Corticotropin-releasing hormone (CRH) is a potent mediator of endocrine, autonomic, behavioural and immune responses to stress, and has been implicated in the stress-like and other aversive consequences of drug abuse, such as withdrawal from alcohol. Two CRH receptors, Crhr1 and Crhr2, have been identified in the mouse. Crhr1 is highly expressed in the anterior pituitary, neocortex, hippocampus, amygdala and cerebellum, and activation of this receptor stimulates adenylate cyclase. Here we show that in mice lacking Crhr1, the medulla of the adrenal gland is atrophied and stress-induced release of adrenocorticotropic hormone (ACTH) and corticosterone is reduced. The homozygous mutants exhibit increased exploratory activity and reduced anxiety-related behaviour under both basal conditions and following alcohol withdrawal. Our results demonstrate a key role of the Crhr1 receptor in mediating the stress response and anxiety-related behaviour.

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To model aspects of trait anxiety/depression, Wistar rats were bred for extremes in either hyper (HAB)-or hypo(LAB)-anxiety as measured on the elevated plus-maze and in a variety of additional behavioral tests. Similar to psychiatric patients, HAB rats prefer passive stress-coping strategies, indicative of depression-like behavior, show hyper-reactivity of the hypothalamo-pituitary-adrenal axis, and a pathological response to the dexamethasone/corticotropin-releasing hormone (CRH) challenge test. Here we tested central mRNA expression, release patterns, and receptor binding of neuropeptides critically involved in the regulation of both anxiety-related behavior and the HPA axis. Thus, CRH, arginine-8-vasopressin (AVP), and oxytocin (OXT) were studied in brains of HAB and LAB males both under basal conditions and after exposure to a mild emotional stressor. In HAB rats, CRH mRNA was decreased in the bed nucleus of the stria terminalis only. While no significant difference in CRH1-receptor binding was found in any brain area, CRH2-receptor binding was elevated in the hypothalamic paraventricular nucleus (PVN), the ventromedial hypothalamus, and the central amygdala of HABs compared to LABs. AVP, but not OXT, mRNA expression as well as release of the neuropeptide, were higher in the PVN of HABs, whereas AVP V1a-receptor binding failed to show significant differences in any brain region studied. Remarkably, intra-PVN treatment of HABs with the AVP V1-receptor antagonist d (CH 2 ) 5 Tyr (Me) AVP resulted in a decrease in anxiety/depression-related behavior. The elevated expression and release of AVP within the PVN of HAB rats together with the behavioral effects of the AVP V1-receptor antagonist suggest a critical involvement of this neuropeptide in neuroendocrine and behavioral phenomena associated with trait anxiety/ depression.

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used as a therapeutic tool in various neurological and psychiatric disorders, and we recently found that it has a neuroprotective effect both in vitro andTranscranial magnetic stimulation (TMS), a technique in which a time-varying strong electric current is applied through a coil held in direct contact with the subject's head, was originally developed for diagnostic use in neurology (for review see Rossini and Rossi 1998). A possible effect of TMS on mood was first reported in 1987 (Bickford et al. 1987) and, although discussed controversially, to date several lines of evidence resulting from both preclinical (Fleischmann et al. 1995;Zyss et al. 1997) and clinical (e.g., Pascual-Leone et al. 1996) studies support the notion that repetitive TMS (rTMS) may have antidepressant properties: rTMS induces transient enhancement of mood in healthy subjects, and daily application alleviates symptoms in patients suffering from treatment-resistant major depression (for review see George et al. 1999).Although rTMS is currently being evaluated as a possible alternative or add-on therapy in the treatment of refractory depression, knowledge concerning its effects at the molecular and cellular level is still very limited. Recently, Ji et al. (1998) reported a specific activation of brain regions in terms of immediate early gene expression in rats in response to rTMS. In addition, we provided a first evidence for a neuroprotective effect of long-term rTMS in vivo and in vitro (Post et al. 1999). The in vitro studies showed that magnetic stimulation analogous to TMS increased the overall viability of mouse monoclonal hippocampal HT22 cells and had a neuroprotective effect against oxidative stressors such as amyloid beta (A ␤ ) and glutamate. Moreover, the treatment increased the release of the potentially neuroprotective secreted amyloid precursor protein (sAPP) into the supernatant of HT22 cells and into cerebrospinal fluid from rats. Accordingly, HT22 cells preincubated with cerebrospinal fluid from long-term rTMStreated rats were found to be protected against A ␤ (Post et al. 1999). However, the neurochemical mechanisms underlying these neuroprotective properties as well as the putative therapeutic effects of rTMS in neurological and psychiatric disorders still remain to be elucidated.Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is abundantly expressed in the adult brain. The neurotrophic and also neuroprotective effects of BDNF have been characterized extensively both in vitro and in vivo. In addition, upregulation of BDNF has been implicated in neuronal responses to various kinds of injuries, such as epileptic seizures, cerebral ischemia, and hypoglycemia (for review see Connor and Dragunow 1998). Recent work raised the possibility that one of the many long-term effects of antidepressant treatment may be regulation of neurotrophins: antidepressant drug treatment and electroconvulsive seizures (ECS) were shown to marke...