atrial-natriuretic-factor and Anxiety-Disorders

Neuropeptide systems have been considered a major opportunity for the development of novel treatment approaches for anxiety disorders based on preclinical evidence and neurochemical alterations seen in anxiety disorders. This excitement was further facilitated by the fact that drugs acting at these systems, such as CRF1 antagonists, NK1 antagonists, NK3 antagonists or CCK2 antagonists, may have unique properties not seen with drugs affecting more classical mechanisms involved in anxiety. Consequently, there have been major efforts to develop such small-molecule, nonpeptide receptor ligands. A number of these molecules have been tested in the clinic, either in trials where levels of anxiety served as a secondary measure, or in a few studies with patients suffering from anxiety disorders. But unfortunately, and despite all the efforts of the field as a whole, we still lack convincing clinical proof-of-concept for any of the neuropeptidergic approaches in patients. It must, therefore, be concluded that neuropeptide targets remain a promising approach for the development of the next generation drugs to treat anxiety disorders, but that they continue to be high-risk targets for drug development.

Topics: Acenaphthenes; Animals; Anti-Anxiety Agents; Anxiety Disorders; Aprepitant; Atrial Natriuretic Factor; Clinical Trials as Topic; Drug Discovery; Humans; Morpholines; Neurokinin-1 Receptor Antagonists; Oxytocin; Receptor, Cholecystokinin B; Receptors, Corticotropin-Releasing Hormone; Receptors, Neurokinin-3; Treatment Outcome

Diagnostic symptom provocation has a long tradition in medicine. In psychiatry, symptom provocation studies are used to study the pathophysiology and treatment of disorders. Sudden and unexpected panic attacks have a characteristic course and a typical pattern of somatic, cognitive, emotional, and behavioral symptoms. Beginning with the study of Pitts and McClure, who described the panicogenic activity of sodium lactate, the experimental induction of panic attacks with different challenges has been used to characterize the neurobiology of anxiety. Furthermore, experimentally induced panic attacks can be used to study possible new treatment approaches. The anxiolytic activity of atrial natriuretic peptide suggests that modulation of natriuretic peptide receptors with nonpeptidergic ligands may be a new treatment approach. Experimentally induced panic attacks are a tool to characterize the neurobiology of anxiety and panic and may be used to develop new treatment approaches.

Topics: Anxiety Disorders; Atrial Natriuretic Factor; Bicarbonates; Caffeine; Disease Models, Animal; Lactates; Lauric Acids; Panic Disorder; Sympathomimetics

Clinical and preclinical studies have gathered substantial evidence that stress response alterations play a major role in the development of major depression, panic disorder and posttraumatic stress disorder. The stress response, the hypothalamic pituitary adrenocortical (HPA) system and its modulation by CRH, corticosteroids and their receptors as well as the role of natriuretic peptides and neuroactive steroids are described. Examplarily, we review the role of the HPA system in major depression, panic disorder and posttraumatic stress disorder as well as its possible relevance for treatment. Impaired glucocorticoid receptor function in major depression is associated with an excessive release of neurohormones, like CRH to which a number of signs and symptoms characteristic of depression can be ascribed. In panic disorder, a role of central CRH in panic attacks has been suggested. Atrial natriuretic peptide (ANP) is causally involved in sodium lactate-induced panic attacks. Furthermore, preclinical and clinical data on its anxiolytic activity suggest that non-peptidergic ANP receptor ligands may be of potential use in the treatment of anxiety disorders. Recent data further suggest a role of 3alpha-reduced neuroactive steroids in major depression, panic attacks and panic disorder. Posttraumatic stress disorder is characterized by a peripheral hyporesponsive HPA-system and elevated CRH concentrations in CSF. This dissociation is probably related to an increased risk for this disorder. Antidepressants are effective both in depression and anxiety disorders and have major effects on the HPA-system, especially on glucocorticoid and mineralocorticoid receptors. Normalization of HPA-system abnormalities is a strong predictor of the clinical course, at least in major depression and panic disorder. CRH-R1 or glucorticoid receptor antagonists and ANP receptor agonists are currently being studied and may provide future treatment options more closely related to the pathophysiology of the disorders.

Topics: Adrenal Cortex Hormones; Animals; Antidepressive Agents; Anxiety Disorders; Atrial Natriuretic Factor; Corticotropin-Releasing Hormone; Depressive Disorder, Major; Humans; Hypothalamic Diseases; Hypothalamo-Hypophyseal System; Natriuretic Peptides; Neurotransmitter Agents; Panic Disorder; Pituitary-Adrenal System; Receptors, Atrial Natriuretic Factor; Receptors, Corticotropin-Releasing Hormone; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Receptors, Steroid; Stress Disorders, Post-Traumatic

Panic attacks induced by administration of cholecystokinin tetrapeptide (CCK-4) have been evaluated as a valuable tool to investigate the neurobiological mechanisms involved in panic anxiety. The rationale to study the effects of natriuretic peptides on the CCK-4 response is derived from observations that atrial natriuretic peptide (ANP) is released during panic attacks in humans and has anxiolyticlike actions in various animal models.. A double-blind, placebo-controlled design was conducted in 9 patients with panic disorder and 9 similar healthy control subjects. After pretreatment with an infusion of 150 microg of ANP or placebo in random order, each subject received 50 microg of CCK-4. Psychopathological parameters as well as physiological measures were sampled before and after CCK-4 administration.. After pretreatment with ANP, the number of CCK-4-induced panic attacks decreased from 8 to 6 in patients and from 5 to 2 in controls. Acute Panic Inventory ratings were significantly reduced in patients after ANP vs placebo pretreatment. Infusion of ANP significantly curtailed the CCK-4-induced release of corticotropin in patients. Heart rate variability analysis indicated a sympathetic stimulation by CCK-4 that was inhibited by ANP in patients and controls.. The present study indicates that ANP exerts anxiolyticlike effects on CCK-4-stimulated anxiety attacks in patients with panic disorder. In addition, ANP produced an inhibition of the hypothalamopituitary-adrenocortical system and sympatholytic effects.

Topics: Adrenocorticotropic Hormone; Adult; Anti-Anxiety Agents; Anxiety Disorders; Area Under Curve; Atrial Natriuretic Factor; Blood Pressure; Double-Blind Method; Female; Heart Rate; Humans; Hydrocortisone; Male; Panic Disorder; Placebos; Prospective Studies; Tetragastrin

To explore possible mechanism of electroacupuncture (EA) for regulating immune function in anxiety disorder (AD) rats by observing the effect of acupuncture on the histology of thymus and expressions of atrial natriuretic peptide (ANP) and natriuretic peptide receptor type A (NPR- A) in thymus.. Totally 34 SD healthy rats were randomly divided into the blank control group (n = 10), the model group (n = 12), the EA group (n = 12). Anxiety model was established in rats of the model group and the EA group by using chronic unpredictable stress (CUS) stimulation. EA (15/25 Hz) at Neiguan (PC6) and Shenmen (HT7) was performed in the EA group, with 15-min needle retaining, once every other day, 15 days in total. Needle was fixed at same acupoints for 15 min without electric stimulus in the other two groups. Anxiety-like behavior was measured by elevated plus-maze (EPM) test. Pathological changes of thymus tissue were observed by optical microscope. Expressions of ANP and NPR-A in thymus were measured by immunohistochemical assay.. The thymus tissue in the model group was severely atrophied, with unclear structure of thymic lobules, unclear margin of thymic medulla, loosely arranged lymphocytes ,and obviously enlarged volume of thymic corpuscle. The thymus tissue in the EA group was mildly atrophied, with existent structure of thymic lobules, clear margin of thymic medulla, densely arranged lymphocytes in cortical region, and widened medullary area. Com- pared with the blank control group, the percentage of open-arms entries (OE%) in the total QE times ob- viously decreased in the model group (P < 0.05), ANP expression obviously increased (P < 0.05), and NPR-A expression obviously decreased (P < 0.01). Compared with the model group, OE% was obviously elevated (P < 0.05), ANP expression obviously decreased (P < 0.05), and NPR-A expression obviously increased (P < 0.01) in the EA group.. EA not only could reduce anxiety of rats, but also could improve chronic stress induced thymus injury through intervening synthesis and secretion of ANP, as well as the expression of NPR-A (a specific receptor of ANP).

Topics: Acupuncture Points; Animals; Anxiety Disorders; Atrial Natriuretic Factor; Electroacupuncture; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; Thymus Gland