The effect of SSRIs on unconditioned anxiety: a systematic review and meta-analysis of animal studies.

Rationale: Selective serotonin reuptake inhibitors (SSRIs) are the first choice of treatment for anxiety-like disorders. However, which aspects of anxiety are affected by SSRIs is not yet fully understood.

Objective: We aimed to systematically review the effect of six clinically effective SSRIs on four aspects of unconditioned anxiety: approach-avoidance behaviour (elevated plus maze), repetitive behaviour (marble burying), distress behaviour (ultrasonic vocalization), and activation of the autonomous nervous system (stress-induced hyperthermia).

The effect of SSRIs on fear learning: a systematic review and meta-analysis.

Rationale: Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. Fear learning plays an important role in the development and treatment of these disorders. Yet, the effect of SSRIs on fear learning are not well known.

Pharmacological modulation of conditioned fear in the fear-potentiated startle test: a systematic review and meta-analysis of animal studies.

Rationale And Objectives: Fear conditioning is an important aspect in the pathophysiology of anxiety disorders. The fear-potentiated startle test is based on classical fear conditioning and over the years, a broad range of drugs have been tested in this test. Synthesis of the available data may further our understanding of the neurotransmitter systems that are involved in the expression of conditioned fear.

The contribution of contextual fear in the anxiolytic effect of chlordiazepoxide in the fear-potentiated startle test.

This study evaluated the extent to which a reduction in contextual fear contributes to the anxiolytic effect of benzodiazepines in the fear-potentiated startle response. To this end, chlordiazepoxide, an anxiolytic often used as positive control in preclinical drug studies, and zolpidem, known to have sedative properties and to be devoid of anxiolytic effects, were tested in two contexts: the same context as training had taken place and an alternative context. In addition, the level of muscle relaxation was assessed in a grip strength test.

CRF but not glucocorticoid receptor antagonists reduce separation-induced distress vocalizations in guinea pig pups and CRF overexpressing mouse pups. A combination study with paroxetine.

Rationale: Given the large number of patients that does not respond sufficiently to currently available treatment for anxiety disorders, there is a need for improved treatment.

Objectives: We evaluated the anxiolytic effects of corticotropin releasing factor (CRF) receptor antagonists and glucocorticoid receptor (GR) antagonists in the separation-induced vocalization test in guinea pigs and transgenic mice with central CRF overexpression. Furthermore, we explored effects of these drugs when given in combination with a suboptimal dose of a selective serotonin re-uptake inhibitor (SSRI).

Pharmacological and methodological aspects of the separation-induced vocalization test in guinea pig pups; a systematic review and meta-analysis.

The separation-induced vocalization test in guinea pig pups is one of many that has been used to screen for anxiolytic-like properties of drugs. The test is based on the cross-species phenomenon that infants emit distress calls when placed in social isolation. Here we report a systematic review and meta-analysis of pharmacological intervention in the separation-induced vocalization test in guinea pig pups.

Valproate improves prepulse inhibition deficits induced by corticotropin-releasing factor independent of GABA(A) and GABA(B) receptor activation.

Corticotropin-releasing factor (CRF) is implicated in the pathogenesis of bipolar disorder, an illness associated with deficits in prepulse inhibition (PPI) of the acoustic startle response. Valproate is used in the treatment of bipolar disorder and may alter CRF activity via a GABA(A)-ergic mechanism. This study determined the effect of valproate on CRF-disrupted PPI and examined the role of the hypothalamic-pituitary-adrenal axis and GABA-ergic signaling in the effect of valproate.

CRF1 receptor antagonists do not reverse pharmacological disruption of prepulse inhibition in rodents.

Rationale: As enhanced corticotropin-releasing factor (CRF) transmission is associated with induction of sensorimotor gating deficits, CRF₁ receptor antagonists may reverse disrupted prepulse inhibition (PPI), an operational measure of sensorimotor gating.

Objectives: To determine the effects of CRF₁ receptor antagonists in pharmacological models of disrupted PPI and to determine if long-term elevated central CRF levels alter sensitivity towards PPI disrupting drugs.

Methods: CP154,526 (10-40 mg/kg), SSR125543 (3-30 mg/kg) and DMP695 (40 mg/kg) were tested on PPI disruption provoked by D-amphetamine (2.

Endothelial dysfunction enhances the pulmonary and systemic vasodilator effects of phosphodiesterase-5 inhibition in awake swine at rest and during treadmill exercise.

Cardiovascular disease is characterized by impaired exercise capacity and endothelial dysfunction, i.e. reduced bioavailability of nitric oxide (NO).

Involvement of reperfusion injury salvage kinases in preconditioning depends critically on the preconditioning stimulus.

Different preconditioning stimuli can activate divergent signaling pathways. In rats, adenosine-independent pathways (triple 3-min coronary artery occlusion [3CAO3]) and adenosine-dependent pathways (one 15-min coronary artery occlusion [ICAO15]) exist, both ultimately converging at the level of the mitochondrial respiratory chain. Furthermore, while 3CAO3, 1CAO15 and exogenous adenosine (ADO) are equally cardioprotective, only 1CAO15 increases interstitial myocardial adenosine levels.

Interaction between pre- and postconditioning in the in vivo rat heart.

Patients with an impending myocardial infarction may be preconditioned by pre-infarct angina. Hence, it is important to establish whether ischemic postconditioning is still effective in preconditioned hearts. We therefore studied in anesthetized rats the effect of postconditioning after coronary artery occlusions (CAO) of 60 min in control hearts, hearts preconditioned by a single 15-min CAO (1IPC15) or a triple 3-min CAO (3IPC3).

Activation of the septohippocampal system differentiates anxiety from fear in startle paradigms.

It has been suggested that different brain areas are involved in the modulation and expression of fear and anxiety. In the present study we investigated these potential differences by using the fear-potentiated-startle (FPS) and light-enhanced-startle (LES) paradigms to differentiate between fear and anxiety, respectively. Male Wistar rats were tested in the FPS and LES paradigm and perfused 1 h after the test session.

Models of anxiety: ultrasonic vocalizations of isolated rat pups.

Described in this unit is the ultrasonic distress vocalization test in rat pups. This test is a reliable method for detecting anxiolytic properties of test compounds. In this test, ultrasonic vocalizations (30 to 50 kHz) are elicited by separating rat pups of 9 to 11 days of age from their mother and littermates for a brief period of time.

Ischemic preconditioning modulates mitochondrial respiration, irrespective of the employed signal transduction pathway.

We tested in the in vivo rat heart the hypothesis that although ischemic preconditioning can employ different signal transduction pathways, these pathways converge ultimately at the level of the mitochondrial respiratory chain. Infarct size produced by a 60-min coronary artery occlusion (69%+/-2% of the area at risk) was limited by a preceding 15-min coronary occlusion (48%+/-4%). Cardioprotection by this stimulus was triggered by adenosine receptor stimulation, which was followed by protein kinase C and tyrosine kinase activation and then mitochondrial K(+)(ATP)-channel opening.

CRF1 not glucocorticoid receptors mediate prepulse inhibition deficits in mice overexpressing CRF.

Background: Both corticotropin-releasing factor (CRF) and glucocorticoid receptors (GR) are implicated in the psychotic symptoms of psychiatric disorders. Correspondingly, it is of interest to determine their respective involvement in the sensorimotor gating deficits displayed by transgenic mice overexpressing CRF. These mice reveal lifelong elevations of CRF and corticosterone levels.

Cardiac effects of postconditioning depend critically on the duration of index ischemia.

Postconditioning (POC) is known as the phenomenon whereby brief intermittent ischemia applied at the onset of reperfusion following index ischemia limits myocardial infarct size. Whereas there is evidence that the algorithm of the POC stimulus is an important determinant of the protective efficacy, the importance of the duration of index ischemia on the outcome of the effects of POC has received little attention. Pentobarbital sodium-anesthetized Wistar rats were therefore subjected to index ischemia produced by coronary artery occlusions (CAO) of varying duration (15-120 min) followed by reperfusion, without or with postconditioning produced by three cycles of 30-s reperfusion and reocclusion (3POC30).

Heart rate control via vagus nerve stimulation.

Objectives.  There is ample and well-established evidence that direct electrical stimulation of the vagus nerve can change heart rate in animals and humans. Since tachyarrhythmias cannot always be controlled through medication, we sought, in this pilot study, to elucidate whether a clinical implantable lead system that is used in cervical vagus nerve stimulation therapy (VNS therapy) also can be used for control of heart rate, and tachycardia in particular.

Coronary vasoconstrictor influence of angiotensin II is reduced in remodeled myocardium after myocardial infarction.

The renin-angiotensin system plays an important role in cardiovascular homeostasis by contributing to the regulation of blood volume, blood pressure, and vascular tone. Because AT(1) receptors have been described in the coronary microcirculation, we investigated whether ANG II contributes to the regulation of coronary vascular tone and whether its contribution is altered during exercise. Since the renin-angiotensin system is activated after myocardial infarction, resulting in an increase in circulating ANG II, we also investigated whether the contribution of ANG II to the regulation of vasomotor tone is altered after infarction.

Intravenous adenosine protects the myocardium primarily by activation of a neurogenic pathway.

Endogenous adenosine is a trigger for ischemic myocardial preconditioning (IPC). Although intravascular administration of adenosine has been used to further unravel the mechanism of protection by IPC, it is questionable whether adenosine and IPC employ the same signaling pathways to exert cardioprotection. We therefore investigated whether the active metabolic barrier of the endothelium prevents an increase in myocardial interstitial adenosine concentrations by intravenous adenosine, using microdialysis, and also the role of NO and activation of a neurogenic pathway in the cardioprotection by adenosine.

Exercise unmasks autonomic dysfunction in swine with a recent myocardial infarction.

Objective: Severe congestive heart failure is associated with autonomic imbalance consisting of an increased sympathetic and decreased parasympathetic activity. In the present study, we investigated the influence of alterations in autonomic balance on cardiovascular function in 11 swine with left ventricular (LV) dysfunction produced by a 2- to 3-week-old myocardial infarction (MI).

Methods: Swine underwent permanent occlusion of the left circumflex coronary artery resulting in MI of the lateral LV wall.

Myocardium tolerant to an adenosine-dependent ischemic preconditioning stimulus can still be protected by stimuli that employ alternative signaling pathways.

Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve development of tolerance to repeated episodes of ischemia. Not all preconditioning stimuli use identical signaling pathways, and because patients likely experience varying numbers of episodes of preinfarct angina of different degrees and durations, it is important to know whether myocardium tolerant to a particular preconditioning stimulus can still be protected by stimuli employing alternative signaling pathways. We tested the hypothesis that development of tolerance to a particular stimulus does not affect cardioprotection by stimuli that employ different signaling pathways.

The tyrosine phosphatase inhibitor bis(maltolato)oxovanadium attenuates myocardial reperfusion injury by opening ATP-sensitive potassium channels.

Vanadate has been shown to inhibit tyrosine phosphatase, leading to an increased tyrosine phosphorylation state. The latter has been demonstrated to be involved in the signal transduction pathway of ischemic preconditioning, the most potent endogenous mechanism to limit myocardial infarct size. Furthermore, there is evidence that phosphatase inhibition may be cardioprotective when given late after the onset of ischemia, but the mechanism of protection is unknown.