Cocaine-induced effects on isolation stress in neonatal rats.

The effects of cocaine administration on isolation-induced vocalizations and activity levels in 10-day-old rat pups were examined. Day 10 pups given cocaine (1.25, 2.5, 5, 10, and 20 mg/kg ip) vocalized significantly less than their caffeine- (10 mg/kg) and saline-administered siblings during a 5-min isolation period. Cocaine- and caffeine-administered pups also demonstrated a significant increase in overall activity compared with controls. In addition, ip administration of the dopamine antagonist haloperidol (0.5 and 1.0 mg/kg) before 1.25 and 2.5 mg/kg cocaine produced a significant elevation in vocalizations compared with saline pretreatment, which indicates a blocking of cocaine's effect on calling behavior. These results suggest that the endogenous dopamine system involved with reinforcement and reward may quell the stress of isolation in the infant rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Independence of benzodiazepine and opiate action in the suppression of isolation distress in rat pups.

To determine whether benzodiazepines (BDZs) quiet isolation distress in 10-day-old rat pups by causing a release of endogenous opioids, a blockade of the effects of chlordiazepoxide (CDP) by the opiate antagonist naltrexone (NLX) was sought. Nonsedating doses of morphine (MOR) (0.125 mg/kg) and CDP (2.0 mg/kg) were equally effective in reducing ultrasonic vocalizations and other indices of isolation distress. Appropriate blocking agents NLX (0.5 mg/kg) against MOR and Ro 15-1788 (4.0 mg/kg) against CDP returned distress measures to levels of saline-treated rat pups. However, NLX failed to reverse the quieting effects of CDP. If CDP potentiates endogenous opioid release, then NLX should block the CDP effect. A higher dose of CDP did not reveal a release of endogenous opioids, and a higher dose of NLX did not antagonize CDP. The quieting effects of BDZs on isolation distress do not appear to be mediated by the opiate system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The isolation and companion comfort responses of 7- and 3-day-old rat pups are modulated by drugs active at the opioid receptor.

Rat pups emit ultrasonic vocalizations (USVs) when isolated in a novel environment. In 10-day-olds, USV has been shown to be reduced by either the administration of 0.125 mg/kg morphine (MOR) or the presence of a littermate; these effects were both reversed by naltrexone (NLX), an opioid receptor blocker. The present study reports that the same dose of MOR produced NLX-antagonized quieting without sedation in 7- and 3-day-old pups; higher doses of MOR decreased USV but produced motor deficits as well. The 0.125 mg/kg dose of MOR is less effective in reducing USV in 3- and 7-day-olds; calling rates declined by no more than 42%, compared with 65% at 10 days of age. The presence of a companion also lowered the USV of 3- and 7-day-olds by a lesser amount (55–57%) than the 67% seen in 10-day-olds or the 90% decline when pups are 2 weeks old. This suggests that age-related changes in the opioid system may be relevant to the increased salience of a social companion that comes with maturity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of repeated administrations of EGF and TGF-alpha on mouse neurobehavioral development

In this study we tested the effects of repeated administrations of Epidermal Growth Factor (EGF) and Transforming Growth Factor-alpha (TGF-alpha) on mouse pups' neurobehavioral development. Each subject was injected subcutaneously with either EGF or TGF-alpha on postnatal days 2, 4, 6, 8, and 10. Pups treated with these two peptides showed accelerated eyelid opening and eruption of the lower incisors when compared to Cytochrome c-injected control littermates. EGF, but not TGF-alpha, resulted in a slight body growth retardation. When scored for a number of neurobehavioral parameters, EGF pups showed a delayed appearance of the righting reflex. Also, EGF-treated pups exhibited greater ultrasonic vocalization calling rates than controls when tested on postnatal day 7. Overall, TGF-alpha administration resulted in minor effects, when compared with EGF treatment, probably as a result of the lower dose administered (EGF: 3.5 mg/kg vs TGF-alpha: 1 mg/kg). TGF-alpha affected pups' eyelid opening and incisor eruption, similarly to EGF, but seemed to exert an opposite effect on some neurobehavioral scores, in line with what was already reported for Nerve Growth Factor (NGF) (Calamandrei and Alleva, 1989). These results confirm the role played by polypeptide growth factors on mammalian physical and neurobehavioral development and suggest that TGF-alpha might affect mouse brain development in a similar fashion as NGF.     

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.     

Cannabinoid modulation of rat pup ultrasonic vocalizations

The present study investigated the effects of the cannabinoid receptor agonist CP 55,940 (1-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) and the cannabinoid receptor antagonist SR 141716A (N-(piperidin-l-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1 H-pyrazole-3-carboxamide hydrochloride) on ultrasonic vocalizations, body temperature and activity in 11-13-day-old rat pups. Testing occurred in a 5-min session 30 min following drug administration. CP 55,940 produced a dose-dependent decrease in ultrasonic vocalizations, with a 1000-micrograms/kg dose causing an almost complete inhibition of calls. Doses of 100 and 1000 micrograms/kg of CP 55,940, but not 10 micrograms/kg, caused significant hypothermia in the pups and the 1000 micrograms/kg dose also inhibited activity. The cannabinoid receptor antagonist SR 141716A (20 mg/kg) reversed the effects of 1000 micrograms/kg CP 55,940 on ultrasonic vocalizations and body temperature, but the benzodiazepine receptor antagonist flumazenil (20 mg/kg), the dopamine D1 receptor antagonist SCH 23390 (0.5 mg/kg) and the opioid receptor antagonist naloxone (1 mg/kg) did not. When administered alone, SR 141716A (20 mg/kg) increased pup ultrasonic vocalizations without affecting body temperature or activity. These results indicate that cannabinoids modulate ultrasonic vocalization production in rat pups in a manner that is independent of hypothermia. The increase in ultrasonic vocalizations produced by SR 141716A is one of the first reported behavioural effects of this drug and suggests that the endogenous cannabinoid ligand anandamide may be involved in the regulation of ultrasonic vocalizations.     

Opioidlike effects of intraoral infusions of corn oil and polycose on stress reactions in 10-day-old rats.

The effects of intraoral infusions of corn oil and the polysaccharide Polycose on behavioral reactions to pain and to social isolation were studied in 10-day-old albino rat pups. Both substances significantly increased paw-lift latencies (a measure of pain response) and reduced the number of ultrasonic vocalizations (a measure of isolation distress). Moreover, elevated pain thresholds were normalized by naltrexone (0.25 mg/kg) pretreatment, and the quieting of vocalizations was abolished by pretreatment. These findings indicate an interaction between ingestion, pain, and distress systems in neonatal rats and suggest that fats and polysaccharides influence these systems via endogenous opioids. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

"Socially mediated reduction of isolation distress in rat pups is blocked by naltrexone but not by Ro 15-1788": Correction to Garden and Hofer.

Reports an error in "Socially mediated reduction of isolation distress in rat pups is blocked by naltrexone but not by Ro 15-1788" by Susan E. Carden and Myron A. Hofer (Behavioral Neuroscience, 1990[Jun], Vol 104[3], 457-463). On page 462, the last paragraph of the first column was incorrect. The corrected paragraph is provided in the erratum. (The following abstract of the original article appeared in record 1990-24769-001.) The presence of a single anesthetized littermate significantly reduced the rate of ultrasonic vocalization by 10-day-old pups isolated in a novel environment. Naltrexone (1.0 mg/kg) returned the vocalization rate to the level of pups tested alone and disrupted the maintenance of body contact between the test pup and a companion. This suggests that the companion exerts comforting effects through endogenous opioid mechanisms. Although chlordiazepoxide is as effective as morphine in the quieting of isolation distress, the benzodiazepine (BDZ) antagonist Ro 15-1788 (5, 10, or 20 mg/kg) was ineffective in blocking the comfort effect and facilitated quiet contact with the companion. In isolated pups, Ro 15-1788 caused a significant, but not a dose-related, decrease in vocalization, a possible indication of the displacement of an endogenous anxiogenic ligand at the BDZ receptor complex. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behaviorally functional opioid systems in infant rats: II. Evidence for pharmacological, physiological, and psychological mediation of pain and stress.

Two experiments, with 160 10-day-old Sprague-Dawley rat pups, examined the behavioral characteristics of the neonatal opioid system during distressful situations, using a modification of the hot-plate paw-lick test. Ss were analgesic to heat following intraperitoneal morphine (0.5 mg/kg). Subcutaneous naloxone (0.5 mg/kg) prevented the analgesia. Morphine analgesia was significantly greater in Ss group-isolated from the dam. Saline controls group-isolated from the dam exhibited longer latencies than their nest-housed siblings. Individual isolation for 5 min markedly increased paw-withdrawal latency, and this effect was naltrexone reversible. Analgesia was not seen when Ss were tested directly from the nest or when grouped with others for 5 min. It is suggested that the opioid systems for stress and pain are functional in 10-day-old rats and that short-term isolation from the dam is a probable natural stressor modulated by endogenous opioid release. (51 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral effects of kappa-opioid-receptor stimulation on neonatal rats.

Previous results show that endogenous opioid systems mediate affective responses in neonatal rats. Opioids modulate isolation-induced ultrasonic vocalizations and analgesia. This study further examines the behavioral effects of κ-receptor-system stimulation on 10-day-old rats. With the agonist U50,488, response to isolation in terms of vocalizations, activity levels, and pain sensitivity was tested. In contrast to morphine's effects (primarily a μ-agonist), the κ-agonist U50,488 produced increased vocalizing and hyperactivity, although both opioid agonists caused analgesia. Isolation adds to the U50,488-mediated increase in the latency for paw withdrawal from heat. This study suggests that the kappa system provokes calling and activity as opposed to the quieting effects of μ-agonists found in previous studies. These differential effects may be due in part to the interaction of the opioid and dopamine systems. (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)     

Clonidine antagonizes the aversive effects of opiate withdrawal and the rewarding effects of morphine only in opiate withdrawn rats.

The researchers asked whether clonidine, an α?-noradrenergic agonist, would block selectively the motivational effects of opiate withdrawal and whether clonidine's effects would respect the boundary between nondeprived and deprived motivational states. In a place conditioning paradigm, clonidine (0.05 mg/kg ip) blocked the rewarding effects of morphine in opiate-withdrawn rats (as well as the aversive properties of withdrawal itself), but did not affect morphine place preferences (2 and 20 mg/kg) in drug-naive rats. Furthermore, clonidine blocked the acquisition of morphine (15 mg/kg), but not LiCI (15 mg/kg), conditioned taste aversions in water-deprived rats. The results suggest that the motivational system activated in deprived animals includes dopaminergic and noradrenergic components that are in series with each other. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of warmth on newborn rats' motor activity and oral responsiveness to an artificial nipple.

Temperature is a powerful regulator of the behavior and physiology of newborn altricial animals. The effects of warmth on newborn rats' oral responsiveness to suckling stimuli and spontaneous motor activity in a thermoneutral environment were investigated. Newborn rat pups' oral grasp responses to an artificial nipple and overall motor activity were recorded for 18 min. Near-term pups were delivered by cesarean section so that their 1st experiences with suckling stimuli could be observed. Experimental pups were warmed for 15 s every 2 min; control pups were not warmed. Warmed pups grasped the nipple fewer times than the not-warmed pups. However, oral grasp durations became longer for the warmed pups but not for the not-warmed pups. Warmth increased pups' motor activity but only while the heat was applied. Warmth in a thermoneutral environment may promote longer nipple attachment during newborns' early feeding experiences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Socially mediated reduction of isolation distress in rat pups is blocked by naltrexone but not by Ro 15-1788.

[Correction Notice: An erratum for this article was reported in Vol 104(4) of Behavioral Neuroscience (see record 2008-10515-001). On page 462, the last paragraph of the first column was incorrect. The corrected paragraph is provided in the erratum.] The presence of a single anesthetized littermate significantly reduced the rate of ultrasonic vocalization by 10-day-old pups isolated in a novel environment. Naltrexone (1.0 mg/kg) returned the vocalization rate to the level of pups tested alone and disrupted the maintenance of body contact between the test pup and a companion. This suggests that the companion exerts comforting effects through endogenous opioid mechanisms. Although chlordiazepoxide is as effective as morphine in the quieting of isolation distress, the benzodiazepine (BDZ) antagonist Ro 15-1788 (5, 10, or 20 mg/kg) was ineffective in blocking the comfort effect and facilitated quiet contact with the companion. In isolated pups, Ro 15-1788 caused a significant, but not a dose-related, decrease in vocalization, a possible indication of the displacement of an endogenous anxiogenic ligand at the BDZ receptor complex. [An erratum for this article will appear in Behavioral Neuroscience, 1990 (Aug), Vol 104:4. The erratum concerns an error in the last paragraph of the first column on page 462.] (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behaviorally functional opioid systems in infant rats: I. Evidence for olfactory and gustatory classical conditioning.

Conducted 2 series of experiments to characterize the behavioral function of opioid systems in neonatal rats. In the 1st series, the reinforcing properties of exogenous opioids were investigated in 112 5-day-old pups. Ss' ability to associate the novel taste of saccharin, received while suckling, with intraperitoneal morphine injections was assessed. Results show that Ss that received 0.5 ml of saccharin prior to morphine administration ingested considerably more saccharin on Day 10 than did control rats. The 2nd set of experiments was conducted to determine whether 144 rat pups could associate a novel odor with morphine administration. Five days after conditioning, that stimulus was highly preferred by morphine-treated Ss compared with saline control Ss. Thus positive associations were formed with either a novel taste stimulus experienced while suckling or with an odor experienced during social isolation. Conditioning was cue specific and was retained for at least 5 days. The formation of these associations was blocked with opioid antagonists given prior to conditioning. Data suggest behaviorally functional opioid receptors and raise the possibility of a functional role of the endogenous opioids in motivational processes in infant rats. (38 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Corticosteroid induction of threat-induced behavioral inhibition in preweanling rats.

Termination of ongoing behavior and assumption of defensive postures when threatened are adaptive characteristics of vertebrates. Altricial rat pups develop these characteristics by 14 days of age. At this time, pups inhibit their ultrasonic vocalizations and freeze when threatened. This emergence of behavioral inhibition is impaired when rats are adrenalectomized (ADX) at 10 days of age. That is, 14-day-old ADX pups exhibit deficits in freezing and continue to emit ultrasounds when confronted by an adult male rat. Studies also showed that removal of adrenal hormones does not potentiate vocalizations or render pups incapable of reducing their ultrasounds. More important, 3.0 mg/kg of corticosterone (CORT), but not lower doses, administered daily to ADX pups restored freezing, with lesser effects on ultrasound inhibition. Disrupting the developmental action of endogenous CORT appears to impair the ontogenic expression of behavioral inhibition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The selective estrogen receptor modulator, raloxifene: a segment II/III delivery study in rats

Raloxifene is a nonsteroidal, selective estrogen receptor modulator developed by Eli Lilly and Company as a therapeutic agent for postmenopausal osteoporosis. Raloxifene was administered orally by gavage at doses of 0, 0.1, 1, or 10 mg/kg/d to female CD rats (25/group) on Gestation Day 6 (GD 6) through Postpartum Day 20 (PD 20). Females were allowed to deliver and maintain their progeny until PD 21. All dead pups and pups culled on PD 1 were given internal and external examinations. One pup/sex/litter was assigned to each of the following assessment groups: 1) the primary pair for the F1 generation study, in which survival, growth, development, behavior, indicators of sexual maturation, and reproductive performance were evaluated; 2) terminal necropsy evaluations at PD 21; 3) terminal necropsy evaluations at 60 d of age; and 4) assessments of immune function at 5 to 6 weeks of age. At termination on PD 21, 60, or approximately 140, a necropsy was performed; crown rump and tibia lengths were measured; pituitary weights were taken; and a portion of the anterior pituitary was retained for growth hormone, luteinizing hormone, and prolactin content determinations (control and 10-mg/kg groups only). The remainder of the pituitary and reproductive tissues were retained for histologic evaluations. Dose-related depressions in maternal body weight and food consumption occurred during gestation. Mean gestation length was increased at 1 and 10 mg/kg. Delayed, extended, and/or disrupted parturition occurred in dams given 10 mg/kg, which resulted in a high incidence of maternal morbidity and/or death, increased numbers of dead pups, and the survival of only 66% of live pups to PD 21. Progeny body weights were not decreased at birth, but were depressed progressively in a dose-related manner during the 3-week lactation period. Negative geotaxis and incisor eruption were apparently accelerated in the 1- and 10-mg/kg groups, but eye opening was delayed at 10 mg/kg. Postweaning activity levels, auditory startle, and passive avoidance performance were not affected in the raloxifene groups. Dose-related decreases in spleen cellularity and thymus weights occurred in both sexes, but immune system function, as measured by splenic natural killer cell activity and antibody response to sheep red blood cells, was not affected. Postweaning body weights and growth parameters, as well as pituitary hormone content, were affected in both an age- and sex-specific manner. Preputial separation was not affected, but vaginal patency occurred ca 2 d earlier than controls in females from the 10-mg/kg group. Estrous cycles of the F1 females were not affected during the first two weeks after vaginal opening, but were disrupted at 12 to 14 weeks of age in the 10-mg/kg group. These females showed poorer mating and fertility indices, and litter size was reduced in the two females that were pregnant. Histologically, reproductive organs were not affected in males at any age or in females at PD 21. At PD 60, vaginal mucification occurred in females from the 0.1- and 1-mg/kg groups. At PD 140, the only finding was a high rate of uterine hypoplasia in the 10-mg/kg group, and this finding occurred in the absence of any concomitant ovarian or vaginal changes. These reproductive and developmental findings are consistent with estrogen antagonist activity of raloxifene.     

Association of an odor with an activation of olfactory bulb noradrenergic β-receptors or locus coeruleus stimulation is sufficient to produce learned approach responses to that odor in neonatal rats.

These experiments examined the sufficiency of pairing an odor with either intrabulbar activation of noradrenergic β-receptors or pharmacological stimulation of the locus coeruleus to support learned odor preferences in Postnatal Day 6–7 rat pups. The results showed that pups exposed to odor paired with β-receptor activation limited to the olfactory bulb (isoproterenol, 50 μM) displayed a conditioned approach response on subsequent exposure to that odor. Furthermore, putative stimulation of the locus coeruleus (2 μM idazoxan or 2 mM acetylcholine) paired with odor produced a subsequent preference for that odor. The effects of locus coeruleus stimulation could be blocked by a pretraining injection of the β-receptor antagonist propranolol (20 mg/kg). Together these results suggest that convergence of odor input with norepinephrine release from the locus coeruleus terminals within the olfactory bulb is sufficient to support olfactory learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hypothermic vocalizations of rat pups (Rattus norvegicus) and direct maternal search behavior.

Emissions of ultrasonic vocalizations (USVs) by rat pups (Rattus norvegicus) during hypothermia have consequences for recovery and warming. The effects on dam behavior of USVs emitted by 3- to 11-day-old pups during hypothermia at rectal temperatures between 18 and 22°C was investigated Rat dams were tested in a Y maze with the home cage as a start box. Dams were given, in one condition, a choice between a hypothermic pup emitting USVs or a hypothermic, silent (anesthetized) pup and, in the other, a choice between 2 hypothermic, silent pups. Although differing in some acoustic properties from normal isolation calls, USVs emitted by hypothermic pups both elicited maternal search behavior and acted as directional cues for dams, in comparisons with control dams exposed only to silent pups. Thus USVs of pups recovering from extreme hypothermia have communicative as well as physiological significance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Central dopamine turnover in guinea pig pups during separation from their mothers in a novel environment.

Guinea pig pups that were separated from their mothers and placed into a novel environment for 90 min showed an increase in dopamine (DA) turnover (ratio of metabolites to DA) in the septum compared with undisturbed baseline controls. Pups placed into the novel environment with their mothers exhibited an intermediate level of DA turnover. After 24 hr of separation in the novel environment, pups' DA turnover in the septum had returned to the baseline level. DA turnover in the caudate nucleus was unaffected by these procedures. Also, turnover in both septum and caudate nucleus when pups were not separated was positively correlated with the number of vocalizations emitted during 30 min of separation. These results closely parallel findings in separated monkeys and indicate that the guinea pig represents a useful rodent model for studying such effects. That elevated DA turnover during separation occurred in the septum suggests involvement of the mesolimbic system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)