The prolonged effects of naloxone on play behavior and feeding in the rat

The effects of naloxone on social play and feeding behaviors of postweanling and adult Long-Evans hooded rats were studied. Administration of 1.0, 5.0, or 10.0 mg/kg naloxone reduced play in a dose-related fashion. The effects of a 5.0-mg/kg dose of naloxone could be detected at least 3 h after administration, in terms of both a decrease in social behavior and decreased food consumption, indicating that the behavioral time course of naloxone effects is greater than some reports in the pharmacokinetic literature suggest.     

Opiates and homing

Beginning at 15 days of age. Long-Evans rat pups were trained to run toward their home cage in a T-maze task. Morphine (.5-1.0 mg/kg sc) slowed initial acquisition running times but did not change the number of trials required to learn the position habit. Morphine markedly impeded extinction of the homing behavior. Opiate-treated animals ran as accurately and as quickly toward home on the 12th day of extinction as on the first (10 trials given per day). Conversely, naloxone (1 mg/kg sc) reduced resistance to extinction. The morphine effect was not state-dependent since the drug also impeded extinction in animals that had acquired the task under saline. The morphine effect was blocked by naloxane, which indicates that the increased resistance to extinction was due to an opiate receptor effect. These results indicate that morphine has a strong capacity to sustain a social habit in the absence of reinforcement.     

Male-related chemical cues promote sexual receptivity in the female musk shrew

The role of conspecific chemical cues in the activation of sexual behavior was investigated in the female musk shrew (Suncus murinus). In Experiment 1, virgin female musk shrews were exposed to either clean cages or cages recently vacated by an adult male. Regardless of whether the male used for the sexual behavior test was "familiar" to the female (having spent the 24 h exposure in his vacant cage) or "unfamiliar," females exposed to male-related cues received mounts from males significantly sooner than females exposed to clean cages. In Experiment 2, females housed for 24 h in a cage soiled by an adult male allowed males to mount significantly sooner than females housed in a cage soiled by a castrated male, another female, or a clean cage. These results demonstrate that chemical cues, produced exclusively by adult males, promote sexual receptivity in female musk shrews.     

Pavlovian Conditioning to a Diazepam Cue with Yohimbine as the Unconditional Stimulus

On multiple occasions, rats were administered diazepam (2.0 mg/kg, ip) followed 30 min thereafter by yohimbine hydrochloride (2.5 or 5.0 mg/kg) or isotonic saline (forward conditioning groups). Three additional groups (backward conditioning controls) were given equivalent injections, but in reverse order. After eight such pairings, the effects of a single injection of diazepam on motor performance (balancing on a rotating drum) was assessed. Rats that had received either dose of yohimbine during forward conditioning trials maintained their balance longer than the saline controls. After four additional conditioning trials, the animals’ activity patterns in a plus-maze screening test for anxiolytics were examined. Placed into the maze after a single test injection of isotonic saline, the behavior of all groups was virtually identical: less than 16% of total entries into or time spent in the four arms of the maze was spent in the two “open” arms (unprotected by surrounding walls). When tested in the maze again, but 35 min after a single injection of diazepam, the groups that had received diazepam but not yohimbine during the conditioning phase exhibited the expected increase in open-arm activity, and equivalent increases were found in backward conditioning groups. However, the group previously conditioned with 2.5 mg/kg of yohimbine following diazepam also showed an increased open-arm activity when tested with diazepam alone, but it was significantly greater than that seen in the control group. In contrast, the group conditioned with 5.0 mg/kg yohimbine following diazepam exhibited no effect of diazepam upon their plus maze activity; consequently, these animals spent less time in the open arms than either of the other groups. Yohimbine alone normally decreases open-arm activity (a putative “anxiogenic” effect) in a linear dose-dependent fashion. The fact that it had a bidirectional conditional effect on the diazepam cue drug demonstrates that a conditional response in drug → drug conditioning cannot always be predicted on the basis of the behavioral response to the signaled drug. Consideration is given to possible reasons for these effects of diazepam → yohimbine pairings in terms of the known neuropharmacological properties of yohimbine.     

Interaction between catecholaminergic and opioid systems in an active avoidance task

Male NMRI mice were given intravenous injections of the noradrenergic neurotoxin DSP4 or the vehicle 24 to 72 h prior behavioral testing. Animals were given 2 days of training on a one-way active avoidance task. Naloxone was given in one of three doses prior to training on Day 1 and Day 2 or prior to training on Day 1 only (saline was given prior to training on Day 2). There was a dose-dependent impairment of acquisition by naloxone in the vehicle-pretreated groups; 10 mg/kg naloxone produced a significant impairment of acquisition. Naloxone also modulated retention (Day 2) performance of the active avoidance task. For vehicle-pretreated mice, 1 mg/kg naloxone facilitated and 10 mg/kg naloxone-impaired performance on Day 2. DSP4 alone produced an impairment of acquisition of this task but had no effect on retention; Day 2 scores were slightly higher in the DSP4-pretreated group than in the vehicle-pretreated group. Naloxone produced somewhat different effects in DSP4-pretreated animals than in vehicle-pretreated animals. Naloxone (1 mg/kg) ameliorated the DSP4-induced impairment of acquisition; 10 mg/kg naloxone did not significantly alter the acquisition performance of this group. For the DSP4-pretreated mice that received naloxone before training on both days, the dose-response characteristics for retention scores were similar to those of vehicle-pretreated mice; 1 mg/kg naloxone was the facilitatory dose. However, for DSP4-treated mice that received naloxone before training on Day 1 only, there was a shift to the right in the effective facilitatory dose of naloxone. For these animals, 10 mg/kg naloxone but not 1 mg/kg naloxone significantly enhanced retention performance. We discuss these results in the context of a possible state-dependent modulation by naloxone in the DSP4-treated animals.     

Strain‐specific aggressive behavior of male mice submitted to different husbandry procedures

Severe aggression within groups of male laboratory mice can cause serious welfare problems. Previous experiments have shown that the transfer of specific olfactory cues during cage cleaning and the provision of nesting material decrease aggression and stress in group‐housed male mice. In this study, the combined effect of these husbandry procedures was tested for their long‐term effect on aggression in two strains of male mice (BALB/c and CD‐1). We used postcleaning aggressive behavior, wound counts, and testosterone levels as indicators of aggressiveness. Physiological responses to social challenge were investigated through urinary corticosterone and adrenal tyrosine‐hydroxylase measurements. Furthermore, the aggression‐modulating effects of two enrichment items (ShepherdShack/DesRes and PVC tube) were explored. Marked differences were found between the two strains. CD‐1 mice were more aggressive, had higher testosterone levels but lower corticosterone levels, and had fewer wounds than BALB/c mice. However, in neither of the two strains was long‐term enrichment with nesting material and its transfer after cage cleaning effective in lasting reduction of intermale aggression. This may be explained by the fact that aggression levels were generally low. It seems that housing mice in small, socially stable groups or keeping social disturbances to a minimum considerably modulates aggression in group‐housed male mice. Mice of both strains housed in cages enriched with nesting material had lower urinary corticosterone levels than standard‐housed mice. We therefore conclude that the long‐term provision of nesting material, including the transfer of nesting material during cage cleaning, may enhance the welfare of laboratory mice. Aggr. Behav. 29:69–80, 2003. © 2002 Wiley‐Liss, Inc.     

纳络酮、地卓西平(MK-801)对大鼠食物渴求的影响

实验以条件性位置偏爱（CPP）的表达为渴求模型观察纳络酮及MK-801对大鼠食物CPP表达,探讨摄食行为调控的心理机制。48只SD大鼠分成食物组（24）与对照组（24）,3轮食物匹配训练后,在CPP表达前分别注射生理盐水、纳络酮（1.0 mg˙kg -1）及MK-801(0.1 mg˙kg -1),观察各组动物在食物匹配训练侧停留时间的变化。结果发现,MK-801促进食物CPP的表达,但纳络酮对食物CPP的表达没有显著影响。以上结果表明MK-801（0.1mg˙kg -1）增强动物的食物渴求至少是其增加摄食量的原因之一,而1.0 mg˙kg -1的纳络酮降低动物的摄食量并不是由于食物渴求的下降导致的。MK-801与纳络酮调节动物摄食行为的心理机制可能不一致。     

A method for determining the aversive threshold in the rat using repeated measures: Tests with morphine sulfate

The procedure described here provides an objective automated technique for the psychophysical assessment of the aversive threshold and allows the animal Ss to serve as their own controls. Sensitivity to drug effects, as well as comparisons between drugs, using the same animals are possible also. Using a rectangular tilt cage, the aversive threshold to grid shock was defined as that intensity avoided 75% of the time. Each shock intensity (30, 60, 90, 120, and 150 microA) was presented for 5 min on one side of the cage and then switched to the other side for 5 min, thereby forcing the animal to sample each shock intensity. Aversive thresholds were determined daily for each rat. The analgesic effects of morphine sulfate were compared to saline. Animals were tested for 3 days at each morphine dose level (2, 4, 8, and 16 mg/kg). Each 3-day morphine series alternated with 3 days of testing under saline. Significant differences were detected between saline and morphine at 4, 8, and 16 mg/kg.     

Effects of chronic administration with high doses of testosterone propionate on behavioral and physiological parameters in mice with differing basal aggressiveness

The effects of testosterone propionate, an anabolic‐androgenic steroid, on the behavior displayed during a social encounter by gonadally intact male mice were investigated. Animals were distributed into three groups according to their attack latency in a pre‐screening test (high‐, moderate‐, and low‐ attacking mice) and each group received weekly injections of 60 or 120 mg/kg of testosterone or sesame oil for 10 weeks. Behavioral tests were then carried out. Afterwards, organs were weighed and blood samples collected in order to obtain hormonal data. Treatment had a differential impact on attack in the three groups of animals. Only the high‐attacking testosterone‐treated mice showed lower total duration of attack than their controls. Those that received 60 mg/kg spent more time exhibiting exploratory behaviors. As an index of the anabolic activity of the drug, all testosterone‐treated mice had heavier kidneys and, as an index of the androgenic activity of testosterone propionate, they had heavier seminal vesicles, lighter testes, and showed higher testosterone levels in a dose‐dependent way than their controls. Hence, the effect of treatment on peripheral physiological parameters was similar in all three groups whereas behavioral effects differed depending on basal aggressiveness, considered a characteristic of coping style. Aggr. Behav. 29:173–189, 2003. © 2003 Wiley‐Liss, Inc.     

Stress in cynomolgus monkeys (Macaca fascicularis) subjected to long-distance transport and simulated transport housing conditions

The stress associated with transportation of non-human primates used in scientific research is an important but almost unexplored part of laboratory animal husbandry. The procedures and routines concerning transport are not only important for the animals' physical health but also for their mental health as well. The transport stress in cynomolgus monkeys (Macaca fascicularis) was studied in two experiments. In Experiment 1, 25 adult female cynomolgus monkeys were divided into five groups of five animals each that received different diets during the transport phase of the experiment. All animals were transported in conventional single animal transport cages with no visual or tactile contact with conspecifics. The animals were transported by lorry for 24 h at ambient temperatures ranging between 20 degrees C and 35 degrees C. Urine produced before, during and after transport was collected and analysed for cortisol by enzyme-linked immunosorbent assay (ELISA). All monkeys exhibited a significant increase in cortisol excretion per time unit during the transport and on the first day following transport.Although anecdotal reports concerning diet during transport, including the provision of fruits and/or a tranquiliser, was thought likely to influence stress responses, these were not corrobated by the present study. In Experiment 2, behavioural data were collected from 18 cynomolgus macaques before and after transfer from group cages to either single or pair housing, and also before and after a simulated transport, in which the animals were housed in transport cages. The single housed monkeys were confined to single transport cages and the pair housed monkeys were kept in their pairs in double size cages. Both pair housed and singly housed monkeys showed clear behavioural signs of stress soon after their transfer out of their group cages.However, stress-associated behaviours were more prevalent in singly housed animals than in pair housed animals, and these behaviours persisted for a longer time after the simulated transport housing event than in the pair housed monkeys. Our data confirm that the transport of cynomolgus monkeys is stressful and suggest that it would be beneficial for the cynomolgus monkeys to be housed and transported in compatible pairs from the time they leave their group cages at the source country breeding facility until they arrive at their final laboratory destination in the country of use.     

Social factors influence haloperidol-induced catalepsy in rat

This study employed manipulations which presumably influence social interactions in rats: (1) paired housing with a heavier conspecific and (2) exposure to the odors of other rats. The dependent variable was the akinetic state induced by haloperidol, a neuroleptic and dopamine antagonist. In Experiment 1, adult male Long-Evans hooded rats were matched by weight and caged alone or in pairs with one rat 30 g heavier than its cagemate. All rats received haloperidol (1.5 mg/kg) and catalepsy testing. Heavy rats showed more catalepsy than the lighter member of pairs or weight-matched, singly housed controls. In Experiment 2, adult male rats were left unrecaged or were recaged into cages with bedding recently soiled by females or other adult males. After haloperidol (1.0 mg/kg), the rats exposed to bedding soiled by other adult males showed more catalepsy than did the control groups. Thus, the results of both experiments indicated that social factors can influence the akinesia induced by dopamine antagonists.     

Muscimol Induces Retrograde Amnesia for Changes in Reward Magnitude

These experiments examined the effect of the GABA_A, agonist, muscimol (MUS), on memory for changes in reward magnitude. In Experiment 1 rats were trained to run a straight alley for either a large or small food reward. After reaching asymptotic performance rats in the high reward group were shifted to the small food reward. Half the animals received 1.0 or 3.0 mg/kg (ip) of MUS or the equivalent volume of saline immediately after training. Shifted training continued for 3 more days and no further injections were given. Shifted saline animals displayed an increase in response latencies compared to unshifted controls with a sharp peak on the day after the shift. Shifted MUS receiving 1.0 mg/kg performed comparably to shifted saline animals. In contrast, shifted MUS animals receiving 3.0 mg/kg displayed performance comparable to shifted saline animals on the day of the shift but displayed a sharp increase in response latencies on the second day after the shift. These findings indicate that post-training systemic MUS injections delay the peak increase in response latencies and suggest that MUS induces retrograde amnesia for reward reduction. Experiment 2 examined the effect of MUS on the memory of a reward increase. Rats were first trained as in Experiment 1 and rats under the high reward condition were then shifted to the small reward. On the next training session, the large food reward was reinstated. Immediately after the session all animals were injected with saline or 3.0 mg/kg of MUS. The large food reward was continued for the remainder of training and no further injections were given. On the following session, the performance of the shifted saline animals was comparable to that of the unshifted controls while shifted MUS animals displayed significantly higher response latencies. The findings that MUS prevented the reduction in response latencies seen in saline-injected animals suggest that MUS also induces retrograde amnesia for reward increases.     

Conditioned activity and the interaction of amphetamine experience with morphine's activity effects

This experiment assessed the transfer effect of Pavlovian conditioning with d-amphetamine sulfate (1 mg/kg) on morphine's activity effects. Prior experience with amphetamine resulted in higher levels of activity when challenged with morphine (10 and 20 mg/kg). This interactive effect of amphetamine, however, was present only in those animals who had experienced amphetamine paired with the activity test situation. Animals who had received equivalent doses of amphetamine unpaired with the testing environment did not differ from drug-naive control animals. Analysis of predrug activity levels revealed a conditioned activity response in paired animals compared to the controls. These findings suggest that the response interaction between drug conditioned responses and drug unconditioned responses is an important determinant of cross-drug effects between drugs of different pharmacological classes.     

Selective antiaggressive effect of an alpha-2 adrenoceptor agonist naphthylmedetomidine in mice

Alpha-2 adrenoceptors (alpha(2)-ARs) are critically involved in regulating neurotransmitter release from sympathetic nerves and neurons and play an important role in the regulation of awareness, arousal and vigilance. In our recent study, dexmedetomidine, a full alpha(2)-AR agonist, produced antiaggressive effects in the social conflict test in mice at doses that were twice smaller than those producing sedation. The aim of this study was to ascertain antiaggressive effect of a novel drug naphthylmedetomidine, with a more selective alpha(2)-AR activity. Behavioral effects of naphthylmedetomidine (150-1200 microg/kg i.p.) were studied in the activity cage and in the social conflict tests in mice. Naphthylmedetomidine dose dependently decreased aggressive behavior during social conflict in aggressive mice with significant reduction already at the lowest doses tested (150 microg/kg), whereas locomotion and social investigation were significantly decreased only after four times bigger dose of naphthylmedetomidine (600 microg/kg) in aggressive mice. Naphthylmedetomidine had no effect on aggression in nonaggressive mice. Naphthylmedetomidine reduced locomotion in the activity cage significantly only at the highest doses tested (600 and 1200 microg/kg), and this effect was only partially reversed by administration of high doses of an alpha-2 antagonist atipamezole (3 and 10 mg/kg). In nonaggressive mice, the difference between the dose reducing dominant social behavior (social investigation) and locomotion (150 and 300 microg/kg, respectively) was smaller than in aggressive mice. In conclusion, naphthylmedetomidine showed a very strong and selective antiaggressive effect in aggressive mice, which was devoid of locomotion-inhibiting/sedative effect. This study suggests that naphthylmedetomidine may have clinical potential as antiaggressive drug.     

The behavioral effects of depletions of brain serotonin induced by 5,7-dihydroxytryptamine vary with time after administration

Ether-anesthetized Sprague-Dawley rats were depleted of brain serotonin (5HT) by intraventricular injections of 50 micrograms 5,7-dihydroxtryptamine (57DHT). Oral pretreatment with 25 mg/kg desmethylimipramine was used to protect brain noradrenergic neurons from 57DHT. Liquid chromatographic assays revealed that this treatment did not significantly alter catecholamine levels but depleted hippocampal 5HT by 92% and striatal 5HT by 45%. Three or eleven days after lesioning, locomotor and exploratory behavior was characterized in separate groups of animals with a behavioral pattern monitor (BPM). On Days 4 and 12, the animals were retested following saline or 1.0 mg/kg amphetamine. Three days after depletion, lesioned rats exhibited a decrease rate of habituation of locomotor activity relative to controls. When challenged with amphetamine (1.0 mg/kg), 5HT-depleted rats exhibited increased corner and decreased center activity, as well as stereotyped patterns of locomotion. Eleven days following lesion, 5HT-depleted rats exhibited habituation rates greater than controls; amphetamine challenge yielded patterns of activity similar to those of control animals. These results show that central serotonergic pathways play an important role in modulating both spontaneous and amphetamine-elicited activity in rats, and that compensatory mechanisms operate over time to alter the behavioral effects of 57DHT-induced depletions of brain 5HT.     

The effect of ethanol treatment on social behavior in male rats

The effect of 0.50 g/kg of EtOH in male rats interacting with a stimulus male juvenile in a newly developed test of social interaction was examined. The adult male rats were treated with EtOH (8.0 to 12.0 g/kg/day) or equicaloric dextrin maltose for 2 weeks (studies 1 and 2) or 8 weeks (study 3) and social interaction was assessed both before and after chronic drug treatment was ended in study 1 and after chronic drug treatment was ended in studies 2 and 3. It was found that prior to chronic drug treatment, in study 1, 0.50 g/kg of EtOH increased both aggressive behavior and time spent interacting with the stimulus juvenile male from the first presentation of the juvenile to the second presentation (20 min apart) while saline injection decreased it. After chronic drug treatment was ended, in study 1 animals treated chronically with EtOH were more aggressive when they were not intoxicated than when they had been treated with 0.50 g/kg of EtOH. In studies 2 and 3, after chronic drug treatment was ended, aggressive behavior and time spent interacting with the juvenile were greater in the animals treated chronically with EtOH, regardless of whether they were injected with saline or 0.50 g/kg of EtOH. The results of these studies showed that chronic EtOH treatment can produce long-lasting changes in social behavior after drug treatment is over and can alter the animal's normal response to EtOH in a social setting.     

Impairment of spontaneous alternation performance by an NMDA antagonist: attenuation with non-NMDA treatments.

N-Methyl-D-aspartate (NMDA) receptor antagonists disrupt learning on a variety of tasks. Previous findings indicate that glucose, naloxone, and physostigmine ameliorate learning deficits produced by several treatments. The present experiment examines whether these agents also reverse the amnestic effects of NMDA receptor blockade. Mice were tested for spontaneous alternation performance in a Y-maze. The animals received either saline or the NMDA antagonist, NPC 12626 (35 mg/kg, IP), 50 min prior to testing and received an additional injection of saline, glucose, naloxone, or physostigmine 30 min prior to testing. NPC 12626 significantly decreased alternation scores. Glucose (250 mg/kg), physostigmine (0.01 mg/kg), and naloxone (1 mg/kg) reversed the effects of NPC 12626. Thus, impairments of learning after NMDA receptor blockade share with other amnestic conditions the susceptibility to attenuation by glucose, naloxone, and physostigmine.     

Telemetry provides new insights into entrainment of activity wheel circadian rhythms and the role of body temperature in the development of ulcers in the activity-stress paradigm

Two methods of monitoring the circadian rhythm of activity in rodents: (1) an activity wheel cage, which detects the number of wheel revolutions, and (2) an internal radio transmitter, which records gross motor activity (GMA) of the animal, were compared in both normal circadian cycles and during the development of activity-stress ulcers. Rats were implanted with a biotelemetry transmitter that detected GMA and body temperature (BT) and placed in activity wheel cages. A 12 hour/12 hour light/dark cycle was maintained throughout the experiment. Subjects were subdivided into two groups: (1) unlimited access to activity wheel (AW) cages and (2) locked activity wheel (LW) cages. Following an ad-libitum habituation period, animals were allowed food access for 1 hour/day during the light. In the habituation period, the animals showed higher GMA and BT during the dark phase when housed in AW cages than in LW cages. Both GMA and number of wheel revolutions increased dramatically after the onset of food restriction for the AW animals. There was a deleterious drop in BT in AW animals as the food-restricted period continued and a significant correlation existed between severity of ulcerations and BT. The findings of this experiment demonstrate that the activity wheel imposes an alternation of the circadian cycle, which, in turn, influences rhythmicity through reentrainment. Additionally, in the activity-stress paradigm, a significant drop in BT correlates with severity of ulcerations. A disrupted circadian cycle, involving hypothermia, is proposed as the mechanism underlying the demise of animals in the activity-stress paradigm.     

Telemetry Provides New Insights into Entrainment of Activity Wheel Circadian Rhythms and the Role of Body Temperature in the Development of Ulcers in the Activity-Stress Paradigm

Two methods of monitoring the circadian rhythm of activity in rodents: (1) an activity wheel cage, which detects the number of wheel revolutions, and (2) an internal radio transmitter, which records gross motor activity (GMA) of the animal, were compared in both normal circadian cycles and during the development of activity-stress ulcers. Rats were implanted with a biotelemetry transmitter that detected GMA and body temperature (BT) and placed in activity wheel cages. A 12 hour/12 hour light/dark cycle was maintained throughout the experiment. Subjects were subdivided into two groups: (1) unlimited access to activity wheel (AW) cages and (2) locked activity wheel (LW) cages. Following an ad-libitum habituation period, animals were allowed food access for 1 hour/day during the light. In the habituation period, the animals showed higher GMA and BT during the dark phase when housed in AW cages than in LW cages. Both GMA and number of wheel revolutions increased dramatically after the onset of food restriction for the AW animals. There was a deleterious drop in BT in AW animals as the food-restricted period continued and a significant correlation existed between severity of ulcerations and BT. The findings of this experiment demonstrate that the activity wheel imposes an alternation of the circadian cycle, which, in turn, influences rhythmicity through reentrainment. Additionally, in the activity-stress paradigm, a significant drop in BT correlates with severity of ulcerations. A disrupted circadian cycle, involving hypothermia, is proposed as the mechanism underlying the demise of animals in the activity-stress paradigm.     

Enrichment versus exercise effects on motor impairments following cortical removals in rats

Groups of rats were exposed to an enriched environment, given access to an activity wheel, or individually housed in wire mesh cages, impoverished. Rats were exposed in groups of four to the enriched environment or placed individually in the activity wheel for 2 h per day for 25 days preoperatively. Within each exposure group, rats sustained bilateral removals of sensorimotor cortex, or were sham-operated controls. Animals were trained preoperatively to locomote across a narrow elevated runway. Postoperatively, locomotor testing was initiated 17 days after surgery throughout which time all animals were maintained under impoverished conditions. Locomotor deficits following cortical damage were a function of preoperative exposure: enriched rats were least impaired; impoverished rats were most impaired. Rats allowed running wheel activity initially showed the same marked deficits as impoverished animals but recovered more rapidly. The opportunity for physical exercise afforded wheel animals preoperatively may have enhanced motor capabilities that aided recovery. However, physical activity alone did not yield the same protective effects from initial impairment as enrichment. Greater elaboration of neural structures associated with perceptual-motor enrichment probably accounted for the initial sparing of the enriched group.