Effects of peripherally administered corticotropin-releasing factor (CRF) and a CRF antagonist: Does peripheral CRF activity mediate behavior of guinea pig pups during isolation?

Guinea pig pups vocalized and ambulated when first isolated in a test cage; at 1 and 24 hr, levels of these behaviors had waned, and pups frequently exhibited a crouched stance, eye-closing, and piloerection. Injection (SC) of corticotropin-releasing factor (CRF) prior to isolation diminished the initial vocalization and locomotor responses and induced pups to exhibit the crouched stance, eye-closing, and piloerection at the beginning of the isolation period. Pretreatment with a CRF-receptor antagonist reversed the behavioral effects of CRF. CRF had no effect on blood pressure. Thus, SC CRF produced the same behavioral profile as seen with the passage of time in untreated isolated pups. The behavioral effects appeared to be CRF-receptor-mediated events and were not secondary to hypotension. These results support the hypothesis that during prolonged isolation, high or sustained peripheral CRF activity modulates behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intravenous gestational cocaine in rats: effects on offspring development and weanling behavior

Pregnant rats were injected with cocaine (CN; 6 mg/kg) or an equal volume of saline (SAL), via the tail vein, on gestation days 8-20. A third group was untreated (UT). Maternal weight gain was not affected by dam treatment despite slight differences in food intake. Litter characteristics (e.g., litter size, pup weight) did not differ among groups. Indices of fetal mortality were not affected by the treatments. Developmental tests, initiated on postnatal day (PND) 2, indicated slight delays in the negative geotaxic response and eye opening in cocaine-exposed pups. Open-field and tail-flick tests were performed on PND 21. Pups were acutely injected with cocaine (10 mg/kg, IP), saline, or received no treatment before placement in a novel open field; morphine (1.5 mg/kg, SC) or saline was injected prior to the tail flick test. Pups from CN dams exhibited a significant decrease in spontaneous exploratory behavior compared to both controls, and a time-dependent increase in rearing compared to pups from UT dams. The acute cocaine injection prior to placement in the open field did not alter locomotion or rearing among dam treatment groups. However, the acute cocaine injection did increase stereotypy ratings for female pups from CN dams compared to similarly treated males, and females from SAL and UT dams. No differences were observed among groups in the tail-flick test. These data suggest that the IV route of administration provides a viable method of cocaine delivery in pregnant rats, and provides further evidence of the developmental and behavioral teratogenicity of prenatal cocaine exposure.     

Factors influencing cortisol and behavioral responses to maternal separation in guinea pigs.

Infant guinea pigs recently were found to respond to brief maternal separation with an increase in plasma cortisol (COR) levels. The present experiments were conducted to further characterize this response and compare it with the COR separation response previously observed in primates. In Exp 1, separation of guinea pig pups from their mothers did not elevate the plasma COR levels of the pups at either 30 or 180 min when they remained alone in their home cages during the separation. Exp 2 showed that COR levels of pups placed alone in a novel cage were greater at 30, 90, and 180 min than were those of pups placed in the cages together with their mothers. In contrast, the separated pups vocalized more than did pups tested with their mothers during the initial 30 min only. In Exp 3, pups raised on inanimate surrogates responded less intensely to rearing-figure separation in terms of COR and vocalizations than did mother-reared controls. Results indicate differences (response to home cage separation) and similarities (dissociation of COR and vocalization responses, effect of surrogate separation) in the separation responses of guinea pig and primate infants. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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)     

Potentiation of isolation-induced vocalization by brief exposure of rat pups to maternal cues

Since their discovery in 1956, the highest rates of ultrasonic vocalization (USV) have been recorded from infant rats when first isolated in an unfamiliar place. We now report that peak USV rates can be doubled by allowing test pups a brief initial period of contact with their anesthetized dam (1-10 min) in the test chamber before isolating the pup by her removal. Potentiation of the isolation response was specific to the dam, for it failed to occur following initial contact with a group of 4 warm, anesthetized littermates. Control experiments showed that potentiation could not be attributed to thermal contrast, experimenter handling, general behavioral activation, novelty of maternal cues, or nursing deprivation. Furthermore, it did not occur when pups were taken for isolation testing directly from prolonged contact with their anesthetized dam in the home cage. Potentiation may be understood in terms of the communicative role of the pups' call and/or prior learning contingencies within the mother-infant interaction.     

Differential effects of maternal and sibling presence on hyperactivity of 6-hydroxydopamine-treated developing rats.

Assessed the influence of test environment on the expression of hyperactivity produced by neonatal 6-hydroxydopamine (6-OHDA) administration in Sprague-Dawley rat pups at 15, 19, and 22 days of age in 3 experiments. The 6-OHDA Ss and an equal number of controls were tested in isolation, mixed groupings of 2 treated and 2 control pups, mixed groupings with their anesthetized mothers, mixed groupings with an anesthetized sibling, and homogeneous groupings of all treated and all control siblings. Social factors had differential effects on activity, particularly at 19 days of age: the 6-OHDA Ss were hyperactive relative to controls in isolation, and both treated and control pups were equally active in the mixed grouping and were hyperactive relative to control isolation levels. The addition of an anesthetized mother sharply attenuated the activity of both types of pups. It is concluded that social factors strongly influenced the behavior of rat pups with whole brain dopamine depletion produced by 6-OHDA and, within the confines of this animal model of hyperactivity, exerted greater attenuating effects on their activity than previously observed with stimulant medication. (32 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Social-seeking and novelty-seeking behavior as a function of differential rearing histories.

Rats were handled daily from birth until weaning or were nonhandled controls. At weaning Ss were reared with littermates or in isolation. At 90 days some of the socially reared Ss were placed into isolation. Total N = 44 males, 1 from each of 44 different litters. At 100 days S was placed for 10 min. into the stem of a T shaped unit. S could remain where it was, enter a social chamber, or enter a novel chamber. Time in each chamber, activity, and defecation were recorded for 4 successive days. Handled Ss were significantly more active, and spent significantly more time in the social and novel chambers than nonhandled controls. Ss reared in a social environment until testing spent significantly less time in the novel chamber than Ss undergoing long-term or short-term social isolation. The handling variable was found to interact significantly with postweaning rearing and test days. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Corticotropin-releasing factor modulates defensive-withdrawal and exploratory behavior in rats.

The role of corticotropin-releasing factor (CRF), an endogenous neuropeptide, in modulating species-typical responses was examined in an unfamiliar open field containing a small chamber. Rats placed in this small chamber spent most of their time withdrawn in it. However, rats given an icv injection (20 μg) of α-helical CRF(9–41), a CRF receptor antagonist, emerged from the chamber and explored the unfamiliar open field. Results of additional studies with vehicle-treated rats suggest that reexposure reduces the threatening impact of an unfamiliar open field. CRF (300 ng) injected centrally, but not peripherally, before reexposure to the test environment significantly reduced exploration in the open field and increased a pattern of defensive-withdrawal into the chamber. Data suggest that whether defensive-withdrawal or exploratory behavior is exhibited may depend on CRF actions in brain systems that mediate the perception of threat in the environment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of isolation conditions on brain regional enkephalin and !b-endorphin levels and vocalizations in 10-day-old rat pups.

Young rat pups were isolated from their dams under different conditions. The endogenous opioid peptides were measured in brain regions after isolation. Because there is no uptake mechanism for peptides released at the synapse and because released peptide is rapidly degraded enzymatically, decreases in peptide levels over this time course can be interpreted as release from terminals. No change was observed in either peptide in the hypothalamus, septum, or amygdala after isolation compared with controls. Significant decreases were seen in the midbrain after isolation. A comparison of peptide levels and ultrasonic vocalizations in the pups isolated in familiar, novel, or control conditions was also performed. Enkephalin levels in the midbrain were decreased in familiar and novel conditions, but in the brainstem opioid peptides were decreased only in the familiar condition. The greater involvement of the opioid peptides in the pups isolated in familiar conditions may contribute to the ability of naltrexone to block vocalization. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral effects of selective and nonselective dopamine agonists on young rats after irreversible antagonism of D1 and/or D2 receptors

In general, preweanling and adult rats respond similarly when challenged with competitive dopamine (DA) agonists or antagonists. In contrast, results using a noncompetitive antagonist suggest that the D1 and D2 receptor systems of preweanling and adult rats differ in some critical way. To further assess this phenomenon, the behavioral effects of irreversible receptor blockade were assessed across 8 days in NPA (a nonselective DA agonist), quinpirole (a D2 agonist), or SKF 38393 (a D1 agonist) treated 17-day-old rat pups. The irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) did not block the locomotor activity and rearing of NPA- or quinpirole-treated rat pups, nor did EEDQ reduce SKF 38393-induced grooming. Moreover, pretreatment with EEDQ appeared to potentiate the normal increases in locomotor activity and rearing produced by NPA, but only when D2 receptors were not protected by a previous injection of sulpiride (a D2 antagonist). Taken together, these results are consistent with the presence of large reserves of D1 and D2 receptors in the preweanling rat pup.     

Effect of postweaning social experience on response of Siberian hamsters (Phodopus sungorus sungorus) toward young.

Between 18 and 50 days of age, 83 male and 66 female Siberian hamsters were housed either with (a) same-sex littermates; (b) opposite-sex littermates; (c) opposite-sex littermates and parents; or (d) opposite-sex littermates, parents, and a younger litter. When adults, Ss were presented with 2 3–8 day old pups for 8 hrs, and their responses were recorded. Rearing conditions did not affect behavior of females. Males housed with female littermates in the absence of a younger litter showed fewer pup attacks and more nesting with pups than did males housed only with other males. Thus, housing with females in the early postweaning period may influence males' adult responses toward pups. Only among Ss housed with same-sex littermates did males and females differ in their response to pups, a result emphasizing that sex differences in behavior may depend on early social rearing. (11 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increase of locomotor activity underlying the behavioral disinhibition in Tg2576 mice.

The transgenic Tg2576 mouse is a widely used animal model that develops some of the cognitive and neuropathological deteriorations observed in patients suffering Alzheimer's disease. The authors investigated 9-month-old Tg2576 mice with respect to behavioral and endocrinological (hypothalamic- pituitary-adrenal [HPA] axis activity) parameters. The locomotor activity test revealed that Tg2576 mice moved almost twice as much as controls. Tg2576 mice spent significantly more time visiting the open arms and performed more entries into these open arms than did controls. However, the amount of time that Tg2576 mice remained in each entry to the open arm was similar to that of controls, and the number of arm entries correlated positively to locomotor activity. In the forced swimming test, Tg2576 mice showed a significant decrease in immobility time, which correlated negatively to locomotor activity. Parameters of the HPA axis, such as plasma level of corticosterone, adrenal gland weight, and noradrenaline or adrenaline release, did not differ between controls and Tg2576 mice. These data suggest that the disinhibitory behavior of Tg2576 mice seems to be related to increased locomotor activity but not to any disturbance of the HPA axis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Regulation of contextual conditioning by the median raphe nucleus

The median raphe nucleus (MRN) has been suggested as the origin of a behavioral inhibition system that projects to the septum and hippocampus. Electrical stimulation of this mesencephalic area causes behavioral and autonomic manifestations characteristic of fear such as, freezing, defecation and micturition. In this study we extend these observations by analyzing the behavioral and autonomic responses of rats with lesions in the MRN submitted to a contextual conditioning paradigm. The animals underwent electrolytic or sham lesions of the median raphe nucleus. One day (acute) or 7 days (chronic) later they were tested in an experimental chamber where they received 10 foot-shocks (0.7 mA, 1 s with 20-s interval). The next day, sham and MRN-lesioned animals were tested again either in the same or in a different experimental chamber. During this, the duration of freezing, rearings, bouts of micturition and number of fecal boli were recorded. Sham-operated rats placed in the same chamber showed more freezing than rats exposed to a different context. This freezing behavior was clearly suppressed in rats with acute or chronic lesions in the MRN. MRN lesions also reduced the bouts of micturition and number of fecal boli. These rats showed a reduced number of rearings than sham-lesioned rats. This effect is probably the result of the displacement effect provoked by freezing since no significant differences in the number of rearings could be observed between these animals and the NMR-lesioned rats tested in an open field. This lesion produced higher horizontal locomotor activity in this test than the controls (sham-lesioned rats). These results point to the importance of the median raphe nucleus in the processing of fear conditioning with freezing being the most salient feature of it. Behavioral inhibition is also under control of MRN but its neural substrate seems to be dissociated from that of contextual fear.     

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.     

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.     

Isolation disrupts retention in preweanling rat pups.

Expression of an olfactory memory in 18-day-old rat pups was examined in eight experiments following brief manipulations of environmental conditions prior to a retention test. In the first experiment we found that retention was disrupted if a pup was placed in isolation for 3 hr prior to the retention test. The retention deficit persisted even when pups had 3-hr exposure to an anesthetized dam and siblings before testing. However, there was no deficit in retention if pups spent the pretest interval with a nonlactating foster dam, their father, or littermates. Finally, we found that this deficit in retention could be alleviated by cuing treatments that preceded the retention test following isolation. Both discrete cues used during training and returning the pup to the home cage with parents and siblings for 3 hr were found to alleviate the retention deficit caused by isolation. These data demonstrate that housing conditions can influence postacquisition memory processes in the young animal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Olfactory denervation: its biological and behavioral effects in infant rats

Two-week-old infant rats were treated with intranasal ZnSO4 and compared with littlemate controls 24 hr later. When infants were returned to their mother and littermates, those with olfactory deficits lost weight, had reduced cardiac and respiratory rates and lower body temperatures, and showed increased locomotor behavior in an unfamiliar test area. Subsequent experiments showed that in the absence of the mother and also in isolation, differences between ZnSO4-treated and control infants involved fewer systems were less marked, and presented different patterns. Isolated infants given oral ZnSO4 did not differ from controls on any measures. Olfactory denervation appears to produce these effects by disrupting nursing, by altering littermate interaction, and by other central nervous system effects that are independent of social interaction.     

Cardiovirulent coxsackieviruses and the decay-accelerating factor (CD55) receptor

To determine the differences in behavioral effects between intrastriatal and intracerebroventricular glial cell-derived neurotrophic factor (GDNF) administration, spontaneous locomotor activity was measured after intrastriatal or intracerebroventricular injection of GDNF (10 microg) in normal adult rats with implanted guide cannulae. In addition, the distribution of GDNF after intracerebral injection was studied immunohistochemically. Intrastriatal administration of GDNF significantly increased rearing behavior 3-4 h after injection. Increases in all three aspects of locomotor activity (motility, locomotion, and rearing) were most pronounced 3 days after intrastriatal injection, and they lasted for several days. This hyperactivity was blocked by the selective dopamine D1 receptor antagonist SCH22390 and by the selective D2 receptor antagonist raclopride at doses of the dopamine receptor antagonists, which by themselves did not affect spontaneous locomotor activity. These results suggest that GDNF has both acute and long-lasting pharmacological effects on dopamine neurons in adult animals and stimulates locomotor activity by activating both dopamine D1 and D2 receptors. On the other hand, intracerebroventricular administration of the same dose of GDNF failed to increase locomotor activity at any time during the test period (12 days). The immunohistochemical study demonstrated widespread distribution of GDNF in the entire body of the striatum within 24 h after intrastriatal injection. It also revealed deep penetration of GDNF from the ventricular space into the brain parenchyma after intracerebroventricular injection. GDNF-immunoreactive neuronal cell bodies were seen in the ipsilateral substantia nigra pars compacta most frequently 6 h after intrastriatal injection. The number of such cell bodies after intracerebroventricular administration, on the other hand, was much lower than that seen after intrastriatal administration. Taken together, these data suggest that intrastriatal administration of GDNF is an effective approach for affecting DA transmission. Long-lasting behavior effects are mediated via dopamine D1 and D2 receptors. Higher doses of GDNF would probably be needed using the intracerebroventricular route as compared to intraparenchymal delivery to exert effects on the nigrostriatal system in Parkinson's disease patients.     

Maternal interactions prior to separation potentiate isolation-induced calling in rat pups.

The vocal response rates of 12–13 day old infant rats to isolation in a bare test box are markedly increased by brief (1-min) periods of contact with an anesthetized dam prior to isolation, without affecting other isolation-induced behaviors. No such potentiation followed brief contact with littermates, novel test conditions, or experimenter handling. Brief contact with the dam was equally effective in the test chamber or home cage and was not further enhanced by repeated contact-separation sequences. Passive contact became ineffective when prolonged to 30 min, and potentiation could not be restored by providing the additional reinforcing events of continuous suckling, periodic oxytocin-induced milk letdown, or bouts of simulated maternal licking. However, when pups engaged in active interaction with an awake dam, potentiation was significantly enhanced following 1-, 10-, and 30-min periods. A working hypothesis is outlined for the adaptive role of potentiation in the development of the rat pup. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned flavour preference negatively reinforced by caffeine in human volunteers

This study examined the effects of neonatal cocaine exposure on responsivity to the alpha2 noradrenergic agonist clonidine in 11-day-old rat pups. On postnatal day (PND) 4 neonatal rats were assigned to one of four treatment groups: artificially reared (AR) receiving 40 mg/kg/day cocaine hydrochloride, AR receiving 20 mg/kg cocaine, AR control receiving no drug, and a normally reared control group. Pups were maintained in this fashion from PND 4 to 9 and received no drug on PND 10. On PND 11 subjects received an IP injection of either 0, 0.25, or 1.0 mg/kg clonidine hydrochloride and were observed for locomotor activity and wall-climbing during a 15-min test session. Subjects exposed to the 40 mg/kg dose of cocaine demonstrated an enhanced sensitivity to the locomotor stimulating effects of clonidine relative to both control groups. This cocaine-related enhanced sensitivity was not observed on the wall-climbing measure. All groups showed evidence of wall-climbing, although this behavior was somewhat dampened among AR groups. The 20 mg/kg cocaine-exposed males also took longer to display wall-climbing behavior than their respective females regardless of clonidine dose, although this sex difference was not apparent for any other treatment group. These findings suggest that neonatal cocaine exposure may alter response of the noradrenergic system.