The purpose of this study was to explore how genetic deletion and pharmacological antagonism of the P2X7 receptor (P2rx7) alter mood-related behaviour, gene expression and stress reactivity in the brain. The forced swim test (FST), tail suspension test (TST) and amphetamine-induced hyperlocomotion (AH) tests were used in wild-type (P2rx7+/+) and P2rx7-deficient (P2rx7−/−) mice. Biogenic amine levels were analysed in the amygdala and striatum, adrenocorticotropic hormone (ACTH) and corticosterone levels were measured in the plasma and pituitary after restraint stress. Chimeric mice were generated by bone marrow transplantation. A whole genome microarray analysis with real-time polymerase chain reaction validation was performed on the amygdala. In the absence of P2rx7s decreased behavioural despair in the FST, reduced immobility in the TST and attenuated amphetamine-induced hyperactivity were detected. Basal norepinephrine levels were elevated in the amygdala, whereas stress-induced ACTH and corticosterone responses were alleviated in P2rx7−/− mice. Sub-acute treatment with the selective P2rx7 antagonist, Brilliant Blue G, reproduced the effect of genetic deletion in the TST and AH test in P2rx7+/+ but not P2rx7−/− mice. No change in behavioural phenotype was observed in chimeras lacking the P2rx7 in their haematopoietic compartment. Whole genome microarray analysis indicated a widespread up- and down-regulation of genes crucial for synaptic function and neuroplasticity by genetic deletion. Here, we present evidence that the absence of P2rx7s on non-haematopoietic cells leads to a mood-stabilizing phenotype in several behavioural models and suggest a therapeutic potential of P2rx7 antagonists for the treatment of mood disorders.

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. Role of hypothalamic inputs in maintaining pituitary-adrenal responsiveness in repeated restraint. Am J Physiol Endocrinol Metab 285: E1110-E1117, 2003; 10.1152/ ajpendo.00219.2003.-The role of hypothalamic structures in the regulation of chronic stress responses was studied by lesioning the mediobasal hypothalamus or the paraventricular nucleus of hypothalamus (PVH). Rats were acutely (60 min) and/or repeatedly (for 7 days) restrained. In controls, a single restraint elevated the plasma adrenocorticotropin (ACTH), corticosterone, and prolactin levels. Repeated restraint produced all signs of chronic stress, including decreased body and thymus weights, increased adrenal weight, basal corticosterone levels, and proopiomelanocortin (POMC) mRNA expression in the anterior pituitary. Some adaptation to repeated restraint of the ACTH response, but not of other hormonal responses, was seen. Lesioning of the mediobasal hypothalamus abolished the hormonal response and POMC mRNA activation to acute and/or repeated restraint, suggesting that the hypothalamo-pituitaryadrenal axis activation during repeated restraint is centrally driven. PVH lesion inhibited the ACTH and corticosterone rise to the first restraint by ϳ50%. In repeatedly restrained rats with PVH lesion, the ACTH response to the last restraint was reduced almost to basal control levels, and the elevation of POMC mRNA level was prevented. PVH seems to be important for the repeated restraint-induced ACTH and POMC mRNA stimulation, but it appears to partially mediate other restraintinduced hormonal changes. adrenocorticotropin; corticosterone; mediobasal hypothalamus; paraventricular nucleus; proopiomelanocortin; rat IN ACUTE STRESS, the hypothalamic paraventricular nucleus of hypothalamus (PVH) is known to be a key site in the activation of the hypothalamo-pituitary-adrenal (HPA) axis by providing the hypophysiotropic neuropeptides corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) to stimulate ACTH secretion from the anterior pituitary (see Ref. 2). Various stress paradigms act through different pathways, because in some cases the elimination of PVH abolished acute stress-induced ACTH elevation [hemorrhage (10), early response after bacterial lipopolysaccharide (13), elevated platform stress (28)], but with some other stressors, considerable ACTH and/or corticosterone elevation occurs even after lesioning the PVH [hypovolemia (7), ether (8, 27, 29), immobilization, electrical stimulation of the skin (14), footshock, IL-1␤ (40)].Chronic stress can be elicited by repeated exposure to short-acting stressors or by action of a sustained or persistent stimulus, e.g., a disease. Chronic stress is characterized by the classical symptoms of decreased body and thymus weight and a parallel increase in adrenal size and width of the adrenal cortex, consistent with chronic activation of the HPA axis (6, 12). The sustained activation of the CRH/AVP cells in the PVH is suggested to have a central role during chronic stress-induced HPA axis activation, and t...

OBJECTIVE:To determine whether the anorexigenic peptide, nesfatin-1 affects energy expenditure, and to follow the time course of its effects. DESIGN: Food intake duration, core body temperature, locomotor activity and heart rate of rats were measured by telemetry for 48 h after a single intracerebroventricular injection of 25 or 100 pmol nesfatin-1 applied in the dark or the light phase of the day. Body weight, food and water intake changes were measured daily. Furthermore, cold-responsive nesfatin-1/NUCB2 neurons were mapped in the brain. RESULTS: Nesfatin-1 reduced duration of nocturnal food intake for 2 days independently of circadian time injected, and raised body temperature immediately, or with little delay depending on the dose and circadian time applied. The body temperature remained higher during the next light phases of the 48 h observation period, and the circadian curve of temperature flattened. After light phase application, the heart rate was elevated transiently. Locomotion did not change. Daily food and water intake, as well as body weight measurements point to a potential decrease in all parameters on the first day and some degree of compensation on the second day. Cold-activated (Fos positive) nesfatin-1/NUCB2 neurones have been revealed in several brain nuclei involved in cold adaptation. Nesfatin-1 co-localised with prepro-thyrotropin-releasing hormone in cold responsive neurones of the hypothalamic paraventricular nucleus, and in neurones of the nucleus raphe pallidus and obscurus that are premotor neurones regulating brown adipose tissue thermogenesis and skin blood flow. CONCLUSION: Nesfatin-1 has a remarkably prolonged effect on food intake and body temperature. Time course of nesfatin-1's effects may be varied depending on the time applied. Many of the nesfatin-1/NUCB2 neurones are cold sensitive, and are positioned in key centres of thermoregulation. Nesfatin-1 regulates energy expenditure a far more potent way than it was recognised before making it a preferable candidate anti-obesity drug.

Adverse events need to be quickly evaluated and memorized, yet how these processes are coordinated is poorly understood. We discovered a large population of excitatory neurons in mouse median raphe region (MRR) expressing vesicular glutamate transporter 2 (vGluT2) that received inputs from several negative experience–related brain centers, projected to the main aversion centers, and activated the septohippocampal system pivotal for learning of adverse events. These neurons were selectively activated by aversive but not rewarding stimuli. Their stimulation induced place aversion, aggression, depression-related anhedonia, and suppression of reward-seeking behavior and memory acquisition–promoting hippocampal theta oscillations. By contrast, their suppression impaired both contextual and cued fear memory formation. These results suggest that MRR vGluT2 neurons are crucial for the acquisition of negative experiences and may play a central role in depression-related mood disorders.

a b s t r a c tThe prevalence of obesity is increasing worldwide with serious consequences such as diabetes mellitus type 2 and cardiovascular diseases. Emotional stress is considered to be one of the main reasons of obesity development in humans. However, there are some contradictory results, which should be addressed. First of all stress induces anorexia, but not overeating in laboratory animals. Glucocorticoids, the effector molecules of the hypothalamo-pituitary-adrenocortical (HPA) axis stimulate and stress inhibits food intake. It is also not clear if stress is diabetogenic or an antidiabetogenic factor. The review will discusses these issues and the involvement of the whole HPA axis and its separate molecules (glucocorticoids, adrenocorticotropin, corticotropin-releasing hormone) in food intake regulation under stress.

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