Congenital absence of vasopressin and age-dependent changes in ACTH and corticosterone stress responses in rats

The hypothalamic components of the hypothalamo-pituitary-adrenal axis (HPA) are corticotropin-releasing hormone (CRH) and vasopressin. To test the hypothesis that HPA regulation changes with age, we compared ether and bacterial lipopolysaccharide (LPS) injection induced stress reactions in adult and 10-day-old Brattleboro rats, which naturally lack vasopressin owing to mutation of the gene (di/di). The LPS stimulus was used also with V(1b) receptor antagonist pretreatment (SSR149415). In adult di/di or V(1b) pretreated rats, we observed normal pituitary and adrenocortical secretory responses, while in all 10-day-old rats stress-induced serum corticosterone increases were marked, but adrenocorticotropin (ACTH) increases were significantly smaller. Compared to control pups the adenohypophysis of the 10-day-old di/di rats responded normally to CRH, but their adrenal glands were hyper-responsive to ACTH, while in adults there was greater secretion at both levels with no difference between the genotypes. The serum transcortin level was higher in adults than pups, with the di/di pups having higher transcortin levels than controls. Hence, using the same stressors in adults and pups with both a genetic model and pharmacological pretreatment, we have shown that the role of vasopressin in ACTH regulation is more important during the neonatal period than in adulthood. Blunted hypophysial sensitivity to CRH and similar adrenal gland sensitivity to ACTH in the pups compared to adults suggest that hypothalamic factors could be responsible for the neonatal stress hyporesponsive period.     

Differential sensitisation to central cardiovascular effects of angiotensin II in rats with a myocardial infarct: relevance to stress and interaction with vasopressin

The purpose of the present study was to elucidate if rats with myocardial infarction manifest altered responsiveness to central cardiovascular effects of low doses of angiotensin II (ANG II), and if ANG II and vasopressin (VP) cooperate in the central regulation of cardiovascular functions at rest and during stress. Conscious Sprague-Dawley rats with myocardial infarction induced by left coronary artery ligation, or sham-ligated (SL) controls were infused intracerebroventricularly with artificial cerebrospinal fluid (aCSF), ANG II, ANG II + VP or ANG II + V1a receptor antagonist (V1ANT) 4 weeks after cardiac surgery. In the infarcted but not in the SL rats, the resting mean arterial blood pressure (MABP) was significantly elevated by infusions of ANG II and ANG II + VP, while infusion of ANG II + V1ANT was not effective. During administration of aCSF, the pressor, and tachycardic responses to an air-jet stressor were significantly greater in the infarcted than in the SL rats. In the SL rats, the pressor responses to the stressor were significantly greater during infusions of ANG II, ANG II + VP and ANG II + V1ANT than during infusion of aCSF. The tachycardic response in the SL rats was enhanced only by the combined infusion of ANG II + VP. In the infarcted rats, the pressor and the tachycardic responses to the stressor were similar in all groups. It is concluded that: (1) under resting conditions the infarcted rats manifest sensitisation to the central pressor effect of ANG II and that this effect depends on concomitant stimulation of V1a VP receptors, (2) central ANG II may enhance the pressor response to an alarming stressor in the SL rats through an action which does not depend on the concomitant stimulation of V1a receptors, (3) the cooperative action of ANG II and VP is required for intensification of the tachycardic response to the alarming stressor in the SL rats and (4) exaggeration of the cardiovascular responses to the alarming stressor in the infarcted rats cannot be further augmented by an additional stimulation of central ANG II receptors or combined stimulation of ANG II and VP receptors.     

Enhanced involvement of brain vasopressin V1 receptors in cardiovascular responses to stress in rats with myocardial infarction

Stress is one of the factors provoking cardiovascular complications. The purpose of the study was to explore the role of vasopressin (VP) in central control of arterial blood pressure and heart rate under resting conditions and during stimulation by an alarming stress (air jet stress) in myocardial infarct-induced cardiac failure. Six groups of male Sprague Dawley (SD) rats were subjected either to sham surgery (sham rats) or to ligation of a left coronary artery (infarcted rats). After 5 weeks both infarcted and sham rats were subjected either to intracerebroventricular infusion of artificial cerebrospinal fluid (aCSF) (sham aCSF and infarcted aCSF), [Arg8]-VP (sham VP and infarcted VP) or VP V1a receptor antagonist (d(CH2)5[Tyr(Me)2Ala-]VP, sham V1ANT and infarcted V1ANT). Air jet stress elicited significantly greater increases in mean arterial blood pressure (MABP) and heart rate in the infarcted aCSF than in the sham aCSF rats. Intracerebroventricular infusion of V1ANT significantly reduced resting MABP and MABP and heart rate increases in response to stress in the infarcted but not in the sham rats. Intracerebroventricular infusion of VP elicited a significant increase in resting MABP in the infarcted VP but not in the sham VP rats. The results provide evidence for enhanced engagement of the brain V1 VP receptors in regulation of resting MABP and in generation of exaggerated cardiovascular responses to air jet stress during the post-infarct state.     

Regulation and Mechanism of L-Type Calcium Channel Activation via V1a Vasopressin Receptor Activation in Cultured Cortical Neurons

We have sought to elucidate the biochemical mechanisms that underlie the memory enhancing properties of the neural peptide vasopressin. Toward that goal we have investigated vasopressin induction of calcium signaling cascades, long held to be involved in long-term memory function, in neurons derived from the cerebral cortex, a brain region associated with long-term memory. Our previous studies demonstrated that in cultured cortical neurons, V1a vasopressin receptor (V1aR) activation resulted in a sustained rise in intracellular calcium concentration that was dependent on calcium influx (Son & Brinton, 1998). To investigate the mechanism of V1aR-induced calcium influx, we investigated V1aR activation of the calcium channel subtype(s) in cortical neurons cultured from Sprague-Dawley rat embryonic day 18 fetuses. The results of these analyses demonstrated that the L-type calcium channel blocker nifedipine blocked 250 nM V1 vasopressin receptor agonist (V1 agonist)-induced calcium influx. Intracellular calcium imaging analyses using fura-2AM demonstrated that blockade of L-type calcium channels prevented the 250 nM V1 agonist-induced rise in intracellular calcium concentration. These results indicate that the influx of extracellular calcium via L-type calcium channels is an essential step in the initiation of the V1 agonist-induced rise in intracellular calcium concentration. To determine the mechanism of V1aR activation of L-type calcium channels, regulatory components of the phosphatidylinositol signaling pathway were investigated. The results of these analyses demonstrated that V1 agonist-induced calcium influx was blocked by both a phospholipase C inhibitor (U-73122) and a protein kinase C inhibitor (bisindolylmaleimide I). Further analysis of V1aR activation of protein kinase C (PKC) demonstrated that V1 agonist induced PKC activity within 1 min of exposure in cultured cortical neurons. These data indicate that in cultured cortical neurons, V1aR activation regulates the influx of extracellular calcium via L-type calcium channel activation through a protein kinase-C-dependent mechanism. The results of these studies provide biochemical mechanisms by which vasopressin could enhance memory function. Those mechanisms include a complex cascade that is initiated by activation of the phosphatidylinositol pathway, activation of protein kinase C, followed by phosphorylation of L-type calcium channels to initiate the influx of extracellular calcium to activate a cascade of calcium-dependent release of intracellular calcium.     

GABA(A) receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders

Protracted social isolation in laboratory animals causes stress, which induces a variety of behavioral abnormalities including increased aggressiveness, anxiety-related behaviors, cognitive deficits and hyper locomotion. Many of these disorders are similar to the symptoms found in psychiatric disorders, such as depression, anxiety, premenstrual dysphoria and posttraumatic stress disorders (PTSD). Recent studies have demonstrated that male mice that have been socially isolated for more than 4 weeks show: (a) reduced responsiveness of GABA(A) receptors (GABA(A)-R) to the administrations of GABA mimetic drugs at GABA(A)-R; (b) downregulated biosynthesis of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP) (allopregnanolone: ALLO), a neurosteroid with a potent positive allosteric modulatory effect on the action of GABA on GABA(A)-R; and (c) alterations in the expression of GABA(A)-R subunits (i.e. a decrease of alpha1/alpha2 and gamma2 subunits and an increase of alpha4 and alpha5 subunits). The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) and its congener norfluoxetine (Nor-FLX), when administered systemically at nmol/kg doses, normalize the reduced content of brain ALLO and the reduced responsiveness of GABA(A)-R to GABA mimetic drugs (i.e. pentobarbital) and also attenuate aggressive behavior in socially isolated mice in a stereospecific manner. Although these compounds inhibit ex vivo serotonin reuptake into brain tissue, their SSRI activities require high micromol/kg dose ranges and are not stereospecific. These studies suggest that in socially isolated mice, abnormalities of GABA(A)-R signal transduction are attributable to the downregulation of ALLO production and to a switch in heteropentameric GABA(A)-R subunit assembly composition. Hence, the normalization of ALLO biosynthesis may be a new target for the development of drugs effective for psychiatric disorders related to neurosteroid biosynthesis downregulation.     

Facilitation of inhibitory avoidance by hypertonic saline is reversed by a vasopressin and a nicotinic antagonist

Hypertonic saline (1 ml of 0.25, 0.50, and 1.00 M NaCl, ip) facilitated retention of a one-trial, step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. A similar result was obtained after a subcutaneous injection of lysine vasopressin (LVP, 0.03 microgram/kg). Neither hypertonic saline nor LVP modified latencies to step-through of mice that had not received a footshock during training. The enhancement of retention produced both by hypertonic saline and by LVP was prevented by the vasopressin receptor antagonist AAVP (0.01 microgram/kg, sc) given after training, but 10 min before the treatments. The effect of hypertonic saline was also prevented by the central acting cholinergic nicotinic receptor antagonist mecamylamine (5 mg/kg, sc). On the contrary, neither hexamethonium (5 mg/kg, sc), a peripheral acting nicotinic receptor blocker, nor atropine (0.5 mg/kg, sc) or methylatropine (0.5 mg/kg, sc), two anticholinergic drugs which are known to act on cholinergic muscarinic receptors, prevented the effect of post-training hypertonic saline. These results suggest that a peripheral osmotic stimulus, probably through an endogenous release of vasopressin, may be behaviorally significant, and are consistent with the view that vasopressin may modulate the activity of central cholinergic nicotinic mechanisms which are critical for the behavioral change observed.     

CRHR1 antagonists as novel treatment strategies

Research has provided considerable evidence for the hypothesis that corticotropin-releasing hormone (CRH), the key central coordinator of stress-hormone homeostasis, also plays a role in the development and course of depression and anxiety disorders. Studies using animal models of anxiety, as well as mouse mutants, in which the gene coding for the CRH type 1 receptor (CRHR1) was genetically deleted supported the notion that enhanced CRH/CRHR1 signaling underlies depression and anxiety disorders. Therefore, a number of small nonpeptide molecules that antagonize CRHR1 have been developed. In animal models, these molecules had anxiolytic and other stress-alleviating effects. An initial clinical study showed that CRHR1 antagonism has beneficial effects on depression and anxiety symptoms at doses unharmful to neuroendocrine stress responsivity.     

Vasopressin response to osmotic and hemodynamic stress: neurotransmitter involvement

Osmotic and hemodynamic stress are the two primary regulators of vasopressin (VP) release from the posterior pituitary. The pathways providing information about plasma osmolality and blood pressure or blood volume are distinct and utilize different chemical neurotransmitters. Osmotic regulation of VP release is dependent upon afferents from the lamina terminalis region. Glutamate is an important transmitter in this system and angiotensinergic afferents from this region to the VP neurons modulate responses to osmotic challenges. Hemodynamic information is transmitted to the VP neurons via multisynaptic pathways from the brainstem with the A1 catecholamine neurons of the ventrolateral medulla providing the final link for information about decreases in blood pressure and volume. Several neurotransmitters and neuropeptides are expressed in the A1 neurons including norepinephrine (NE), ATP, neuropeptide Y, and substance P. The impact of co-release of these agents on VP release is reviewed and the potential physiological significance is discussed.     

Gender differences in alcohol dependence: personality variables, psychopathological profile and personality disorders

In this paper, gender differences in personality, psychopathology and personality disorders of alcohol-dependent patients are described. The sample consisted of 158 alcohol-dependent patients attending a psychiatric outpatient clinic (105 men and 55 women). All participants were assessed with various assessment tools related to personality (Impulsiveness Scale, Sensation Seeking Scale and STAI), psychopathology (SCL-90-R, BDI and Inadaptation Scale) and personality disorders (IPDE). There were no differences in personality variables, but the women had more anxiety and depressive symptoms and also more problems to adapt to everyday life than did the men. Personality disorders were not as prevalent as in the case of men, and the most frequent among women were obsessive-compulsive, dependent and histrionic personality disorders. Implications of this study for further research are commented on.     

Zur Prävalenz von Depersonalisation und Derealisation in der stationären Psychotherapie

Depersonalization (DP) and derealization (DR) remain poorly recognized in clinical routine. Active exploration through structured interviews is strongly recommended, because patients rarely describe spontaneously their experiences with DP/DR. 143 psychosomatic, first-admission inpatients were interviewed about the 1-month prevalence of DP/DR using the Structured Clinical Interview for DSM-IV dissociative disorders. Additionally, the German questionnaires of the Cambridge Depersonalization Scale, the Dissociative Experiences Scale, the SCL-90-R and the Inventory of Interpersonal Problems were used. In the sample we found a prevalence of 23.1% (N=33) for depersonalization-derealization syndrom (ICD-10 F48.1) and 7% (N=10) for secondary pathological DP/DR. A total percentage of 62.9% reported DP/DR to some degree or other. There was a noticeably high co-occurrence of anxiety disorders in patients with pathological DP/DR. Patients with pathological DP/DR were generally more impaired, suffered many more interpersonal problems and were particularly characterized by introversion. Considering the high prevalence of this phenomenon, more attention should be paid to DP/DR in routine diagnostic procedures, treatment and research.     

The effect of stress and in vivo vasoactive intestinal peptide (VIP) treatment on the response of isolated rat aorta to norepinephrine, angiotensin II and vasopressin, and adventitial mast cells

The effects of cold-restraint stress, repeated over 3 days, and treatment of rats with vasoactive intestinal peptide (VIP) on the contractile responses of isolated aorta to vasoconstrictors, and on aortic adventitial mast cells were investigated. Stress significantly reduced the contractile response of rat aorta smooth muscle to norepinephrine (NE), angiotensin II (Ang II) and vasopressin (VP). Decreased sensitivity to NE, Ang II and VP may result from decreased receptor density, and affinity or reduced effector efficacy. Stress induced degranulation, decreased the number and changed the granular content of mast cells; all degranulated mast cells were stained with alcian blue, and the percentage of safranin staining cells was decreased. Given prior to stress, VIP reversed the reduced contractile responses and sensitivity of aorta to NE and Ang II but had no effect on VP subsensitivity. VIP also inhibited stress-induced degranulation of mast cells, and after VIP only alcian blue-stained mast cells were seen. When VIP was given to non-stressed rats, the contractile response of the aorta to NE, but not Ang II or VP, was increased compared with control. Mast cell count was decreased in the adventitia of non-stressed VIP treated rats. The results indicate that stress decreases the heparin content of mast cells and VIP has an additive effect. In conclusion, VIP modulates both stress-induced mast cell activity and reduced sensitivity of aorta smooth muscle to NE and Ang II. It can be suggested that VIP may moderate some effects of stress on vascular pathophysiology.     

Personality variables, psychopathological alterations and personality disorders in alcohol-dependent patients according to Cloninger's typology of alcohol abuse

In this paper, an evaluation of Cloninger's typology of alcohol abuse in personality, psychopathology and personality disorders is carried out. The sample consisted of 158 alcoholics in treatment (56 Type I alcohol-dependent patients and 102 Type II alcohol-dependent patients). All subjects were assessed with diverse assessment tools related to personality (Impulsiveness Scale, Sensation Seeking Scale and STAI), psychopathology (SCL-90-R, BDI and Inadaptation Scale) and personality disorders (IPDE). The main findings were that Type II alcohol-dependent patients were more impulsive and sensation-seeking and they displayed more hostility and emotional distress than Type I alcohol-dependent patients. Personality disorders were not so prevalent in the case of Type I alcohol-dependent patients. The most specific personality disorders for Type II alcohol-dependent patients were narcissistic and paranoid. The implications of this study for further research are commented on.     

Neuropattern: a new translational tool to detect and treat stress pathology. II. The Teltow study

The present study was designed to test the clinical utility of Neuropattern (NP), a newly developed translational diagnostic tool. NP consists of biological and psychological measures that facilitate the identification of functional changes (called "neuropatterns") in patients with stress-related health problems. In this prospective, randomized control trial, we expected NP to improve therapeutic efficacy, as compared with the usual treatment. NP was applied to 101 in-patients suffering from various mental disorders (mainly depression, anxiety disorders, and adjustment disorders), and scoring high on the Symptom Checklist-90-R (SCL-90-R) somatization scale. The patients (73% females, mean?±?standard deviation age 46?±?9.03 years) were randomly assigned to two groups: in the experimental group (n?=?51), physicians received results from NP diagnostics, while in the control group (n?=?50), this information was not available until discharge from the hospital. Improvements of symptoms in consequence of treatment were monitored by two self-rating scales, the SCL-90-R and Short Form-12 health survey, and a physician's clinical global rating (Beeintr?chtigungs-Schwere Score). There was a significantly greater improvement in the experimental group in the self-rating assessments on symptom severity (p?=?0.03) and quality of life (p?=?0.05), but not in the observer rating of emotional, physical, and social-communicative functioning (p?=?0.13). Treatment efficacy in patients can be improved by providing the attendant physician and the patient with diagnostic information and treatment recommendations by NP. The role of concrete mediators of treatment efficacy awaits further research.     

Microdialysis administration of vasopressin and vasopressin antagonists into the septum during pole-jumping behavior in rats.

Wistar rats (n = 95) were trained in a pole-jumping apparatus (10 trials/session/day) to investigate the involvement of centrally and peripherally released endogenous AVP in their acquisition rate and to examine the feasibility of the microdialysis technique for the administration of peptides during a behavioral test. After session 1, a microdialysis probe was implanted into the septum; during sessions 2 and 3 the probe was perfused with artificial cerebrospinal fluid (aCSF) alone or containing either AVP (delivered amount via the probe: 0.2 ng) or the V1 (d(CH2)5Tyr(Me)AVP, 5.0 ng) or the V2/V1 (d(CH2)5-D-Tyr(Et)VAVP, 5.0 ng) antagonist. Administration of AVP via microdialysis into the septum failed to alter the acquisition rate of pole jumping. Also, ip application of both hypertonic saline and the AVP V1 antagonist (10 micrograms) in another experiment failed to show a significant effect upon behavior. Septal administration of the V1 or the V2/V1 antagonist via microdialysis, however, produced a significantly impaired performance. The results indicate that AVP release within the septum is involved in the acquisition of pole-jumping behavior probably mediated by the V1 receptor subtype. An additional involvement of the V2 receptor subtype, however, cannot be entirely excluded. The microdialysis technique proved to be a potent tool to administer substances concomitantly with behavioral tests.     

CHRM3基因与孤独症谱系障碍

孤独症谱系障碍是一类具有遗传基础的儿童发展障碍疾病。近些年, 研究者们从分子病理学层面发现中枢胆碱能神经系统异常与孤独症患者认知和行为异常存在相关性。尸检研究、临床案例、动物模型研究均发现毒蕈碱型(M型)乙酰胆碱受体异常和孤独症的发生有着密切的关系。在以小鼠为模型的行为学研究中, 编码毒蕈碱型乙酰胆碱受体Ⅲ亚型的CHRM3基因突变会导致小鼠出现认知障碍、刻板行为等孤独症样表现。深入了解CHRM3基因的功能将能够帮助研究者进一步解释孤独症的相关行为特征, 为孤独症儿童教育方案的制定提供新的思路和方法。     

The NK3 receptor agonist senktide ameliorates scopolamine-induced deficits in memory for object, place and temporal order

Senktide, a potent neurokinin-3 receptor (NK₃-R) agonist, increases acetylcholine (ACh) release in the striatum, the prefrontal cortex (Schäble et al., 2011), the amygdala and hippocampus, presumably via postsynaptic mechanisms. A promnestic action of NK₃-R agonists has been described in a variety of learning/memory tasks. The memory-enhancing effects of NK₃-R agonists and their activating influence on ACh suggest a possible role of the NK₃-R in learning and memory via cholinergic modulation. Deterioration of the cholinergic system in the basal forebrain has been associated with learning and memory deficits and cholinergic agents have promnestic effects in a variety of learning paradigms. The anticholinergic drug, scopolamine, a muscarinic ACh receptor antagonist, incurs deficits in a variety of learning tasks and provides a useful tool to investigate the role of the cholinergic systems in mechanisms underlying learning and memory. The aim of this study was to ascertain the effect of the NK₃-R agonist, senktide, in the scopolamine-induced deficit model. We hypothesized that senktide treatment would attenuate scopolamine-induced (subcutaneous – s.c. 0.75 mg/kg) memory impairment in three novelty preference paradigms based on spontaneous object exploration: namely object recognition, object–place recognition and object recognition for temporal order. Administration of senktide reversed the scopolamine-induced memory deficits by re-establishing object recognition (s.c. 0.2 mg/kg), object–place recognition (0.2 and 0.4 mg/kg), as well as object recognition for temporal order (0.4 mg/kg) in adult Wistar rats. These results indicate memory enhancing effects of senktide in animals subjected to scopolamine-induced memory impairments and indicate that the promnestic action of NK₃-R agonists is mediated by muscarinic cholinergic mechanisms.     

The neurogenetics of nice: receptor genes for oxytocin and vasopressin interact with threat to predict prosocial behavior

Oxytocin, vasopressin, and their receptor genes influence prosocial behavior in the laboratory and in the context of close relationships. These peptides may also promote social engagement following threat. However, the scope of their prosocial effects is unknown. We examined oxytocin receptor (OXTR) polymorphism rs53576, as well as vasopressin receptor 1a (AVPR1a) polymorphisms rs1 and rs3 in a national sample of U.S. residents (n = 348). These polymorphisms interacted with perceived threat to predict engagement in volunteer work or charitable activities and commitment to civic duty. Specifically, greater perceived threat predicted engagement in fewer charitable activities for individuals with A/A and A/G genotypes of OXTR rs53576, but not for G/G individuals. Similarly, greater perceived threat predicted lower commitment to civic duty for individuals with one or two short alleles for AVPR1a rs1, but not for individuals with only long alleles. Oxytocin, vasopressin, and their receptor genes may significantly influence prosocial behavior and may lie at the core of the caregiving behavioral system.     

Behavioral pharmacology of methocinnamox: A potential new treatment for opioid overdose and opioid use disorder

Opioid overdose and opioid use disorder continue to be significant public health challenges despite the availability of effective medications and significant efforts at all levels of society. The emergence of highly potent and efficacious opioids such as fentanyl and its derivatives over the last decade has only exacerbated what was already a substantial problem. Behavioral pharmacology research has proven invaluable for understanding the effects of drugs as well as developing and evaluating pharmacotherapies for disorders involving the central nervous system, including substance abuse disorders. This paper describes a program of research characterizing a potent, selective, and long-lasting mu opioid receptor antagonist, methocinnamox, and evaluating its potential for treating opioid overdose and opioid use disorder. Studies in rodents and nonhuman primates demonstrate that methocinnamox prevents and reverses opioid-induced ventilatory depression and selectively blocks opioid self-administration. This work, taken together with rigorous in vitro and ex vivo studies investigating methocinnamox neuropharmacology, lays a solid foundation for the therapeutic utility of this potentially life-saving medication. Moreover, these studies demonstrate how rigorous behavioral pharmacological studies can be integrated in a broader drug discovery and development research program.