G. B. Makara

Immunoreactive corticotropin-releasing hormone in the hypothalamoinfundibular tract.

Ovine corticotropin-releasing hormone (CRF)-like immunoreactivity has been examined in the rat hypothalamus by light microscopy. Immunoreactivity was found in nerve fibers of the median eminence, mainly in the external zone around the portal vessels. In rats pretreated with colchicine or with hypothalamic knife cuts, small to moderate sized cells with two (bipolar) or rarely more (multipolar) dendrites, showing CRF-like immunoreactivity were present in the anterior and medial parvocellular subdivisions of the paraventricular nucleus. Scattered CRF-like immunopositive cells were found in the periventricular and medial preoptic nuclei. CRF-like immunoreactivity was clearly enhanced in the median eminence and paraventricular nucleus 8-10 days after bilateral adrenalectomy. A variety of hypothalamic transections had to be performed to determine reliably the topography of CRF-like nerve fibers projecting to the stalk-median eminence. Axons left the paraventricular nucleus in a lateral direction, turned ventrally in the lateral hypothalamus then medially as they approached the base of the hypothalamus above and behind the optic chiasm (lateral retrochiasmatic area). Fibers reached the median eminence by traveling caudally and medially from the rostral half of the lateral retrochiasmatic area. Scattered fibers were present in the retroinfundibular (posterior) portion of the median eminence. No immunoreactive fibers remained in the stalk-median eminence 1 or 4 weeks after transection of that loop-like pathway of CRF-containing fibers in the lateral retrochiasmatic area.

Glucocorticoid Implants around the Hypothalamic Paraventricular Nucleus Prevent the Increase of Corticotropin-Releasing Factor and Arginine Vasopressin Immunostaining Induced by Adrenalectomy

The site of inhibitory action of glucocorticoids on the hypothalamic corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) was studied using a combination of glucocorticoid implantation and immunohistochemistry. Adrenalectomy increased the number and the staining intensity of the neurons containing CRF-like immunoreactivity in the anterior and medial parvicellular subdivisions of the paraventricular nucleus (PVN) and induced the appearance of AVP-like immunoreactivity in the same cell population. These effects of adrenalectomy were inhibited only by those dexamethasone implants which were placed close to the PVN. Unilateral implantation of dexamethasone into the PVN inhibited the adrenalectomy-induced changes in CRF and AVP immunostaining only on the implanted side. Dexamethasone implants placed into the hippocampus decreased the effect of adrenalectomy in the PVN while similar implants into the amygdala and cerebral cortex were ineffective. These results suggest that the primary site of glucocorticoid feedback inhibition on the hypothalamic secretagogues of adrenocorticotropin is the PVN.

Effect of Gamma-Aminobutyric Acid (GABA) and GABA Antagonist Drugs on ACTH Release

Corticotrophin (ACTH) release has been studied in rats given intraventricular gamma-aminobutyric acid (GABA) infusions or injections of picrotoxin and bicuculline. As an index of ACTH release the cort

Catecholaminergic involvement in the control of aggression: hormones, the peripheral sympathetic, and central noradrenergic systems.

Noradrenaline is involved in many different functions, which all are known to affect behaviour profoundly. In the present review we argue that noradrenaline affects aggression on three different levels: the hormonal level, the sympathetic autonomous nervous system, and the central nervous system (CNS), in different, but functionally synergistic ways. Part of these effects may arise in indirect ways that are by no means specific to aggressive behaviour, however, they are functionally relevant to it. Other effects may affect brain mechanisms specifically involved in aggression. Hormonal catecholamines (adrenaline and noradrenaline) appear to be involved in metabolic preparations for the prospective fight; the sympathetic system ensures appropriate cardiovascular reaction, while the CNS noradrenergic system prepares the animal for the prospective fight. Indirect CNS effects include: the shift of attention towards socially relevant stimuli; the enhancement of olfaction (a major source of information in rodents); the decrease in pain sensitivity; and the enhancement of memory (an aggressive encounter is very relevant for the future of the animal). Concerning more aggression-specific effects one may notice that a slight activation of the central noradrenergic system stimulates aggression, while a strong activation decreases fight readiness. This biphasic effect may allow the animal to engage or to avoid the conflict, depending on the strength of social challenge. A hypothesis is presented regarding the relevance of different adrenoceptors in controlling aggression. It appears that neurons bearing postsynaptic alpha2-adrenoceptors are responsible for the start and maintenance of aggression, while a situation-dependent fine-tuning is realised through neurons equipped with beta-adrenoceptors. The latter phenomenon may be dependent on a noradrenaline-induced corticosterone secretion. It appears that by activating very different mechanisms the systems working with adrenaline and/or noradrenaline prepare the animal in a very complex way to answer the demands imposed by, and to endure the effects caused by, fights. It is a challenge for future research to elucidate how precisely these mechanisms interact to contribute to functionally relevant and adaptive aggressive behaviour.

Acute effects of glucocorticoids: behavioral and pharmacological perspectives

There has been evidence since the early eighties that glucocorticoids, apart from their well known chronic effects, may have acute, short-term effects. However, a lack of understanding of the molecular mechanisms of action has hampered appreciation of these observations. Mounting evidence over the years has continued to confirm the early observations on a fast corticosterone control of acute behavioral responses. We summarize experimental data obtained mainly in rats but also in other species which show: (1) that glucocorticoid production is sufficiently quick to affect ongoing behavior; (2) that there exist molecular mechanisms that could conceivably explain the fast neuronal effects of glucocorticoids (although these are still insufficiently understood); (3) that glucocorticoids are able to stimulate a wide variety of behaviors within minutes; and (4) that acute glucocorticoid production (at least in the case of aggressive behavior) is linked to the achievement of the behavioral goal (winning). The achievement of the behavioral goal reduces glucocorticoid production. It is argued that glucocorticoids are regulatory factors having a well-defined behavioral role. Both the acute (stimulatory) effects and the chronic (inhibitory) effects are adaptive in nature. The acute control of behavior by corticosterone is a rather unknown process that deserves further investigation. The pharmacologic importance of the acute glucocorticoid response is that it may readily affect the action of pharmacologic agents. An interaction between acute glucocorticoid increases and noradrenergic treatments has been shown in the case of offensive and defensive agonistic behavior. Non-behavioral data demonstrate that acute increases in glucocorticoids may interfere with other neurotransmitter systems (e.g., with the 5HT system) as well. These observations show the importance of taking into account endocrine background and endocrine responsiveness in behavior pharmacological experiments.

Evidence that the effects of arginine-8-vasopressin (AVP) on pituitary corticotropin (ACTH) release are mediated by a novel type of receptor

Ovine corticotropin releasing factor (oCRF-41) and AVP act synergistically to stimulate pituitary ACTH secretion. In the present study we have investigated whether the effect of AVP, either in the presence or in the absence of oCRF-41 (0.5 nmol/l), could be blocked by V1 (pressor)-antagonists. Furthermore, oxytocin, and [1-deamino,8-D-arginine] vasopressin (dDAVP) were tested for their ability to release ACTH. All experiments were carried out in vitro, using segments of rat anterior pituitary glands. The V1-antagonist [1-deamino,penicillamine(o-methyl-tyrosine)]AVP inhibited ACTH release induced by AVP or AVP + oCRF-41. However, it also had some agonistic activity which was more pronounced in the presence of oCRF-41. An equally potent V1-antagonist, [1-beta-mercapto-beta, beta-cyclopentamethyleneproprionic acid (o-methyl-tyrosine)]AVP, failed to inhibit AVP-stimulated ACTH secretion, and also had weak agonist potency. The relatively selective V2 (antidiuretic)-agonist dDAVP was 20-30 fold less potent than AVP. Oxytocin, a weak V1- and V2-agonist was only 4-8 fold less potent than AVP. These data are compatible with the suggestion that AVP receptors on pituitary corticotrope cells are neither classical V1- nor V2-receptors.

Signs of attenuated depression-like behavior in vasopressin deficient Brattleboro rats

Vasopressin, a peptide hormone functioning also as a neurotransmitter, neuromodulator and regulator of the stress response is considered to be one of the factors related to the development and course of depression. In the present study, we have tested the hypothesis that congenital deficit of vasopressin in Brattleboro rats leads to attenuated depression-like behavior in tests modeling different symptoms of depression. In addition, hypothalamic-pituitary-adrenocortical axis activity was investigated. Vasopressin deficient rats showed signs of attenuated depression-like behavior in forced swimming and sucrose preference tests, while their behavior on elevated plus maze was unchanged. Vasopressin deficiency had no influence on basal levels of ACTH and corticosterone and had only mild impact on hormonal activation in response to forced swimming and plus-maze exposure. However, vasopressin deficient animals showed higher level of dexamethasone induced suppression of corticosterone response to restraint stress and higher basal levels of corticotropin-releasing hormone mRNA in the hypothalamic paraventricular nucleus. In conclusion, present data obtained in vasopressin deficient rats show that vasopressin is involved in the development of depression-like behavior, in particular of the coping style and anhedonia. Moreover, behavioral and endocrine responses were found to be dissociated. We suggest that brain vasopressinergic circuits distinct from those regulating the HPA axis are involved in generating depression-like behavior.

Calcitonin Gene-Related Peptide- Containing Pathways in the Rat Forebrain

The present study focuses on the topographical distribution of calcitonin gene‐related peptide (CGRP)‐containing cell bodies and fibers and their connections and pathways in the rat forebrain. We confirm previously reported CGRP projections from the perifornical area of the hypothalamus to the lateral septum, from the posterior thalamus to the caudate putamen and cerebral cortex, and from the parabrachial nuclei to the central extended amygdala, lateral hypothalamus, and ventromedial thalamus. Despite previous descriptions of CGRP in the central nervous system, important neuroanatomical aspects of the forebrain CGRP system remained obscure, which we addressed by using brain lesion techniques combined with modern immunohistology. We first report CGRP terminal fields in the olfactory‐anterior septal region and also CGRP projections from the parabrachial nuclei to the olfactory‐anterior septal region, the medial prefrontal cortex, the interstitial nucleus of the anterior commissure, the nucleus of the lateral olfactory tract, the anterior amygdaloid area, the posterolateral cortical amygdaloid nucleus, and the dorsolateral part of the lateral amygdaloid nucleus. In addition, we identified a CGRP cell group in the premamillary nuclei and showed that it projects to the medial CGRP layer of the lateral septum. CGRP fibers usually join other pathways rather than forming bundles. They run along the fornix from the hypothalamus, along the supraoptic decussations or the inferior thalamic peduncle‐stria terminalis pathway from the posterior thalamus, and along the superior cerebellar peduncle, thalamic fasciculus, and ansa peduncularis from the parabrachial nuclei. This description of the forebrain CGRP system will facilitate investigation of its role in higher brain functions. J. Comp. Neurol. 489:92–119, 2005.

Social stress of variable intensity: physiological and behavioral consequences

Stress effects in humans depend on stress type, intensity, and duration. Animal models of social stress serve as good ways to mimic stress experienced in humans. However, the available stress paradigms pay little attention to the relationship between the intensity and the type of social stressors. The aim of the present work is to study behavioral and endocrinological consequences of social stress by varying the intensity and type of agonistic social contacts. Subjects were exposed to the attacks of an experienced fighter resident rat once a day for 4 consecutive days. Mild versus strong effects were studied by varying the length of daily confrontations (30 min vs. 4 h). The type of social confrontations was varied by ceasing or maintaining sensory contacts among contestants between encounters. Endocrinological variables were measured on the 5th day. Anxiety was assessed by means of the elevated plus-maze. The stress state depended on the length of daily encounters: 30-min encounters did not, whereas 4-h encounters did result in weight loss and chronic elevation of plasma corticosterone. The type of contacts between subjects and dominants also affected the resulting stress state: adrenal hypertrophy was obtained only when contacts between contestants were maintained between encounters. Although the mildest stress procedure (30-min encounters on 4 consecutive days) did not affect endocrinological variables, it resulted in subtle behavioral modifications that changed the anxiety-related effects of additional acute stressors. Thus, anxiety-related behavioral changes resulting from repeated mild stressors may be hidden factors that can have long-term consequences on the development of anxiety-like behavioral deficits. Results outline the necessity of studying the effects of social stressors of different intensities and different types.

Gender-specific effect of maternal deprivation on anxiety and corticotropin-releasing hormone mRNA expression in rats

The long-term behavioral and neurochemical effects of 24h maternal separation were assessed in rats of both genders. Maternal deprivation was applied at the age of 9 days, whereas consequences were assessed 3 months later. Deprived rats (irrespective of gender) showed a considerable growth retardation that disappeared till adulthood. The plus-maze performance of control and deprived males did not differ under normal conditions, but deprived males showed more anxiety when the test was applied shortly after stress exposure. CRH mRNA expression in the amygdala, but not in the hypothalamus, was more intense in deprived as compared with control males. Deprived females were not affected. These data suggest that (i) the maternal deprivation induced changes are larger in males than in females, (ii) maternal deprivation induces a latent behavioral disposition towards anxiety that is precipitated by acute stressors, and (iii) the changes noticed in amygdalar CRH expression may serve as mechanisms for the behavioral changes noticed.