Corticotropin-releasing factor antagonist attenuates defensive-withdrawal behavior elicited by odors of stressed conspecifics.

This study examined the hypothesis that defensive responsiveness induced by threatening stimuli of biological origin is mediated by the action of endogenous corticotropin-releasing factor (CRF). Rats were exposed for 15 min to a large open field containing a small chamber. Twenty-four hours later, rats received intracerebroventricular injections of either vehicle or 20 μg of α-helical CRF(9–41), a CRF receptor antagonist. After 20 min, rats were reexposed to the open field, which now contained odors of urine and feces from a stressed conspecific. In the reexposure test, vehicle- and antagonist-treated rats withdrew rapidly into the chamber. Antagonist-treated rats, however, emerged subsequently from the chamber to explore the open field as indicated by a significant increase in the number of passages made between the chamber and the open field. Results suggest that central injection of α-helical CRF(9–41) reduces the level of fear induced by odors associated with threat. In addition, CRF receptors are implicated in mediating the species-typical display of defensive withdrawal behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Environmental Enrichment Facilitates Amygdala Kindling but Reduces Kindling-Induced Fear in Male Rats.

The purpose of this experiment was to determine the effect of prior environmental enrichment on the acquisition of kindling and the expression of kindling-induced fear. Sixty male rats were housed either in an enriched environment or in isolation, starting immediately after weaning. As adults, they were subjected to either 50 amygdala-kindling stimulations or sham stimulations, followed by testing in an unfamiliar open field. The kindled-enriched rats acquired the kindled state more quickly than did the kindled-isolated rats, but they also showed less fear in the open field than did the kindled-isolated rats. These results suggest that environmental enrichment has differential effects on kindling acquisition and its behavioral consequences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Characterization of the defensive nature of kindling-induced emotionality.

Long-term amygdala kindling produces substantial changes in emotional behavior in rats. The purpose of these experiments was to determine whether kindling-induced emotionality is fundamentally defensive or aggressive in nature. In Experiment 1, amygdala-kindled rats tested as intruders in a resident-intruder paradigm preferred an active defense strategy (i.e., defensive upright stance, jump attacks), whereas the sham-stimulated rats preferred a passive defense strategy (i.e., freezing). In Experiment 2, amygdala-kindled rats explored an unfamiliar open field significantly less than did the sham-stimulated rats, and they were significantly more resistant to capture from the unfamiliar open field than were the sham-stimulated rats. In contrast, them were no significant differences between the kindled and sham-stimulated rats in resistance to capture from their home cages. These results suggest that the emotionality produced by long-term amygdala kindling is fundamentally defensive in nature. (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.     

Extracellular serotonin is enhanced in the striatum, but not in the dorsal hippocampus or prefrontal cortex, in rats subjected to an operant conflict procedure.

In rats trained in an operant fixed-interval-30-s schedule of food reward (FI-30s), acute exposure to contingent footshock resulted in a response suppression that was released by diazepam (DZP; 4 mg/kg ip) but not by buspirone (0.25 or 0.50 mg/kg ip). Compared with baseline, hippocampal and cortical extracellular levels of serotonin (5-HText) did not change, regardless of operant period (punished or nonpunished) and drug. In contrast, in the striatum, an increase of 5-HText levels (535%) occurred during the punished period, counteracted by DZP. This effect was observed only in rats that were low responders during both nonpunished and punished periods, that is, those that exerted an efficacious control over responding. Uncontrollable shocks or exposure to an unfamiliar open field did not modify striatal 5-HText. Together, these results suggest that an acute activation of 5-HT neurons afferent to the striatum allows the rats to efficiently block responses that are negatively reinforced. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Context-specific morphine withdrawal in rats: Duration and effects of clonidine.

Rats previously injected with morphine in a particular environment (paired rats) emitted more withdrawal symptoms in that environment than did rats previously injected with morphine in another environment (unpaired rats) after both 1 day and 5 days of morphine abstinence. Thus, reexposure to an environment previously associated with morphine can elicit context-specific withdrawal even after several days of morphine abstinence. Clonidine (0.06 mg/kg) reduced most of the withdrawal symptoms seen 5 days after morphine abstinence in both the paired and unpaired rats. However, clonidine enhanced many of the withdrawal symptoms in both groups of rats during naltrexone-precipitated withdrawal 1 day after morphine abstinence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alterations in behavioral responses to stressors following excitotoxin lesions of dorsomedial hypothalamic regions

The dorsomedial hypothalamus is important for regulation of cardiovascular responses associated with emotional arousal. This region has also been identified as a component of neural circuitry involved in fear/anxiety, yet clear evidence as to the effects of lesioning on stress-related behaviors is missing. In this study, we lesioned the dorsomedial hypothalamic region with the neurotoxin, ibotenic acid (IBO; 2.0 micrograms in 0.2 microliter), and studied the impact on spontaneous and unlearned behavioral responses to stressors. In the open field test, we observed non-generalized increases in motility parameters in the IBO rats with the differences occurring in the latter two-thirds of the test. In the elevated plus-maze, the IBO rats displayed a classic anxiolytic response with a greater proportion of entries into (and greater time spent in) the open arms of the maze. In the environment-specific social interaction (SI) test, the IBO rats showed a normal familiar/unfamiliar environment discrimination with respect to Total SI; however, the composition of the behaviors ('curiosity' vs. physical contact) by the IBO rats was markedly altered, with there being a 2-fold increase in non-violent physical interactions. Additionally, the differences in these traditional indices of anxiety were associated with lesioned animals exhibiting greater acoustic startle responsiveness than controls as a function of prepulse intensity. Overall, the results following IBO lesions indicate an altered responsiveness to sudden stressors, particularly as relates to novelty or exploration-oriented behaviors. The hypothalamic lesion may, therefore, have resulted in a disinhibition of normally suppressed responding to innate fear or challenging stimuli. This study contributes to those that have begun to define neural interactions that are essential for integrated stress responses.     

Naloxone, but not flupenthixol, disrupts the development of conditioned ejaculatory preference in the male rat.

Male rats display a conditioned preference to ejaculate with a female bearing an odor paired previously with copulation to ejaculation. The present study examined the role of endogenous opioid and dopamine systems in this preference. Male rats received saline, the opioid receptor antagonist naloxone, or the dopamine receptor antagonist flupenthixol prior to 10 conditioning trials in a pacing chamber with an almond-scented female. On the final test, all males were injected with saline and given access to 2 females, 1 scented and the other unscented, in an open field. Only males injected with naloxone during training failed to manifest a conditioned ejaculatory preference. These findings suggest that activation of opioid, but not dopamine, systems during sexual interaction are necessary for conditioned ejaculatory preference in male rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spatial memory and N-methyl-D-aspartate receptor antagonists APV and MK-801: Memory impairments depend on familiarity with the environment, drug dose, and training duration.

Rats given N-methyl-D-aspartate (NMDA) antagonists were tested in the radial maze in spatial working memory (WM) and reference memory (RM) tasks. 16 female rats given (+)-10,11-dihydro-5-methyl-5H-dibenzo [a,d] cycloheptene-5,10 imine (MK-801; 0.0625 mg/kg intraperitoneal/ly (ip)) before daily testing in an 8-arm WM task were impaired even after 70 days. Control rats learned quickly, were assigned to a group given MK-801 or saline, and were trained to avoid 4 of the 8 arms. MK-801 impaired this reversal learning but did not affect WM performance. 15 male rats were trained on an 8-arm WM task for 19 days and then given intracranial aminophosphonovaleric acid (APV; 33 mM), which impaired both WM and motor behavior. 24 male rats were trained for 65 days to enter 4 of 8 arms and then given intracranial APV (20 or 30 mM). WM and RM were normal in the familiar environment but were both impaired in an unfamiliar environment. Results suggest that the mnemonic effects of NMDA antagonists depend on environmental familiarity, dose, and training duration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Locomotor and exploratory behavior in the rat following bilateral vestibular deafferentation.

Despite many studies of the postural and ocular reflex deficits caused by chronic bilateral vestibular loss in rats and guinea pigs, there have been few systematic studies of the effects of vestibular loss on locomotor activity and exploratory behavior over a period of several months following the lesion. In this study, the authors quantified locomotor and exploratory behavior in an open field maze at 3 weeks, 3 months, and 5 months following bilateral vestibular loss in rats. As a result of bilateral surgical vestibular lesions, rats exhibited a persistent increase in locomotor velocity, duration, and distance traveled, with a marked tendency for increased inner field activity and reduced thigmotaxis. Rats without balance-sense were also found to spend less time exploring the environment, as indicated by a decreased frequency and duration of wall-supported rearings. These results suggest that sudden and complete loss of balance-sense has persistent and complex effects on the way that rats navigate through and explore the environment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of age on object exploration, habituation, and response to spatial and nonspatial change.

To measure their ability to detect novel arrangements in a given environment, young (6 months old) and senescent (22-24 months old) male F344 rats were repeatedly exposed to a given spatial configuration of objects contained in an open field. After the rats were habituated to the novel environment (1 trial with no objects, followed by 3 trials with 5 salient objects), the spatial arrangement of the objects was modified (2 trials), and object novelty was tested (2 trials) by substituting a familiar object with a new one at the same location (nonspatial change). The results indicated that the senescent rats explored old objects less than young rats, particularly on Trial 2. On the 1st trial with displaced objects (Trial 5), the senescent rats explored the displaced objects less than the young rats. However, when a new object was placed in the field (Trials 7-8), there were no age differences in new object exploration. These results Suggest that senescent rats have decrements in the ability to build spatial representations of the environment and to use this information to detect such changes, even though object recognition is not impaired with age. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Food stealing by young Norway rats (Rattus norvegicus).

Six experiments were undertaken to explore factors affecting young rats' (Rattus norvegicus) frequencies of stealing food from conspecifics when identical food is available in surplus. It was found that (a) rats would walk across a bed of pellets to steal the particular pellet a peer was eating, (b) frequency of stealing within a pair did not decrease over days, (c) rats stole unfamiliar foods more frequently than familiar foods, (d) younger rats stole from older rats more frequently than older rats stole from younger ones, (e) hungry rats stole more frequently than replete rats, and (f) rats that had stolen a pellet of unfamiliar food from an anesthetized conspecific subsequently exhibited an enhanced preference for that food. Results suggest that food stealing is a mode of active seeking of information about what foods to eat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The involvement of nitric oxide (NO) in the CGRP-induced behavior of rats

The possible role of nitric oxide (NO) in CGRP-induced passive avoidance, active avoidance, and open field behavior was tested in rats. A specific NO synthase inhibitor, N omega-nitro-L-arginine (L-NA), was used to disrupt NO synthesis. ICV administration of 5 micrograms of L-NA reversed the action of CGRP in passive and active avoidance tests. In an open field, L-NA prevented the action of CGRP on locomotion and grooming. The inactive isomer D-NA had no effect on behavior of animals. The data suggest that NO might contribute to CGRP-induced behavior in rats.     

Serotonin stimulates corticotropin-releasing factor gene expression in the hypothalamic paraventricular nucleus of conscious rats

To examine the direct effects of serotonin (5-HT) on the release and synthesis of corticotropin-releasing factor (CRF) in the hypothalamic paraventricular nucleus (PVN), 5-HT was microinjected just onto the bilateral PVN of conscious rats. Plasma adrenocorticotropic hormone (ACTH) levels peaked at 30 min and returned to the basal levels in 90 min. Northern blot analysis revealed that the CRF messenger RNA (mRNA) level in the PVN as well as the proopiomelanocortin mRNA level in the anterior pituitary significantly increased 120 min after the 5-HT injections (50-250 nmol/side). Pretreatment with intracerebroventricular (i.c.v.) injection of pindobind 5-HT1A (5 nmol) or LY-278584 (500 nmol) completely abolished the 5-HT-induced ACTH response, whereas LY-53857 (100 nmol) was without effect. These results suggest that 5-HT stimulates CRF release, which has interactions with 5-HT1A and 5-HT3 receptors on CRF neurons in the PVN, and activates CRF synthesis in conscious rats.     

Play fighting between kindling-prone (fast) and kindling-resistant (slow) rats.

Differences in the play behavior of 2 strains of rats suggest that different components of play fighting can be modified independently. The development of play fighting in cross-strain pairs of familiar and unfamiliar rats was examined to determine whether interacting with a noncongruent pairmate would alter the pattern of play typical for each strain. In both strains, changes in play fighting were observed throughout development, but partner identity appeared to influence play fighting in different ways depending on age. These data suggest that some components of play may be more impervious to changes in social environment than other components. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Brain corticotropin-releasing factor immunoreactivity and receptors in five inbred rat strains: relationship to forced swimming behaviour

In the present work we studied the relationship between behaviour in the forced swimming test (FST), a test that presumably measures depressive-like behaviour in rodents, and central corticotropin-releasing factor (CRF) concentration and binding in five strains of rats. The strains were: Brown-Norway (BN), Fisher (FIS) 344, Lewis (LEW), spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The FST data corresponding to the pretest showed significant inter-strain differences in both struggling and immobility: BN and WKY rats displayed lower levels of struggling and longer periods of immobility, LEW and SHR rats showed intermediate levels, and FIS rats were the most active. The results of the pretest were roughly similar to those observed in the test, the activity of WKY being extremely low. The CRF binding revealed significant inter-strain differences in prefrontal cortex and hippocampus, but not in cerebellum, pons-medulla or hypothalamus: in the prefrontal cortex, BN and FIS rats showed greater CRF binding than LEW, SHR and WKY rats; in the hippocampus BN rats showed higher levels of CRF binding than the other strains. The study of CRF content in various brain areas revealed inter-strain differences in prefrontal cortex and pons-medulla, but not in parietal-temporal cortex or in hypothalamus (CRF concentrations in the hippocampus were not detectable): CRF content in the prefrontal cortex was higher in BN than in the other strains, although the differences with FIS were not statistically significant; in the pons-medulla, FIS and LEW showed significantly higher CRF content than the other strains. From the present results it appears that BN and WKY rats were more prone to adopt passive strategies in the FST, but they did not show higher brain CRF immunoreactivity or down-regulation of CRF receptors. Hence, although there were inter-strains differences in all variables studied, no evidence for a relationship between the FST behaviour and central CRF activity was found.     

Further characterization of the behavioral effects of peripherally administered corticotropin-releasing factor in guinea pigs

Guinea pig pups were either not injected (NI) or given SC injection of either saline vehicle (SAL) or 14 micrograms of corticotropin-releasing factor (CRF). In an isolation test, mean number of vocalizations and several measures of locomotor activity were markedly lower for CRF pups than for NI or SAL controls. CRF pups defecated less than did SAL pups. No differences were found among conditions for self-grooming. Behavioral freezing was shown by only two pups in the entire study. Significantly more CRF pups displayed piloerection, eye-closing, and a characteristic crouched stance than did controls. In a defensive withdrawal test, no differences among conditions were found for the proportion of pups entering a darkened chamber or for the latency to enter the chamber; however, CRF pups entered the chamber significantly fewer times during the 60-min test than did controls. There were no differences among conditions in the distance swum or number of turns made in a forced-swim test. These results replicate our earlier findings that peripheral injection of CRF suppresses vocalizing and a measure of locomotor activity in isolated guinea pig pups and identifies a number of additional behavioral effects. Of central interest here, the results indicate that the suppression of vocalizing and locomotion during isolation is not due to an increase in competing stress-related behavior or to diminished motor capacity.     

Parathyroidectomy does not prevent the renal PTH/PTHrP receptor down-regulation in uremic rats

In a recent study we demonstrated that the PTH/PTHrP receptor (PTH-R) mRNA was markedly down-regulated in the remnant kidney of uremic rats with severe secondary hyperparathyroidism. Among the factors potentially implicated in this down-regulation, to date only PTH has been demonstrated to modulate PTH-R expression. Here, we examined the effect of thyroparathyroidectomy (TPTX) on the renal expression of PTH-R in rats with normal renal function or with chronic renal failure (CRF) induced by 5/6 nephrectomy. Four groups of rats were studied: control, TPTX, CRF, and CRF + TPTX. Moderate-degree renal failure was documented by mean (+/- SD) creatinine clearances (microliter/min/100 g body wt) of 259 +/- 40 and 212 +/- 45 in CRF and CRF + TPTX rats, compared with 646 +/- 123 and 511 +/- 156 in control and TPTX rats, respectively. Plasma phosphorus, calcitriol, and ionized calcium were significantly lower in CRF and CRF + TPTX than in control animals. Plasma ionized calcium and calcitriol were also lower in TPTX than in control rats. Plasma PTH levels (pg/ml) were increased in CRF rats (41.8 +/- 29.4), and markedly decreased in TPTX (10.1 +/- 7.8) and CRF + TPTX (8.0 +/- 3.8) rats compared with control rats (21.7 +/- 7.5). Northern blot analysis showed that the level of the steady-state PTH-R mRNA in the kidney of CRF and CRF + TPTX rats was markedly decreased compared with that of control rats, the ratios of PTH-R mRNA/beta-actin mRNA being 0.28 +/- 0.04 and 0.27 +/- 0.03 versus 0.54 +/- 0.05, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered responsivity to central administrations of corticotropin-releasing factor in rats with a history of opiate exposures.

The authors studied the effects of a history of opiate exposures on behavioral responses to intracerebroventricular (ICV) microinjections of the stress-related peptide corticotropin-releasing factor (CRF). Rats were injected for 10 days with morphine (10 mg/kg) or saline, and 1 or 7 days later they received an ICV microinjection of CRF (0.5 μg or 2.5 μg) or artificial cerebrospinal fluid. Microinjections of CRF produced anxiety-like behavior, locomotor activity, and self-grooming. The anxiogenic response was altered so that morphine-treated rats showed reduced responses to 0.5-μg CRF but showed exaggerated responses to 2.5-μg CRF 1 or 7 days after last opiate exposure. These findings suggest that alterations in central CRF circuits may underpin the increased vulnerability to anxiety observed following opiate exposures. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exposure to novelty induces naltrexone-reversible analgesia in rats.

The exposure of rats for 2 min to an open field, to a small box, or to inhibitory avoidance training in the small box was followed by a mild analgesia measured by the tail-flick method. The analgesia was observed as soon as 10 s after the exposure and lasted between 10 and 30 min. It was not observed in animals previously made familiar with the test situation, and it was reversed by the administration of naltrexone (0.1 mg/kg). The data suggest that novelty per se is a sufficient stimulus to activate an opioid-mediated analgesic stimulus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)