A corticotropin-releasing factor antagonist reverses the stress-induced changes of exploratory behavior in mice

Corticotropin-releasing factor (CRF) administered intracerebroventricularly (ICV) to rats and mice has been shown to elicit a variety of behaviors resembling those that occur in stress. In a novel multicompartment chamber, ICV CRF altered the behaviors in a manner closely resembling that observed following a period of restraint. In particular, 75 ng CRF ICV or 30-40 min restraint markedly reduced the time mice spent in contact with novel stimuli. ICV injections of a peptide antagonist of CRF, alpha-helical CRF9-41 (ahCRF), reversed the effects of restraint on this measure. This effect of ahCRF was dose dependent, with a minimal effective dose of 10 micrograms. Other behavioral measures appeared normal, and ahCRF did not significantly alter the stimulus-contact time in unrestrained mice. These results provide strong evidence to support the hypothesis that endogenous CRF may be a factor affecting stress-induced changes in exploratory behavior in mice.     

Naloxone alters locomotion and interaction with environmental stimuli

Rats were injected with saline or naloxone (0.5, 5.0 or 25 mg/kg) and monitored for locomotion and both frequency and duration of contact with stimuli in a multicompartment exploratory chamber. Naloxone produced a dose-related reduction in locomotion and in frequency of contact with stimuli. At the lowest dose tested this reduction was accompanied by an increase in total duration of contact and in time spent per contact with the stimuli. In contrast, the highest dose of naloxone decreased the duration of contact with stimuli and induced prolonged periods of inactivity. An intermediate response was observed with 5.0 mg/kg naloxone. These results indicate that lower doses of naloxone may enhance interaction with environmental stimuli while the predominant effect of higher doses is a general suppression in behavioral activity. Similarities with the antimanic agent lithium chloride and possible clinical implications are discussed.     

Effects of adrenalin on novelty choices and activity in rats

Rearing, ambulation and occupancy of the novel half of an exploration box were observed in Wistar albino rats following intraperitoneal injections of saline, 0.03 or 0.06 mg/kg adrenalin. All three responses were decreased by the drug in a dose-related manner. Adrenalin did not seem to impair ability to discriminate between novel and familiar stimuli since the percentage of rearing that occurred in the novel half was highest in rats who received the 0.06 mg/kg dose. It was concluded that the suppression of novelty choices (and probably rearing and ambulation) by adrenalin was mainly due to its aversive peripheral properties. Pretreatment with 20 mg/kg oxprenolol HCl largely prevented the effects observed earlier, thereby implicating -adrenoceptors in adrenalin's behavioral action.     

Corticotropin releasing factor induces anxiogenic locomotion in trout and alters serotonergic and dopaminergic activity

Corticotropin releasing factor (CRF) and serotonin (5-HT) are strongly linked to stress and anxiety in vertebrates. As a neuromodulator in the brain, CRF has anxiogenic properties often characterized by increased locomotion and stereotyped behavior in familiar environments. We hypothesized that expression of anxiogenic behavior in response to CRF will also be exhibited in a teleost fish. Rainbow trout were treated with intracerebroventricular (icv) injections of artificial cerebrospinal fluid (aCSF), 500 or 2000 ng ovine CRF, or not injected. Treatment with either dose of CRF elicited greater locomotion and pronounced head shaking behavior but did not influence water column position. Locomotor and head shaking behaviors may be analogous to the increased stereotypy evoked by icv CRF in rats and may reflect the expression of stress/anxiety behavior. Injection with either aCSF or CRF produced significant increases in plasma cortisol. The absence of behavioral changes in aCSF-injected fish suggests that the behavioral responses following CRF were not due to cortisol. Treatment with 2000 ng CRF significantly increased serotonin, 5-HIAA and dopamine concentrations in the subpallium and raphé and increased 5-HIAA in the preoptic hypothalamus (POA). Concurrent effects of CRF on central monoamines, locomotion and head shaking in trout suggest that anxiogenic properties of CRF are evolutionarily conserved. In addition, positive linear correlations between locomotion and serotonergic and dopaminergic function in the subpallium, POA and raphé nuclei suggest a locomotory function for these monoamines.     

Corticotropin releasing factor induces anxiogenic locomotion in trout and alters serotonergic and dopaminergic activity

Corticotropin releasing factor (CRF) and serotonin (5-HT) are strongly linked to stress and anxiety in vertebrates. As a neuromodulator in the brain, CRF has anxiogenic properties often characterized by increased locomotion and stereotyped behavior in familiar environments. We hypothesized that expression of anxiogenic behavior in response to CRF will also be exhibited in a teleost fish. Rainbow trout were treated with intracerebroventricular (icv) injections of artificial cerebrospinal fluid (aCSF), 500 or 2000 ng ovine CRF, or not injected. Treatment with either dose of CRF elicited greater locomotion and pronounced head shaking behavior but did not influence water column position. Locomotor and head shaking behaviors may be analogous to the increased stereotypy evoked by icv CRF in rats and may reflect the expression of stress/anxiety behavior. Injection with either aCSF or CRF produced significant increases in plasma cortisol. The absence of behavioral changes in aCSF-injected fish suggests that the behavioral responses following CRF were not due to cortisol. Treatment with 2000 ng CRF significantly increased serotonin, 5-HIAA and dopamine concentrations in the subpallium and raphé and increased 5-HIAA in the preoptic hypothalamus (POA). Concurrent effects of CRF on central monoamines, locomotion and head shaking in trout suggest that anxiogenic properties of CRF are evolutionarily conserved. In addition, positive linear correlations between locomotion and serotonergic and dopaminergic function in the subpallium, POA and raphé nuclei suggest a locomotory function for these monoamines.     

Alcohol reverses the proconflict effect of corticotropin-releasing factor

Alcohol has tension reducing properties in man that are reflected in a release of punished responding in a rat operant conflict test. In contrast, corticotropin releasing factor (CRF), injected centrally produces a suppression of punished and non-punished responding in the conflict test consistent with its hypothesized role in mediating behavioral responses to stress. Alcohol in a dose of 0.75 g/kg reversed the suppressive effects of 0.5 microgram CRF injected intracerebroventricularly on punished responding but augmented the suppression of unpunished responding by CRF. Results suggest that one mechanism for the tension reducing properties of acute alcohol intoxication may involve a suppression of brain CRF systems.     

CRF type 1 receptors in the dorsal periaqueductal gray modulate anxiety-induced defensive behaviors

The dorsal periaqueductal gray (dPAG) is involved in defensive coping reactions to threatening stimuli. Corticotropin releasing factor (CRF) is substantially implicated as a direct modulator of physiological, endocrine and behavioral responses to a stressor. Previous findings demonstrate a direct role of the central CRF system in dPAG-mediated defensive reactions toward a threatening stimulus. These include anxiogenic behaviors in the elevated plus maze (EPM) in rats and defensive reactions in both the mouse defense test battery (MDTB) and rat exposure test (RET) paradigms in mice. Furthermore, CRF was shown to directly and dose-dependently excite PAG neurons in vitro. The aim of the present series of experiments was to directly evaluate the role of the CRF1 receptor (CRF1) in dPAG-induced defensive behaviors in the MDTB and the RET paradigms. For this purpose, cortagine, a novel CRF1-selective agonist, was directly infused into the dPAG. In the RET the high dose of cortagine (100 ng) significantly affected spatial avoidance measures and robustly increased burying behavior, an established avoidance activity, while having no effects on behaviors in the MDTB. Collectively, these results implicate CRF1 in the dPAG as a mediator of temporally and spatially dependent avoidance in response to controllable and constant stimuli.     

Neuropeptide Y blocks anxiogenic-like behavioral action of corticotropin-releasing factor in an operant conflict test and elevated plus maze

Central administration of neuropeptide Y (NPY) produces anxiolytic-like behavioral effects in rat models of anxiety. Because previous evidence has suggested a relationship between NPY and corticotropin-releasing factor (CRF) in the brain, we have focused on the interaction of these neuropeptide systems in emotional responsiveness to stressful stimuli. Intracerebroventricular administration of CRF produced a marked response suppression in an operant incremental shock conflict paradigm. NPY [(1 microg, intracerebroventricularly (i.c.v.)] significantly antagonized the response-suppressing effects of CRF (0.75 microg, i.c.v.) on punished responding in the conflict test at doses that produced little or no behavioral effect when administered alone. Central administration of the CRF antagonist [D-Phe(12), Nle(21,38),C(alpha) MeLeu(37)]CRF (D-Phe CRF(12-41)) alone did not alter punished or unpunished responding in the conflict test. However, pretreatment with the CRF antagonist before a subthreshold dose of NPY (1 microg, i.c.v.) produced a significant potentiation of the release of punished responding relative to NPY alone and untreated controls. NPY also antagonized the "anxiogenic-like" behavioral effects of CRF in the elevated plus maze. These findings support the hypothesis that NPY and CRF may reciprocally modulate an animal's behavioral response to stressful stimuli.     

Effects of adrenergic blockers on corticotropin-releasing factor-induced behavioral changes in rats

The effects of adrenoreceptor blocking agents on corticotropin-releasing factor (CRF)-induced behavioral changes in rats were examined. The i.c.v. injection of 1 micrograms ovine CRF significantly increased the grooming frequency, number of occurrences of rearing and total distance moved. I.c.v. administered phentolamine at a dose of 10 nmol completely suppressed the increase in rearing and total distance moved induced by CRF without affecting the grooming frequency, whereas 100 nmol phentolamine significantly decreased the grooming frequency as well as the rearing and total distance moved. In contrast, propranolol reduced the increase in rearing induced by CRF only at a dose which induced ataxia in rats. The increases in rearing and total distance moved induced by CRF were reduced by 10 nmol of yohimbine and 100 nmol of prazosin. S.c. injection of caffeine (10 mg/kg) produced a significant increase in grooming frequency, rearing, and total movement. Administration of 10 nmol phentolamine and yohimbine did not affect these behavioral changes induced by caffeine, while 100 nmol prazosin suppressed them. Therefore, prazosin depressed the behavior of rats non-specifically. These results suggest that CRF-induced behavioral hyperactivity is mediated at least in part by alpha-noradrenergic, mainly alpha 2-noradrenergic, systems in the brain.     

Influence of substance P on the behavioral changes induced by haloperidol in rats

Locomotor activity and grooming behavior of rats were recorded for a period of 30 min following intraventricular injections of substance P(SP) in doses of 0.60 and 2.50 microgram/rat. The lower dose of the peptide significantly increased locomotion for 10 min and time spent grooming for 25 min. The effects of the same two doses of SP on the hypokinesia induced by various pharmacological treatments modifying catecholaminergic systems were then examined. SP did not affect the behavioral depression produced by alpha-methyl-para-tyrosine (250 mg/kg), FLA-63 (25 mg/kg) and phenoxybenzamine (20 mg/kg). However, SP, in dose of 0.60 microgram/rat, systematically reversed the decrease in locomotor activity induced by a relatively small dose of haloperidol, 0.1 mg/kg. The dame dose of the peptide significantly counteracted the rigidity but not the hypokinesia and catalepsy resulting from the previous administration of a higher dose of haloperidol, 3 mg/kg. The results support the hypothesis that SP may exert direct or indirect function in motor behavior, possible via a modulatory action on brain dopaminergic systems.     

产前轻微应激易化由围产期注射引起的行为改变并弱化奥氮平的作用

产前母体处于应激状态下,可以削弱子代的神经系统对外界不良刺激影响的抵抗能力．但产前应激状态是否可以影响抗精神疾病药物对动物行为的增益作用,目前还没有明确的结论．此外,在动物实验中,动物需要经常接受注射操作,注射操作本身是否会影响动物行为,尚未有相关研究．在本实验中,探索了产前轻微应激状态、围产期注射操作和抗精神疾病药物对动物行为可能的交互影响．母鼠在经历产前轻微应激状态后生产子代,雄性仔鼠在围产期(日龄第7, 9, 11天)不接受注射或接受盐水或奥氮平注射(2 mg/kg,腹腔注射)．在其亚成年期(日龄第35天)和成年期(日龄第60天),观察其社交和嗅觉辨识行为,分析了总探索时间和对新旧刺激的偏好程度两个参数．我们发现,围产期重复注射操作可以改变产前应激组大鼠在社交和嗅觉辨识实验中的偏好程度,对无应激组大鼠没有影响．奥氮平注射可以增长无应激组大鼠在社交活动中的总探索时间,对应激组大鼠没有影响．研究表明,产前轻微应激状态可以易化诸如围产期注射操作等不良环境刺激导致的行为异常,并减弱抗精神疾病药物的对神经系统的影响．     

Midazolam Ameliorates the Behavior Deficits of a Rat Posttraumatic Stress Disorder Model through Dual 18 kDa Translocator Protein and Central Benzodiazepine Receptor and Neurosteroidogenesis

Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder that may develop after an individual has experienced or witnessed a severe traumatic event. It has been shown that the 18 kDa translocator protein (TSPO) may be correlated with PTSD and that the TSPO ligand improved the behavioral deficits in a mouse model of PTSD. Midazolam, a ligand for TSPO and central benzodiazepine receptor (CBR), induces anxiolytic- and anti-depressant-like effects in animal models. The present study aimed to determine whether midazolam ameliorates PTSD behavior in rats as assessed by the single prolonged stress (SPS) model. The SPS rats received daily Sertraline (Ser) (15 mg/kg, p.o.) and midazolam (0.125, 0.25, 0.5, and 1 mg/kg, p.o.) during the exposure to SPS and behavioral assessments, which included the open field (OF) test, the contextual fear paradigm (CFP), and the elevated plus-maze (EPM). The results showed that, like Ser (15 mg/kg, p.o.), midazolam (0.25 and 0.5 mg/kg, p.o.) significantly reversed the behavioral deficiencies of the SPS rats, including PTSD-associated freezing and anxiety-like behavior but not the effects on spontaneous locomotor activity. In addition, the anti-PTSD effects of midazolam (0.5 mg/kg, p.o.) were antagonized by the TSPO antagonist PK11195 (3 mg/kg, i.p.), the CBR antagonist flumazenil (15 mg/kg, p.o.) and the inhibitor of steroidogenic enzymes finasteride (30 mg/kg, p.o.), which by themselves had no effect on PTSD-associated freezing and anxiety-like behavior. In summary, this study demonstrated that midazolam improves the behavioral deficits in the SPS model through dual TSPO and CBR and neurosteroidogenesis.     

Behavioral effects of acute and chronic triazolam treatments in albino rats

Previous behavioral studies on triazolam (TZ), which are small in number, could only speculate about tolerance to the anxiolytic effect of TZ, as the experiments did not cover sufficient time (of 4 to 7 days) for tolerance to develop. Therefore longer time for chronic TZ administration is used. We investigated the effects of TZ on motor activity and exploratory behavior using plus maze and open field. Three experiments were conducted. In the first, five groups of rats were acutely treated with different doses of TZ (0.25 mg/kg-4.0 mg/kg). In the second set of experiments, rats were treated chronically with a single daily dose of TZ (started with 0.25 mg/kg and increased by time to 1.0 mg/kg) for 5 weeks (representing clinical use). In the third, rats were treated chronically with three daily doses of TZ (started with 0.25 mg/kg and increased by time to 0.5 mg/kg) for 20 days (mimicking drug abuse). Acute TZ administration produced dose dependent anxiolytic effects and a decrease in motor activity with higher doses. Chronically treated rats, either once daily or three times daily doses, showed tolerance to both anxiolytic and sedative effects of TZ. It may be concluded that tolerance to the anxiolytic and sedative effects of TZ would develop after chronic administration either with clinical use or its abuse.     

Corticotropin-releasing factor antagonist blocks stress-induced fighting in rats

Corticotropin-releasing factor (CRF) has been shown to have potent central nervous system-activating effects when administered intracerebroventricularly (i.c.v.). In the present experiment, this activating effect was exaggerated by use of a stress-motivated behavioral paradigm. Low doses of CRF (0.01 and 0.1 micrograms/rat) administered i.c.v. facilitated stress-induced fighting. More importantly, alpha-helical CRF-(9-41), a CRF antagonist, blocked stress-induced fighting produced by higher levels of stress. These results suggest that CRF in the central nervous system may have a role in mediating behavioral responses to stress.     

The selective glucocorticoid receptor antagonist CORT 108297 decreases neuroendocrine stress responses and immobility in the forced swim test

Pre-clinical and clinical studies have employed treatment with glucocorticoid receptor (GR) antagonists in an attempt to limit the deleterious behavioral and physiological effects of excess glucocorticoids. Here, we examined the effects of GR antagonists on neuroendocrine and behavioral stress responses, using two compounds: mifepristone, a GR antagonist that is also a progesterone receptor antagonist, and CORT 108297, a specific GR antagonist lacking anti-progestin activity. Given its well-documented impact on neuroendocrine and behavioral stress responses, imipramine (tricyclic antidepressant) served as a positive control. Male rats were treated for five days with mifepristone (10 mg/kg), CORT 108297 (30 mg/kg and 60 mg/kg), imipramine (10 mg/kg) or vehicle and exposed to forced swim test (FST) or restraint stress. Relative to vehicle, imipramine potently suppressed adrenocorticotropin hormone (ACTH) responses to FST and restraint exposure. Imipramine also decreased immobility in the FST, consistent with antidepressant actions. Both doses of CORT 108297 potently suppressed peak corticosterone responses to FST and restraint stress. However, only the higher dose of CORT 108297 (60 mg/kg) significantly decreased immobility in the FST. In contrast, mifepristone induced protracted secretion of corticosterone in response to both stressors, and modestly decreased immobility in the FST. Taken together, the data indicate distinct effects of each compound on neuroendocrine stress responses and also highlight dissociation between corticosterone responses and immobility in the FST. Within the context of the present study, our data suggest that CORT 108297 may be an attractive alternative for mitigating neuroendocrine and behavioral states associated with excess glucocorticoid secretion.     

Corticotropin-releasing factor has an anxiogenic action in the social interaction test

The effects of intracerebroventricular (icv) injections of corticotropin-releasing factor (CRF, 100 and 300 ng) were investigated in the social interaction test of anxiety in rats. Both doses of CRF significantly decreased active social interaction without a concomitant decrease in locomotor activity. CRF also significantly increased self-grooming, an effect that was independent of the decrease in social interaction. These results indicate an anxiogenic action for CRF. Chlordiazepoxide (CDP, 5 mg/kg ip) pretreatment reversed the anxiogenic effects of icv CRF (100 ng), but CRF did not prevent the sedative effects of CDP. There were no statistically significant changes due to CRF in locomotor activity or rears or head dipping in the holeboard test. Both doses of CRF significantly increased plasma concentrations of corticosterone. The possible mechanisms of the behavioral effects of CRF are discussed.     

Effects of a Post-Shock Injection of the Kappa Opioid Receptor Antagonist Norbinaltorphimine (norBNI) on Fear and Anxiety in Rats

Exposure of rats to footshocks leads to an enduring behavioral state involving generalized fear responses and avoidance. Recent evidence suggests that the expression of negative emotional behaviors produced by a stressor is in part mediated by dynorphin and its main receptor, the kappa opioid receptor (KOR). The purpose of this study was to determine if a subcutaneous injection of the long-acting KOR antagonist norbinaltorphimine (norBNI; 15.0 and 30.0 mg/kg) given 2 days after an acute exposure of rats to footshooks (5×2 s episodes of 1.5 mA delivered over 5 min) attenuates the expression of lasting fear and anxiety. We report that exposure of rats to acute footshock produced long-lasting (>4 weeks) fear (freezing) and anxiety (avoidance of an open area in the defensive withdrawal test). The 30 mg dose of norBNI attenuated the fear expressed when shock rats were placed in the shock context at Day 9 but not Day 27 post-shock. The same dose of norBNI had no effect on the expression of generalized fear produced when shock rats were placed in a novel chamber at Days 8 and 24. In contrast, the 30 mg dose of norBNI produced consistent anxiolytic effects in shock and nonshock rats. First, the 30 mg dose was found to decrease the latency to enter the open field in the defensive withdrawal test done 30 days after the shock exposure. Second, the same high dose also had anxiolytic effects in both nonshock and shock rats as evidence by a decrease in the mean time spent in the withdrawal box. The present study shows that systemic injection of the KOR antagonist norBNI had mixed effect on fear. In contrast, norBNI had an anxiolytic effect which included the attenuation of the enhanced avoidance of a novel area produced by a prior shock experience.     

Neurally Active Stress Peptide Inhibits Territorial Defense in Wild Birds

It is unclear whether the behavioral effects of peptides in laboratory studies always reflect natural conditions. Here we test whether we can detect measurable behavioral changes after rapidly injecting peptides into the brains of wild birds. We used a modified stereotaxic-like technique to inject corticotrophin-releasing factor (CRF) and arginine vasotocin (AVT, the nonmammalian form of arginine vasopressin), two hormones important in the stress response, into the brains of wild, freely behaving, male white-crowned sparrows (Zonotrichia leucophrys). We then monitored subsequent territorial behavior to determine whether CRF or AVT altered this behavior. Surprisingly, the potent stressors of capture and surgery did not eliminate territorial behavior, with many birds resuming territorial defense within 60–90 min after surgery. Centrally acting CRF, however, significantly reduced territorial defense whereas centrally acting AVT had no effect. These results indicate that the behavioral affects of peptides can be studied under natural conditions.     

Corticotropin-releasing factor: an inhibitor of vascular leakage in rat skeletal muscle and brain cortex after injury

Corticotropin-releasing factor (CRF) and other peptides of the corticoliberin superfamily inhibit development of edema in skin and mucosa after noxious stimuli. Here, the breadth of CRFs protective activity on small blood vessels was examined after injury to skeletal muscle or to brain cortex. Male rats (243 +/- 15 g) were anesthetized with sodium pentobarbital 60 mg/kg i.p. and Monastral blue 60 mg/kg i.v. was injected 3 min before mechanical injury to muscle produced by a 4 cm midline surgical incision in the rectus abdominis or before freeze injury to the cortex produced by applying a cold probe (-50 degrees C) to the skull for 4 min. Vascular leakage, measured as area of dye staining multiplied by its light intensity, was quantified with an image-analysis system. CRF, having the human/rat sequence, 30 micrograms/kg s.c., injected once (30 min) or twice (30 min and 10 min) before injury to muscle or to brain, inhibited the lesion size by 58% and 55%, respectively (tissues taken at 0.5 and 1 h). Microscopy showed that CRF inhibited Monastral blue labeling of small blood vessels. The ED50 (95% C.L.) of CRF for reducing vascular leakage in muscle after celiotomy was 24 (9 to 64) micrograms/kg s.c. h/rCRF injected 30 micrograms/kg s.c. 2 h before celiotomy inhibited vascular leakage after celiotomy in adrenalectomized rats and this effect was not obtained with dexamethasone phosphate, 1 mg/kg s.c. alpha-Helical CRF (9-41), a CRF receptor antagonist, attenuated the actions of CRF on celiotomy. Laser-Doppler flowmeter measurements of skeletal muscle showed that the anti-inflammatory effects of CRF occurred when there were no significant concurrent changes in blood flow. From these results, we surmise that CRF has a versatile protective effect on small blood vessels when it inhibits leakage within different vascular beds.     

Rapid changes in monoamine levels following administration of corticotropin-releasing factor or corticosterone are localized in the dorsomedial hypothalamus

Monoaminergic systems are important modulators of the neuroendocrine, autonomic, and behavioral responses to stress-related stimuli. The male roughskin newt (Taricha granulosa) was used as a model system to investigate the effects of corticotropin-releasing factor (CRF) or corticosterone administration on tissue concentrations of norepinephrine, epinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) in microdissected brain areas. Intracerebroventricular infusion of 25 or 50 ng of CRF increased locomotor activity and site-specifically increased dopamine concentrations within the dorsomedial hypothalamus 30 min after treatment when compared to vehicle-treated controls. In further studies, male newts were treated as follows: (1) no injection, no handling, (2) saline injection, or (3) 10 microg corticosterone and then placed in a novel environment. Monoamine and monoamine metabolite concentrations were similar in the unhandled and saline-injected controls 20 min after treatment. In contrast, corticosterone-injected newts had elevated concentrations of dopamine, serotonin, and 5-HIAA in the dorsomedial hypothalamus (a region that contains dopamine- and serotonin-accumulating neuronal cell bodies in representatives of all vertebrate classes) but not in several other regions studied. These site-specific neurochemical effects parallel neurochemical changes observed in the dorsomedial hypothalamic nucleus of mammals following exposure to a variety of physical and psychological stress-related stimuli. Therefore, these changes may reflect highly conserved, site-specific neurochemical responses to stress and stress-related neurochemicals in vertebrates. Given the important role of the dorsomedial hypothalamus in neuroendocrine, autonomic, and behavioral responses to stress, and a proposed role for this region in fast-feedback effects of glucocorticoids on the hypothalamo-pituitary-adrenal axis, these stress-related monoaminergic changes are likely to have important physiological or behavioral consequences.