the same high-ethanol-drinking behavior, alcohol-preferring P rats appear to show greater sensitivity to ethanol reinforcement than high-alcohol-drinking HAD rats. The present experiment tested the effects of the pharmacological stressor, yohimbine, on the motivation to seek and consume ethanol implementing a combined sipper tube/reinstatement model using male P and HAD-2 rats. Following training to self-administer ethanol using the sipper tube procedure, rats were tested for the effects of yohimbine (0.625–2.5 mg/kg) on ethanol drinking. Subsequently, rats were tested for the effects of 1.25 mg/kg yohimbine on reinstatement of ethanol seeking. Yohimbine (0.625 and 1.25 mg/kg) increased ethanol self-administration, and the latter dose also decreased latency to complete the response requirement. Yohimbine elicited reinstatement of ethanol seeking in both lines. HAD-2 rats drank more ethanol, but showed similar responding on the ethanol-associated lever compared to P rats. These findings extend both the reinstatement and sipper tube models and justify further exploration of this unique combined paradigm. Despite prior evidence suggesting that P rats are more motivated to seek and consume ethanol, differences in these behaviors between P and HAD-2 rats were not systematic in the present experiment. Further investigation may elucidate whether either selected line may be more sensitive than other selectively bred or outbred rats to stress-related changes in ethanol's reinforcing effects.
Cannabinoid receptor signaling and modulation of monoamines: Implications for psychiatric and neurological disorders
2012, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Generalized anxiety disorder
2012, Handbook of Clinical Neurology
Generalized anxiety disorder (GAD) is common in clinical practice. Most cases are comorbid with another Axis I disorder, notably mood disorders like major depressive disorder and bipolar disorders, and with many chronic medical illnesses. Although trivialized as a disorder, GAD is consistently associated with considerable disability and with overutilization of medical services.
The diagnostic criteria for GAD have shifted more than most other Axis I disorders over the past two decades and even differ significantly between DSM-IV and ICD-10. In the past two decades, there have been a substantial number of failed double-blind studies on GAD, even with treatments expected and suspected to work effectively. The neurobiology and genetic underpinnings of the disorder are little understood and its pathophysiology is unclear, especially in differentiating it from its neighboring disorders. These and changes in the healthcare marketplace have led to ever-diminishing interest in investing in scientific research and development of new treatment for this disabling condition. However, there are several effective treatments for GAD. Although time to remission is slow and long-term treatment is usually necessary, many achieve good outcomes when properly managed.
Neuropeptide Y-Y2 receptor knockout mice: Influence of genetic background on anxiety-related behaviors
2011, Neuroscience
Neuropeptide Y (NPY) has been extensively studied in relation to anxiety and depression but of the seven NPY receptors known to date, it is not yet clear which one is mainly involved in mediating its effects in emotional behavior. Mice lacking the NPY-Y2 receptors were previously shown to be less anxious due to their improved ability to cope with stressful situations. In the present study, the behavioral phenotype including the response to challenges was analyzed in NPY-Y2 knockout (KO) mice backcrossed in to congenic C57BL/6 background. In the elevated plus-maze (EPM) and the forced swim test (FST), the anxiolytic-like or antidepressant-like phenotype of the NPY-Y2 KO mice could not be confirmed, although this study differs from the previous one only with regard to the genetic background of the mice. In addition, no differences in response to acute stress or to the antidepressant desipramine in the FST were detected between wild type (WT) and NPY-Y2 KO animals. These results suggest that the genetic background of the animals appears to have a strong influence on the behavioral phenotype of NPY-Y2 KO mice. Additionally, to further characterize the animals by their biochemical response to a challenge, the neurochemical changes induced by the anxiogenic compound yohimbine were measured in the medial prefrontal cortex (mPFC) of NPY-Y2 KO and compared to WT mice. Dopamine (DA) levels were significantly increased by yohimbine in the WT but unaffected in the KO mice, suggesting that NPY-Y2 receptor exerts a direct control over both the tonic and phasic release of DA and that, although the anxiety-like behavior of these NPY-Y2 KO mice is unaltered, there are clear modifications of DA dynamics. However, yohimbine led to a significant increase in noradrenaline (NA) concentration and a slight reduction in serotonin concentration that were identical for both phenotypes.
Fear-potentiated startle, but not light-enhanced startle, is enhanced by anxiogenic drugs
2010, Pharmacology Biochemistry and Behavior
The light-enhanced startle paradigm (LES) is suggested to model anxiety, because of the non-specific cue and the long-term effect. In contrast, the fear-potentiated startle (FPS) is suggested to model conditioned fear. However, the pharmacological profiles of these two paradigms are very similar. The present study investigated the effects of putative anxiogenic drugs on LES and FPS and aimed at determining the sensitivity of LES for anxiogenic drugs and to potentially showing a pharmacological differentiation between these two paradigms.
Male Wistar rats received each dose of the α₂-adrenoceptor antagonist yohimbine (0.25–1.0 mg/kg), the 5-HT_2C receptor agonist m-chlorophenylpiperazine (mCPP, 0.5–2.0 mg/kg) or the GABA_A inverse receptor agonist pentylenetetrazole (PTZ, 3–30 mg/kg) and were subsequently tested in either LES or FPS.
None of the drugs enhanced LES, whereas mCPP increased percentage FPS and yohimbine increased absolute FPS values. Furthermore, yohimbine increased baseline startle amplitude in the LES, while mCPP suppressed baseline startle in both the LES and FPS and PTZ suppressed baseline startle in the FPS.
In contrast to findings in the FPS paradigm, none of the drugs were able to exacerbate the LES response. Thus, a clear pharmacological differentiation was found between LES and FPS.

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Noradrenergic function in generalized anxiety disorder: Effects of yohimbine in healthy subjects and patients with generalized anxiety disorder

Abstract

Life Sciences

Lancet

Psychiatry Research

Progress in Neurobiology

Brain Research

Medical Clinics of North America

DSM-III: Diagnostic and Statistical Manual of Mental Disorders

Benzodiazepine receptors

The psychophysiology of anxiety: With a review of literature concerning adrenaline

Journal of Nervous and Mental Disease

The diagnostic validity of anxiety disorders and their relationship to depressive illness

American Journal of Psychiatry

Urinary MHPG, stress response, personality factors and somatosensory evoked potentials in normal subjects and patients with major affective disorders

Neuropsychobiology

Platelet α2-adrenergic receptor binding and plasma catecholamines: Before and during imipramine treatment in patients with panic anxiety

Archives of General Psychiatry

Abnormal regulation of noradrenergic function in panic disorders: Effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder

Archives of General Psychiatry

Noradrenergic function in panic anxiety: Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder

Archives of General Psychiatry

Assessment of alpha-2 adrenergic autoreceptor function in humans: Effects of oral yohimbine

Life Sciences

Abrupt discontinuation of tricyclic antidepressant drugs: Evidence of noradrenergic hyperactivity

British Journal of Psychiatry

Neurobiological mechanisms of panic anxiety: Biochemical and behavioral correlates of yohimbine-induced panic attacks

American Journal of Psychiatry

Platelet α₂-adrenergic receptor binding and plasma catecholamines: Before and during imipramine treatment in patients with panic anxiety