pituitrin and Anxiety-Disorders

The therapies of mood and anxiety disorders are not solved, because current antidepressants have delayed onset of therapeutic action and a significant number of patients are non-responsive. Research on the field was leaning towards neuropeptides as therapeutic targets. Vasopressin (VP) is a hot candidate, as beyond its peripheral actions VP is implicated in interneuronal communication and modulates the hypothalamo-pituitary-adrenal (HPA), the key stress axis, as well as behavioural functions. Affective disorders are stress related disorders and the most frequently occurring abnormality in depressed subjects is hyperactivity of the HPA. VP with nucleus paraventricularis hypothalami origin is a direct adrenocorticotrophin secretagogue through its V1b receptor. VP seems to have special importance under prolonged stress conditions, which are known to be strong predictive factor of depressive disorder and can induce depressive-like symptoms. Preclinical and clinical data summarized in this review underline the importance of VP in the development of anxiety- and depressive-like symptoms. Orally active nonpeptiderg V1b antagonists were developed and seemed to have effective anxiolytic and antidepressant profile in preclinical studies, which was not fully confirmed by clinical observations. It seems that V1a receptors on special brain areas could have same importance. Taken together current knowledge strongly implies an importance of vasopressinergic regulation in affective disorders and consider VP as endogenous anxiogenic/depressogenic substance. However, wide range of side effects could develop as a result of an intervention on the VP system; therefore there is a need for area-specific targeting of VP receptors (e.g. with modified nanoparticles).

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Antidiuretic Hormone Receptor Antagonists; Anxiety; Anxiety Disorders; Depression; Depressive Disorder; Diabetes Insipidus; Disease Models, Animal; Humans; Hypothalamo-Hypophyseal System; Inappropriate ADH Syndrome; Mice; Mice, Inbred BALB C; Mice, Knockout; Molecular Targeted Therapy; Mood Disorders; Pituitary-Adrenal System; Rats; Rats, Brattleboro; Rats, Mutant Strains; Receptors, Vasopressin; Stress, Psychological; Vasopressins

Affective disorders comprise mood disorders such as unipolar depression and anxiety disorders, including generalized anxiety, post-traumatic stress disorder, panic, phobia and obsessive-compulsive disorder. The etiology of these disorders is related to stress. Further, they are characterized by alterations of the hypothalamus-pituitary-adrenal (HPA) axis function, controlling the endocrine response to stress. Vasopressin is a nonapeptide that is mainly expressed and/or released in the hypothalamus and the pituitary, but also in other brain areas particularly in limbic regions. It strongly contributes to the endocrine and neural response to stress. Therefore, it has been suggested that vasopressin may be involved in affective disorders. Here, we review both clinical and preclinical data that investigated this hypothesis. Several studies show an increased plasmatic level of vasopressin in anxiety disorders as well as in unipolar depression. Further, a single nucleotide polymorphism (SNP) of the vasopressin V(1b) receptor has been found to protect against depression. Preclinical data are convergent with the clinical findings. For example, Brattleboro rats, that display decreased vasopressin function, show reduced anxiety, reduced depressive-like behavior and decreased HPA function. Rats selected for high anxiety behavior exhibit increased HPA function related to a SNP in the vasopressin locus resulting in an overexpression of vasopressin. Antagonism of the V(1b) receptor decreases anxiety and depressive-like behaviors in rodents, as well as HPA responsivity to stress. Taken together, these data indicate that affective disorders may be related to excessive vasopressin function and consequently that a treatment with vasopressin receptor antagonists may be an effective treatment.

Topics: Animals; Anxiety Disorders; Depressive Disorder; Humans; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Receptors, Vasopressin; Vasopressins

The amygdala is a complex structure playing primary role in the processing and memorizing of emotional reactions. The amygdalae send impulses to the hypothalamus for activation of the sympathetic nervous system, to the reticular nucleus for increasing reflexes, to the nuclei of the trigeminal nerve and facial nerve for facial expressions of fear, and to the ventral tegmental area, locus coeruleus, and laterodorsal tegmental nucleus for activation of dopamine, norepinephrine and epinephrine release. The amygdala plays a key role in what has been called the "general-purpose defense response control network" and reacts in response to unpleasant sights, sensations, or smells. Anger, avoidance, and defensiveness are emotions activated largely by the amygdale. The amygdala is responsible for activating ancestral signs of distress such as "tense-mouth" and defensive postures such as crouching. Poor functioning of amygdala has also been associated with anxiety, autism, depression, narcolepsy, post-traumatic stress disorder, phobias, frontotemporal dementia, and schizophrenia. Impairment of emotional event memory in patients with Alzheimer's disease also correlates with the intensity of amygdalar damage. All these events speak out for the importance to preserve the normal function of the amygdala which can only be achieved by constant deepening of our knowledge about this unique structure.

Topics: Alzheimer Disease; Amygdala; Anxiety Disorders; Autistic Disorder; Corticotropin-Releasing Hormone; Dementia; Emotions; gamma-Aminobutyric Acid; Humans; Neurotransmitter Agents; Oxytocin; Schizophrenia; Vasopressins

Affective disorders tend to be chronic and life-threatening diseases: suicide is estimated to be the cause of death in 10-15% of individuals with major depressive disorders. Major depression is one of the most prevalent and costly brain diseases with up to 20% of the worldwide population suffering from moderate to severe forms of the disease. Only 50% of individuals with depression show full remission in response to currently available antidepressant drug therapies which are based on serendipitous discoveries made in the 1950s. Previously underestimated, other severe depression-associated deleterious health-related effects have increasingly been recognized. Epidemiological studies have provided substantial evidence that patients with depression have a 2-4-fold increased risk both of developing cardiovascular disease and of mortality after experiencing a myocardial infarction. The majority of patients suffering from affective disorders have measurable shifts in their stress hormone regulation as reflected by elevated secretion of central and peripheral stress hormones or by altered hormonal responses to neuroendocrine challenge tests. In recent years, these alterations have increasingly been translated into testable hypotheses addressing the pathogenesis of illness. Refined molecular technologies and the creation of genetically engineered mice have allowed to specifically target individual genes involved in regulation of corticotropin releasing factor (CRF) and vasopressin (AVP) system elements. The cumulative evidence makes a strong case implicating dysfunction of these systems in the etiology and pathogenesis of depression and pathological anxiety. Translation of these advances into novel therapeutic strategies has already been started.

Topics: Animals; Anxiety Disorders; Corticotropin-Releasing Hormone; Depressive Disorder; Humans; Hypothalamo-Hypophyseal System; Mutation; Pituitary-Adrenal System; Receptors, Corticotropin-Releasing Hormone; Receptors, Vasopressin; Vasopressins

The brain systems that motivate humans to form emotional bonds with others probably first evolved to mobilize the high-quality maternal care necessary for reproductive success in placental mammals. In these species, the helplessness of infants at birth and their dependence upon nutrition secreted from their mothers' bodies (milk) and parental body heat to stay warm required the evolution of a new motivational system in the brain to stimulate avid and sustained mothering behavior. Other types of social bonds that emerged subsequently in placental mammals, in particular monogamous bonds between breeding pairs, appear to have evolved from motivational brain systems that stimulate maternal behavior. This chapter focuses on aspects of the evolution and neurobiology of maternal and pair bonding and associated behavioral changes that may provide insights into the origins of human violence. The roles of the neuropeptides oxytocin and vasopressin as well as the neurotransmitter dopamine will be emphasized. Maternal and pair bonding are accompanied by increased aggressiveness toward perceived threats to the object of attachment as well as diminished fear and anxiety in stressful situations. The sustained closeness with mother required for the survival of infant mammals opened a new evolutionary niche in which aspects of the mother's care became increasingly important in regulating development in offspring. The quantity and quality of maternal care received during infancy determines adult social competence, ability to cope with stress, aggressiveness, and even preference for addictive substances. Indeed, the development of neurochemical systems within the brain that regulate mothering, aggression, and other types of social behavior, such as the oxytocin and vasopressin systems, are strongly affected by parental nurturing received during infancy. Evidence will be reviewed that the neural circuitry and neurochemistry implicated in studies of lower mammals also facilitate primate/human interpersonal bonding. It is hypothesized that neural bonding systems may also be important for the development in individuals of loyalty to the social group and its culture. Neglect and abuse during early life may cause bonding systems to develop abnormally and compromise capacity for rewarding interpersonal relationships and commitment to societal and cultural values later in life. Other means of stimulating reward pathways in the brain, such as drugs, sex, aggression, and intimidating

Topics: Adolescent; Affect; Anxiety Disorders; Biomarkers; Brain; Culture; Dopamine; Female; Humans; Interpersonal Relations; Leadership; Love; Male; Motivation; Object Attachment; Oxytocin; Peer Group; Sexual Behavior; Social Environment; Stress, Psychological; Vasopressins; Violence

Neuroticism is a fundamental personality trait associated with proneness to feel negative affect. Here we ask how Neuroticism influences the neural response to positive and negative social interactions and how Neuroticism modulates the effect of intranasal oxytocin (OT) and vasopressin (AVP) on the neural response to social interactions. In a double-blind, placebo-controlled study, 153 male participants were randomized to receive 24 IU intranasal OT, 20 IU AVP or placebo. Afterwards, they were imaged with fMRI while playing an iterated Prisoner's Dilemma Game. On a different day, subjects completed the NEO personality inventory to measure Neuroticism. Neuroticism was positively correlated with the neural response to negative social interactions in the anterior cingulate cortex/medial prefrontal cortex and with the neural response to positive social interactions in the insula, indicating that Neuroticism modulates neuropsychological processing of both negative and positive social interactions. Neuroticism did not modulate the effect of intranasal OT treatment on the neural response to either positive or negative social interactions. On the other hand, AVP treatment significantly interacted with Neuroticism to modulate the BOLD response to both positive and negative social interactions. Specifically, AVP increased anterior cingulate cortex/medial prefrontal cortex and lateral temporal lobe responses to negative social interactions to a greater extent in participants scoring high rather than low on Neuroticism. AVP also increased the insula response to positive social interactions to a greater extent in participants scoring high rather than low on Neuroticism. These results imply that AVP may increase emotion regulation in response to negative social interactions and the salience of positive social interactions to a greater extent in individuals high compared to low in Neuroticism. The current findings urge caution against uniform clinical application of nonapeptides and suggest that their efficacy may vary as a function of personality.

Topics: Administration, Intranasal; Adolescent; Anxiety Disorders; Brain; Brain Mapping; Cerebrovascular Circulation; Double-Blind Method; Emotions; Humans; Interpersonal Relations; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Neuroticism; Oxygen; Oxytocin; Personality Tests; Prisoner Dilemma; Psychotropic Drugs; Vasopressins; Young Adult

Using data from the multicenter, observational Diast-CHF (Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure) study, this post-hoc analysis aimed at assessing the association between serum concentrations of C-terminal pro-arginine vasopressin (CT-proAVP) and anxiety in patients with cardiovascular risk factors.. Animal studies have demonstrated that centrally released AVP is involved in the development of anxiety-like behaviors, however, it is unknown whether, also in humans, CT-proAVP used as a proxy for the co-secreted AVP is associated with self-reported anxiety.. In 1463 study participants with cardiovascular risk factors (mean age 66.7 ± 8.1 years, 51.3% males, mean left ventricular ejection fraction 59.8 ± 8.3%), serum concentrations of CT-proAVP were measured by means of an ELISA assay, and anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS).. Data showed that there was a significant and inverse correlation between HADS anxiety and CT-proAVP (rho = -0.074; p = 0.005). Serum CT-proAVP and the HADS anxiety differed between the two sexes: men displayed lower anxiety (4.7 ± 3.5 versus 5.5 ± 3.7) and had higher CT-proAVP levels (5.8 pmol/L, interquartile range 3.5-9.9 pmol/L versus 3.0 pmol/L, interquartile range 2.0-4.7) than women (both, p < 0.001). Using univariate ANOVA adjusted for age, body-mass index, estimated glomerular filtration rate, left ventricular ejection fraction, 6-minute walking distance, SF-36 physical functioning, and the natriuretic peptides NT-proBNP and MR-proANP, the interaction term sex*CT-proAVP was significantly associated with anxiety (p = 0.006). Further analysis showed that CT-proAVP was inversely related to anxiety only in men (B = -0.991; 95%CI = -1.650 to -0.331; p = 0.003), but not in women (p = 0.335).. In male study participants with cardiovascular risk factors, serum concentrations of CT-proAVP showed an inverse association with anxiety, which was independent from the severity of physical impairment.

Topics: Aged; Anxiety; Anxiety Disorders; Arginine Vasopressin; Biomarkers; Cardiovascular Diseases; Cardiovascular System; Female; Humans; Male; Middle Aged; Neurophysins; Prognosis; Protein Precursors; Risk Factors; Sex Factors; Tomography, X-Ray Computed; Vasopressins

The present study was designed to reveal possible common and specific neuroendocrine mechanisms of depression and anxiety-like states in rodents. Animal models of depression and anxiety (in particular, posttraumatic stress disorder, PTSD) were applied including the learned helplessness and the stress-restress paradigms, respectively. Immunocytochemical staining revealed that depressive- and anxiety-like states in animals were accompanied by the rise in corticotropin-releasing hormone (CRH) immunoreactivity in the parvocellular division of the hypothalamic paraventricular nucleus (PVN). Decrease in vasopressin-immunoreactivity in early period of depressive-like state development was followed by the normalization of vasopressin content in the hypothalamic PVN in delayed period. Increased CRH and vasopressin immunoreactivity in the magnocellular part of the PVN in delayed period of anxiety-like state development was detected only in the stress-restress paradigm. These results suggest that CRH hyperdrive in the parvocellular PVN appears to be a common neuroendocrine abnormality for depressive- and anxiety-like states in animals, while over-expression of CRH and vasopressin in the magnocellular PVN represents a specific feature of anxiety/PTSD-like state.

Topics: Animals; Anxiety Disorders; Corticotropin-Releasing Hormone; Depressive Disorder; Disease Models, Animal; Helplessness, Learned; Immunohistochemistry; Male; Paraventricular Hypothalamic Nucleus; Rats; Rats, Wistar; Restraint, Physical; Stress Disorders, Post-Traumatic; Stress, Psychological; Vasopressins

Many psychiatric disorders are a result of a disturbance in or exhaustion of the human stress response system. It is striking that many of these disorders such as depression, anxiety disorders and post-traumatic stress and somatoform and dissociative disorders are more prevalent in women. There are various explanations for this differing prevalence: it can be attributed to molecular, genetic, neurophysiological, relational and neurohormonal differences. Among the topics discussed are differences in exposure to chronic and traumatic stressors, the role of vasopressin and oxytocin in recovery and neurophysiological differences, the differentiating effect of hormones and neuropeptides such as oxytocin and vasopressin, the tend and befriend response and factors such as abuse and attachment disruption in early childhood.

Topics: Anxiety Disorders; Chronic Disease; Depressive Disorder; Dissociative Disorders; Female; Genetic Predisposition to Disease; Humans; Male; Oxytocin; Prevalence; Sex Factors; Stress Disorders, Post-Traumatic; Stress, Psychological; Vasopressins

We investigated the influence of a representative classical benzodiazepine on the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis activity both under basal conditions and stress. Adult male Wistar rats were intravenously administered with temazepam (0.5, 1, and 3 mg/kg body weight) and plasma concentrations of corticotropin (ACTH) and vasopressin (AVP) were measured in blood samples collected via chronically implanted jugular venous catheters. Simultaneously, the release of AVP within the hypothalamic paraventricular nucleus (PVN) was monitored via microdialysis. Plasma AVP levels remained unaffected by the different treatment conditions. Temazepam blunted the stressor exposure-induced secretion of ACTH in a dose-dependent manner. Concurrently, and also in a dose-dependent manner temazepam enhanced the intra-PVN release of AVP, known to originate from magnocellular neurons of the hypothalamic neurohypophyseal system. Furthermore, temazepam did not affect the in vitro secretion of ACTH from the adenohypophyseal cells. Taken together, the results of this study suggest that temazepam modulates the central nervous regulation of the HPA axis by altering intra-PVN AVP release. An increasingly released AVP of magnocellular origin seems to provide a negative tonus on ACTH secretion most probably via inhibiting the release of ACTH secretagogues from the median eminence into hypophyseal portal blood.

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Animals; Anxiety Disorders; Depressive Disorder; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Fluid; GABA Modulators; Hypothalamo-Hypophyseal System; Male; Median Eminence; Microdialysis; Paraventricular Hypothalamic Nucleus; Pituitary Gland; Pituitary-Adrenal System; Rats; Rats, Wistar; Stress, Psychological; Temazepam; Vasopressins

An anxious-retarded subtype of depression has been derived from the DSM-IV category of melancholia. It is defined by combined high scores for anxiety and retardation, and is related to family history of depression and increased plasma vasopressin (AVP) levels. Central problems concerning this hypothesized subcategory are whether elevated plasma AVP is related to family history, whether it would be better operationalized by a cut-off level for plasma AVP than as continuous variable, and whether the anxious-retarded phenotype would be better described in terms that account for full variability of mixed anxiety and retardation. A previous study suggested that above-normal plasma AVP was a more useful endophenotypic parameter than plasma AVP as a continuous variable. To answer these and related questions, 81 patients were investigated. Receiver Operating Characteristic analyses yielded a cut-off value of 5.56 pg/ml for above-normal plasma AVP, log-transformed plasma AVP (ln (AVP)) was used as continuous variable, and the correlation between anxiety and retardation was used to account for full variability of the anxious-retarded phenotype. Family history was related to above-normal plasma AVP (n = 16) and non-significantly to ln (AVP). Depression with above-normal plasma AVP, as well as familial depression with above-normal plasma AVP, showed a high correlation between anxiety and retardation, and this correlation was significantly higher than that found in the depressed patient control groups. The data support the delimitation of a largely familial depression with above-normal plasma AVP, vasopressinergic activation of the hypothalamus-pituitary-adrenal axis and a variable anxious-retarded phenotype.

Topics: Adult; Anxiety Disorders; Depressive Disorder, Major; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Intellectual Disability; Male; Middle Aged; Phenotype; Pituitary-Adrenal System; Surveys and Questionnaires; Vasopressins

The neuroendocrine and behavioral effects of chronic paroxetine treatment were investigated in two rat lines selectively bred for high anxiety-related behavior (HAB) or low anxiety-related behavior (LAB) emotionality. In addition to a characteristic behavioral phenotype with markedly passive stress-coping strategies, HAB rats show a hypothalamic vasopressinergic hyperdrive that is causally related to hypothalamic-pituitary-adrenocortical dysregulation as demonstrated in the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test. A total of 8 weeks of chronic paroxetine treatment induced a more active coping strategy in the forced swim test in HAB rats only. In contrast, paroxetine-treated LAB rats did not change their swimming behavior. To investigate the neuroendocrine alterations linked to these behavioral changes, a combined DEX/CRH test was performed. In HAB rats, the paroxetine-induced behavioral changes towards more active coping strategies were accompanied by a normalization of the CRH-stimulated increase in corticotropin (ACTH) and corticosterone secretion. Concomitantly, the hypothalamic vasopressinergic hyperdrive was found to be reduced in HAB but not LAB rats, as indicated by a decrease in vasopressin mRNA expression, whereas vasopressin 1a receptor binding was unaffected. These findings provide the first evidence that the vasopressinergic system is likely to be critically involved in the behavioral and neuroendocrine effects of antidepressant drugs. This novel mechanism of action of paroxetine on vasopressin gene regulation renders vasopressinergic neuronal circuits a promising target for the development of more causal antidepressant treatment strategies.

Topics: Animals; Anxiety Disorders; Disease Models, Animal; Hypothalamus; Male; Neurosecretory Systems; Paroxetine; Rats; RNA, Messenger; Species Specificity; Vasopressins

Topics: Adolescent; Adult; Anxiety Disorders; Body Weight; Chlorpromazine; Electroconvulsive Therapy; Humans; Male; Schizophrenia; Stimulation, Chemical; Vasopressins