Corticotropin-releasing factor type II (CRF?) receptors in the bed nucleus of the stria terminalis modulate conditioned defeat in Syrian hamsters (Mesocricetus auratus).

In Syrian hamsters (Mesocricetus auratus), social defeat produces a subsequent increase in submissive and defensive behavior and a loss of normal territorial aggression, which the authors have called conditioned defeat. In this study, the authors investigated the effect of blocking corticotropin-releasing factor (CRF) Type I and Type II receptors on conditioned defeat. Intracerebroventricular infusion of the CRF? receptor antagonist antisauvagine-30 prior to testing significantly reduced conditioned defeat compared with vehicle controls, whereas the CRF? receptor antagonist CP-154,526 had no effect. Also, infusion of antisauvagine-30 into the bed nucleus of the stria terminalis (BNST) 15 min, but not immediately, prior to testing reduced conditioned defeat in a dose-dependent manner. The authors' results provide evidence that CRF? receptors in the BNST, but not CRF? receptors, are an important component in the neural circuitry regulating conditioned defeat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Corticotropin-releasing factor-1 receptors in the basolateral amygdala mediate stress-induced anorexia.

Corticotropin-releasing factor (CRF) receptor activation within the basolateral amygdala (BLA) has been relatively unexplored compared with the central nucleus of the amygdala (CeA), despite the fact that CRF receptors are more densely distributed in BLA than in CeA. The authors show that infusion of CRF into BLA, but not CeA, decreases feeding and increases grooming. These effects are mediated by CRF? receptors, because they are blocked by intra-BLA treatment with NBI27914 (NBI), a CRF? antagonist, but not Astressin 2B, a CRF? antagonist. Exposure to a stressor results in behaviors identical to those seen after intra-BLA CRF infusion. These stress-induced changes are prevented by pre-stress treatment with NBI but not Astressin 2B. These data demonstrate that stimulation of intra-BLA CRF? receptors is both necessary and sufficient for eliciting stress-induced anorexia and grooming. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Glutamate and the aggression neural circuit in adolescent anabolic steroid-treated Syrian hamsters (Mesocricetus auratus).

Adolescent exposure to anabolic androgenic steroids (AAS) alters the development and activity of the glutamate neural system in the latero-anterior hypothalamus (LAH) in hamsters (Mesocricetus auratus); that is, an important neural component of the adolescent AAS-induced aggressive response. In this article, we used retrograde tracing to investigate glutamate-specific alterations in the connections between the LAH and several other nuclei implicated in adolescent AAS-induced aggression. Briefly, hamsters were treated with AAS or sesame-oil control during adolescence and then microinjected with retrograde tracer into the medial amygdala (MeA), lateral septum (LS), or bed nucleus of the stria terminalis (BNST). Brains were then processed for vesicular glutamate transporter 2 (VGLUT2) and examined for AAS-induced changes in the number VGLUT2 cells containing retrograde tracer (VGLUT2/tracer) within the LAH. It is interesting to note that while aggressive AAS-treated hamsters injected retrograde tracer into the MeA showed a significant reduction in the number of VGLUT2/tracer cells in the LAH, aggressive AAS-treated hamsters injected tracer into the BNST showed a significant increase in the number of VGLUT2/tracer cells in the LAH when compared with controls. Last, AAS hamsters injected with tracer into the LS had a comparable number of LAH-VGLUT2/tracer cells to controls. The current results indicate that glutamate likely functions as the major aggression output system from the LAH and that adolescent AAS treatment significantly alters the neural circuitry modulating aggression. Moreover, increases in the number of glutamate projections from the LAH to the BNST in AAS hamsters identify the BNST as an area particularly important for the regulation of AAS-induced aggression. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Neural systems involved in fear and anxiety measured with fear-potentiated startle.

A good deal is now known about the neural circuitry involved in how conditioned fear can augment a simple reflex (fear-potentiated startle). This involves visual or auditory as well as shock pathways that project via the thalamus and perirhinal or insular cortex to the basolateral amygdala (BLA). The BLA projects to the central (CeA) and medial (MeA) nuclei of the amygdala, which project indirectly to a particular part of the acoustic startle pathway in the brainstem. N-methyl-D-aspartate (NMDA) receptors, as well as various intracellular cascades in the amygdala, are critical for fear learning, which is then mediated by glutamate acting in the CeA. Less predictable stimuli, such as a long-duration bright light or a fearful context, activate the BLA, which projects to the bed nucleus of the stria terminalis (BNST), which projects to the startle pathway much as the CeA does. The anxiogenic peptide corticotropin-releasing hormone increases startle by acting directly in the BNST. CeA-mediated behaviors may represent stimulus-specific fear, whereas BNST-mediated behaviors are more akin to anxiety. NMDA receptors are also involved in extinction of conditioned fear, and both extinction in rats and exposure-based psychotherapy in humans are facilitated by an NMDA-partial agonist called D-cycloserine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Adaptation to ozone in rats and its association with ascorbic acid in the lung

The present study evaluated the modulatory role of central corticotropin-releasing factor (CRF) systems in the mediation of the effects of acute exposure to the brain cannabinoid receptor agonist HU-210 [3-(1,1-dimethylheptyl)-(-)-11-hydroxy-delta 8-tetrahydrocannabinol] on defensive withdrawal behavior in male rats. The apparatus used for the defensive withdrawal test consisted of a small chamber, set on one side of a one-square meter open field. The actions of the potent CRF antagonist [D-Phe12,Nle21,38,C alpha MeLeu37]CRF (D-Phe CRF12-41) were examined on defensive behavior under both novel and familiar conditions. The acute i.c.v. administration of D-Phe CRF12-41 (0.2-5 micrograms/injection) antagonized the defensive behavior response to stressing conditions such as novelty or swim stress in field-habituated animals. The acute i.p. administration of HU-210 (4, 20 and 100 micrograms/kg) produced a clear dose-dependent stress-like effects in field-habituated animals, as reflected in the HU-210-induced increase in both the emergence latency and the mean time spent in the small chamber. The i.c.v. administration of 5 micrograms of D-Phe CRF12-41, 5 min before the administration of the cannabinoid prevented the stressing actions of HU-210 (20 micrograms/kg, but not 100 micrograms/kg). Acute administration of HU-210 also induced a dose-dependent increase in plasma corticosterone levels which was not antagonized by pretreatment with 5 micrograms of D-Phe CRF12-41. The present study suggests a role of central CRF systems in the mediation of the anxiogenic effects of brain cannabinoid receptor agonists. This finding is consistent with a direct hypothalamic effect of cannabinoids on the activation of the pituitary-adrenal axis.     

The human neuroblastoma cell line, IMR-32, expresses functional corticotropin-releasing factor receptors

Corticotropin-releasing factor (CRF) receptors in IMR-32 human neuroblastoma cells were characterized after differentiation with 2.5 microM 5'-bromo-2'-deoxyuridine for 10 days. Scatchard analysis of [125I-Tyr0]ovine CRF binding revealed a high affinity binding site with a dissociation constant of 0.59 nM and a maximum binding capacity of 142 fmol/mg, the affinity of which was decreased by guanosine 5'-o-(3-thiotriphosphate). This binding was displaced in the following order of potency: human/rat CRF > ovine CRF > urotensin I > sauvagine > bovine CRF > [D-Phe12, Nle21,38, C alpha-MeLeu37]human/rat CRF-(12-41) > alpha-helical CRF-(9-41), indicative of the CRF1 receptor subtype. Functional coupling of this receptor was confirmed by CRF-induced increases in cyclic AMP, which were antagonised by alpha-helical CRF-(9-41) and [D-Phe12,Nle21,38,C alpha-MeLeu37] human/rat CRF-(12-41).     

Co-infusion with a TrkB-Fc receptor body carrier enhances BDNF distribution in the adult rat brain

Intraspecific confrontation between male rats represents a biologically relevant form of social stress. C-fos expression has been used to map the pattern of neural activation following either a single (acute) or repeated (10 times) exposure of an intruder male to a larger male in the latter's home cage. These conditions induce high levels of aggressive interaction. Sixty minutes after a single defeat, there was intense c-fos expression (quantified using image analysis) in restricted areas of the basal forebrain (including lateral septum, bed nucleus of stria terminalis, lateral preoptic area, lateral hypothalamic area, paraventricular nucleus, and medial and central amygdala) as well as in the autonomic and monoaminergic nuclei of the brainstem (central grey, dorsal and median raphe, locus coeruleus and nucleus of the solitary tract). After the tenth defeat, this pattern was modified despite persistently high levels of aggression. Some areas in the forebrain (bed nucleus of stria terminalis, paraventricular nucleus and medial amygdala) continued to express increased c-fos; others (the septum, lateral hypothalamic area, lateral preoptic area and central amygdala) no longer expressed c-fos. The brainstem response was equally varied: the central grey and the raphe nuclei continued to respond after repeated defeat, whereas the solitary nucleus and locus coeruleus did not. On the other hand, there was no change in the behaviour of intruder rats after repeated defeat. This study shows the pattern of adaptation at a cellular level in the basal forebrain and brainstem to repeated defeat. As in our previous studies of repeated restraint, modulation in the expression of c-fos following repeated stress is highly regionally specific, suggesting that differential neural processing is involved in adaptation to social stress.     

Stimulation of neuropeptide Y overflow in the rat paraventricular nucleus by corticotropin-releasing factor

Neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) are present at high concentrations in the hypothalamus where they mediate important endocrine and autonomic functions. Morphological and physiological studies have suggested an interaction between these peptides, and opposing actions of CRF and NPY have been reported on feeding and other behaviors. This study investigated the effect of CRF on NPY release in vivo, measured by push-pull techniques, in the anesthetized rat. Push-pull probes implanted into the paraventricular nucleus of the hypothalamus (PVN) were perfused with modified Ringer solution containing bovine serum albumin at 15 microl/min, and the perfusate was lyophilized prior to NPY radioimmunoassay. NPY overflow from the rat PVN was increased threefold by perfusion of a depolarizing concentration of potassium (50 mmol/L KCl). When CRF was administered into the PVN via the push-pull cannula at 1 or 5 microg/ml, dose-dependent increases in NPY overflow of two- and fivefold were observed (p < 0.05). These increases were abolished by prior intracerebroventricular (i.c.v.) administration of the CRF antagonist [D-Phe12,Nle(21,38),C(alpha)MeLeu32]CRF (12-41) at 1 or 5 microg/microl, respectively. NPY overflow returned promptly to resting levels following CRF administration. In contrast, when CRF was administered by i.c.v. bolus at a similar total dose (2 microg), no significant effect on NPY overflow was observed. These data provide in vivo evidence for an interaction between CRF and NPY at the level of the PVN.     

Effects of corticotropin-releasing factor on circadian locomotor rhythm in the golden hamster

Stress produces a reduction in the amplitude of some circadian rhythms. The neurochemical mechanisms underlying stress-induced changes in circadian rhythms are not known. To investigate a possible role of corticotropin-releasing factor (CRF) in this phenomenon, three related experiments were carried out: activity rhythms of male golden hamsters (10/14 hours light/dark entrained, lights on at 0800 h) were measured 1) following the intracerebroventricular administration of CRF (0.5, 1.0, 2.0, or 4.0 microg) at two different times of day, 2) following social stress (30-min resident-intruder confrontation), 3) and following the administration of the CRF-antagonist alpha-helical CRF9-41 (2.0 microg) prior to a 15-min resident-intruder confrontation. CRF produced a significant, dose-related decrease in circadian rhythm amplitude following administration in the morning hours, but not in the afternoon. CRF also induced transient increases in activity post injection concomitant with an activation of the hypothalamic-pituitary-adrenocortical (HPA) system. Stress similarly reduced the amplitude of activity patterns and stimulated the HPA system. The stress-induced depression of circadian rhythm amplitude was significantly attenuated following alpha-helical CRF9-41. These data suggest a role for CRF in the stress-related modulation of circadian locomotor rhythm amplitude.     

Lesions in the anterior bed nucleus of the stria terminalis in Syrian hamsters block short-photoperiod-induced testicular regression

To elucidate the neural circuitry involved in the photoperiodic control of seasonal reproduction, adult male Syrian hamsters, previously housed under long photoperiods (LD; 14 h of light per day), received sham or bilateral radiofrequency-current lesions directed towards one of three anterior-to-posterior levels of the bed nucleus of the stria terminalis (BNST; far anterior, anterior, posterior). They were then transferred to a short photoperiod (SD; 6 h of light per day) for 12 wk, and their testicular weights and plasma FSH, LH, and testosterone concentrations were determined. All of these parameters became markedly inhibited in the sham-lesioned SD controls and also in the far anterior and posterior BNST lesioned groups. In contrast, this inhibitory response to SD was completely abolished in 8 of 14 animals that had received anterior BNST lesions; only in these 8 animals did the lesion encompass the lateral aspect of the anterior BNST. In a second experiment, hamsters that had previously been exposed to SD for 12 wk in order to induce testicular regression were lesioned in the anterior BNST and for the next 4 weeks were either exposed to LD or further maintained in SD. However, in neither case did the anterior BNST lesions perturb the normal photoperiodic response. Paired testes weights and plasma FSH, LH, and testosterone concentrations at 4 wk did not differ significantly (p > 0.05) between the lesioned animals and their respective sham-lesioned LD and SD controls, which, respectively, showed recrudescence of the reproductive axis or remained in a regressed condition. Taken together, the results suggest that lateral aspects of the anterior BNST contain a cell group that is critical for perception of the SD neuro-inhibitory signal; obliteration of this cell group interrupts the transmission of the inhibitory signal to the reproductive axis but does not directly stimulate it.     

Central Amygdalar and Dorsal Striatal NMDA Receptor Involvement in Instrumental Learning and Spontaneous Behavior.

Glutamate-coded signaling in corticostriatal circuits has been shown to be important in various forms of learning and memory. In the present study, the authors found that N-methyl-D-aspartate (NMDA) receptor antagonism in the central nucleus of the amygdala (CeA) and the posterior lateral striatum (PLS) impaired instrumental conditioning but had no effect in the anterior dorsal striatum. NMDA receptor antagonism in the CeA and PLS also affected spontaneous motor behavior and certain aspects of feeding. The present findings extend knowledge of the dynamic neurophysiological processes, instantiated in a complex neural network, required for instrumental learning in the mammalian brain. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of corticotropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats

We have shown previously that footshock stress and priming injections of cocaine reinstate cocaine seeking in rats after prolonged drug-free periods (Erb et al., 1996). Here we examined the role of brain corticotropin-releasing factor (CRF) and the adrenal hormone corticosterone in stress- and cocaine-induced reinstatement of cocaine seeking in rats. The ability of footshock stress and priming injections of cocaine to induce relapse to cocaine seeking was studied after intracerebroventricular infusions of the CRF receptor antagonist D-Phe CRF12-41, after adrenalectomy, and after adrenalectomy with corticosterone replacement. Rats were allowed to self-administer cocaine (1.0 mg/kg/infusion, i.v) for 3 hr daily for 10-14 d and were then placed on an extinction schedule during which saline was substituted for cocaine. Tests for reinstatement were given after intermittent footshock (10 min; 0.5 mA) and after priming injections of saline and cocaine (20 mg/kg, i.p.). Footshock reinstated cocaine seeking in both intact animals and animals with corticosterone replacement but not in adrenalectomized animals. The CRF receptor antagonist D-Phe CRF12-41 blocked footshock-induced reinstatement at all doses tested in both intact animals and animals with corticosterone replacement. Reinstatement by priming injections of cocaine was only minimally attenuated by adrenalectomy and by pretreatment with D-Phe CRF12-41. These data suggest that brain CRF plays a critical role in stress-induced, but only a modulatory role in cocaine-induced, reinstatement of cocaine seeking. Furthermore, the data show that although reinstatement of cocaine seeking by footshock stress requires minimal, basal, levels of corticosterone, stress-induced increases in corticosterone do not play a role in this effect.     

Corticotropin-Releasing Factor Inhibits Maternal Aggression in Mice.

Lactating females that fiercely protect offspring exhibit decreased fear and anxiety. The authors tested whether decreased corticotropin-releasing factor (CRF), an activator of fear and anxiety, plays a functional role in maternal aggression. Intracerebroventricular (icv) injections of CRF (1.0 and 0.2 μg, but not 0.02 μg) significantly inhibited maternal aggression but not other maternal behaviors. The CRF antagonist D-Phe-CRF12-41 had no effect. Maternal aggression and icv CRF (0.2 μg) induced Fos in 11 of the same regions, including the lateral and medial septum, the bed nucleus of the stria terminalis, the medial and central amygdala, the periaqueductal gray, the dorsal raphe, and the locus coeruleus. These findings suggest that decreased CRF is necessary for maternal aggression and may act by altering brain activity in response to an intruder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sensitivity of brain sites to the inhibitory effect on alcohol intake of the tachykinin aminosenktide

The present study evaluated the sensitivity of several brain sites to the inhibitory effect of the tachykinin (TK) NK-3 receptor agonist aminosenktide (NH2-SENK) on 10% ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring rats. Attention was focused on limbic structures involved in alcohol-seeking behavior and endowed with TK NK-3 receptors. NH2-SENK was bilaterally injected into the shell of the nucleus accumbens (NACC), the medial amygdala (AMY), the dorsal hippocampus (HIPP), the ventral tegmental area (VTA), the bed nucleus of the stria terminalis (BNST), the lateral hypothalamus (LH), and the nucleus basalis magnocellularis (NBM). NH2-SENK (injected up to 25-75 ng/site) into the NACC, AMY, HIPP, and VTA did not significantly modify ethanol intake. Injection of NH2-SENK into the BNST reduced ethanol intake at doses of 25 ng/site or higher, but the same doses also reduced water intake in water-deprived rats and food intake in food-deprived rats. Injection of NH2-SENK into the LH or the NBM at doses of 0.5, 5, or 25 ng/site inhibited 10% ethanol intake even at the lowest dose tested without affecting either food or water consumption in deprived animals. Present results indicate that the LH and the NBM are highly sensitive to the inhibitory effect of the TK NK-3 receptor agonist NH2-SENK on ethanol intake. TK peptides have been shown to evoke conditioned place preference following injection in the LH or the NBM, suggesting that in these brain sites the effect of TK agonists on ethanol intake might be due to interference with reward processes.     

Role of the hippocampus, the bed nucleus of the stria terminalis, and the amygdala in the excitatory effect of corticotropin-releasing hormone on the acoustic startle reflex

Previously, we demonstrated that transection of the fimbria/fornix blocked the excitatory effect of corticotropin-releasing hormone (CRH) on startle (CRH-enhanced startle), suggesting that the hippocampus and its efferent target areas that communicate via the fimbria may be critically involved in CRH-enhanced startle. The bed nucleus of the stria terminalis (BNST) receives direct projections from the ventral hippocampus via the fimbria/fornix. Therefore, the role of the ventral hippocampus, the BNST, and the amygdala in CRH-enhanced startle was investigated. NMDA lesions of the BNST completely blocked CRH-enhanced startle, whereas chemical lesions of the ventral hippocampus and the amygdala failed to block CRH-enhanced startle. However, the same amygdala-lesioned animals showed a complete blockade of fear-potentiated startle, a conditioned fear response sensitive to manipulations of the amygdala. In contrast, BNST-lesioned rats had normal fear-potentiated startle. This indicates a double dissociation between the BNST and the amygdala in two different paradigms that enhance startle amplitude. Microinfusions of CRH into the BNST, but not into the ventral hippocampus, mimicked intracerebroventricular CRH effects. Furthermore, infusion of a CRH antagonist into the BNST blocked CRH-enhanced startle in a dose-dependent manner. Control studies showed that this blockade did not result from either leakage of the antagonist into the ventricular system or a local anesthetic effect caused by infusion of the antagonist into the BNST. The present studies strongly suggest that CRH in the CSF can activate the BNST, which could lead to activation of brainstem and hypothalamic BNST target areas involved in anxiety and stress responses.     

Neuropeptide Y in hamster limbic nuclei: lack of colocalization with substance P

The medial nucleus of the amygdala (Me), bed nucleus of the stria terminalis (BNST), and medial preoptic area (MPOA) regulate copulation in the male hamster. The present study identified neuropeptide Y-immunoreactive (NPY-IR) neurons in the BNST and Me with the greatest concentration in the posteromedial and posteriordorsal subdivisions of these nuclei, respectively. NPY-IR filters are found in all three nuclei with dense plexi of NPY-IR varicosities in the most medial subdivisions. Substance P neurons are also densely concentrated in the posterior BNST and Me; however, no neurons contained both peptides. Thus, NPY and substance P neurons comprise two distinct populations within the BNST and Me of the hamster.     

Adolescent male rats exposed to social defeat exhibit altered anxiety behavior and limbic monoamines as adults.

Social stress in adolescence is correlated with emergence of psychopathologies during early adulthood. In this study, the authors investigated the impact of social defeat stress during mid-adolescence on adult male brain and behavior. Adolescent male Sprague–Dawley rats were exposed to repeated social defeat for 5 days while controls were placed in a novel empty cage. When exposed to defeat-associated cues as adults, previously defeated rats showed increased risk assessment and behavioral inhibition, demonstrating long-term memory for the defeat context. However, previously defeated rats exhibited increased locomotion in both elevated plus-maze and open field tests, suggesting heightened novelty-induced behavior. Adolescent defeat also affected adult monoamine levels in stress-responsive limbic regions, causing decreased medial prefrontal cortex dopamine, increased norepinephrine and serotonin in the ventral dentate gyrus, and decreased norepinephrine in the dorsal raphe. Our results suggest that adolescent social defeat produces both deficits in anxiety responses and altered monoaminergic function in adulthood. This model offers potential for identifying specific mechanisms induced by severe adolescent social stress that may contribute to increased adult male vulnerability to psychopathology. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hyperphagia induced by GABAA receptor-mediated inhibition of the nucleus accumbens shell: Dependence on intact neural output from the central amygdaloid region.

To investigate the role of corticolimbic input in modulating feeding-related nucleus accumbens (Acb) circuitry, researchers temporarily deactivated sites within the basolateral amygdaloid complex (BLA) or central amygdaloid region (CeA) via GABAA agonist (muscimol) infusions and measured feeding responses following muscimol infusions into the Acb shell. Hyperphagia elicited by intra-Acb shell muscimol was not altered by coinfusions of intra-BLA muscimol. In contrast, muscimol infusions into the CeA dose-dependently reduced feeding elicited either by intra-Acb shell GABAA receptor stimulation or by food deprivation and produced a syndrome of forepaw treading. Intra-CeA tetrodotoxin infusions also blocked intra-Acb shell muscimol-induced hyperphagia. Hence, feeding elicited by intra-Acb shell GABAA receptor stimulation requires intact neural output from the CeA but not the BLA. (PsycINFO Database Record (c) 2010 APA, all rights reserved)