Home Cage Environment Research Articles

Nicotine and amphetamine acutely cross-potentiate their behavioral and neurochemical responses in female Holtzman rats

Psychostimulants are often used in close temporal proximity to nicotine and have been reported to enhance acutely nicotine's desirability in humans. To investigate the acute associations between amphetamine and nicotine, we examined the potentiative interactions between clinically relevant, low doses of these drugs on locomotor activity, and dopamine overflow in the rat. Locomotor activity was measured by telemetry in the home cage environment, and dopamine overflow was evaluated in striatal slice preparations from female Holtzman rats. When administered simultaneously, nicotine and amphetamine produced a predominantly additive effect on locomotor behavior. However amphetamine, when given 2-4 h before nicotine, strongly potentiated nicotine-induced locomotor activity. Correspondingly, nicotine given 1-4 h before amphetamine robustly enhanced amphetamine-stimulated locomotor activity even when the effects of the nicotine pretreatment dissipated. Acute nicotine pretreatment similarly potentiated the effects of dopamine transporter ligands, cocaine, nomifensine, and methamphetamine but not a direct dopamine receptor agonist. Consistent with the behavioral studies, in vivo nicotine pretreatment exaggerated amphetamine-induced dopamine efflux from rat striatal slices. Likewise, in vivo pretreatment of rats with amphetamine potentiated nicotine-induced dopamine efflux from striatal slices. Direct pretreatment of striatal tissue by nicotine also potentiated subsequent amphetamine-stimulated dopamine overflow, further suggesting that the nicotine-amphetamine interaction occurs at the level of the dopamine terminal. Overall, the present data demonstrate that acute interactions of nicotine and other psychomotor stimulants produce potentiative effects and that these transient interactions may play a role in the frequent co-use and abuse of nicotine and other stimulants.

Effects of prolonged exposure to context following contextual fear conditioning on synaptic properties in rat hippocampal slices

Acute stressful events enhance plasma corticosterone release and profoundly affect synaptic functions, which are involved in the development of stress-related cognitive and mental disorders. However, how exposure to stressful context immediately after stress further modulates the physiological responses is not fully understood. Here, we found that acute stress inhibited paired-pulse facilitation in hippocampal slices of Wistar rats which were subjected to contextual fear conditioning. But such inhibition was reversed by subsequent prolonged exposure to foot-shock context or returning to home cage for 1 h. Interestingly, foot-shock stress-facilitated LTD induced by low frequency stimulation (LFS, 900 pulses at 1 Hz) was maintained by subsequent exposure to foot-shock context but was reversed by returning to home cage environment. Moreover, plasma corticosterone level was still kept higher in rats exposed to foot-shock context but not to home cage. Findings suggest that remaining in stressful environment immediately after stress maintains acute stress-facilitated LTD and higher level of neuroendocrine response. Our results also contribute to further understanding the critical role of timely intervention in mediating stress-related aversive changes in human.

Social status modulates basal IL-1 concentrations in the hypothalamus of pair-housed rats and influences certain features of stress reactivity

Recent findings from our laboratory and others indicate that exposure to stress can increase expression of the pro-inflammatory cytokine interleukin-1 (IL-1). In a series of studies examining this response, we observed pronounced differences in baseline levels of hypothalamic IL-1 of pair-housed rats. We hypothesized that these pair-wise differences might be a result of prolonged social stress associated with dominance/submissiveness, and that the submissive animal would show heightened baseline levels of IL-1. In order to test this hypothesis, we utilized a food competition paradigm (access to cheerios) to assess dominance within a dyad prior to the assessment of hypothalamic IL-1 levels. Based on the results of this test, clear dominance hierarchies were observed in ∼50% of the dyads, a ratio comparable to what has been reported previously. More importantly, this dominant/submissive categorization could be used to predict pair-wise differences in hypothalamic IL-1 with greater than 90% accuracy. Specifically, the submissive rat in each dyad (determined a priori) consistently evinced hypothalamic IL-1 levels that were nearly double that of its dominant cage mate. Further studies demonstrated that submissive rats showed a more rapid and pronounced hyperthermic response to novel environment stress relative to dominant rats. Interestingly, social status had no effect on corticosterone reactivity, even when the nature and intensity of the stressor was varied. Finally, maintenance of a clear dominance hierarchy obfuscated hypothalamic IL-1 responses to footshock exposure, with the most robust increases in hypothalamic IL-1 provoked by footshock being observed in pairs where there was no clear dominance hierarchy. Together, these findings suggest that social status can have a significant impact on stress reactivity and neuroimmune consequences of stressor exposure even in the unperturbed home cage environment.

The δ-Opioid Receptor Agonist SNC80 [(+)-4-[α(R)-α-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] Synergistically Enhances the Locomotor-Activating Effects of Some Psychomotor Stimulants, but Not Direct Dopamine Agonists, in Rats

The nonpeptidic delta-opioid agonist SNC80 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] produces many stimulant-like behavioral effects in rodents and monkeys, such as locomotor stimulation, generalization to cocaine in discrimination procedures, and antiparkinsonian effects. Tolerance to the locomotor-stimulating effects of SNC80 develops after a single administration of SNC80 in rats; it is not known whether cross-tolerance develops to the effects of other stimulant compounds. In the initial studies to determine whether SNC80 produced cross-tolerance to other stimulant compounds, it was discovered that amphetamine-stimulated locomotor activity was greatly enhanced in SNC80-pretreated rats. This study evaluated acute cross-tolerance between delta-opioid agonists and other locomotor-stimulating drugs. Locomotor activity was measured in male Sprague-Dawley rats implanted with radiotransmitters, and activity levels were recorded in the home cage environment. Three-hour SNC80 pretreatment produced tolerance to further delta-opioid receptor stimulation but also augmented greatly amphetamine-stimulated locomotor activity in a dose-dependent manner. Pretreatments with other delta-opioid agonists, (+)BW373U86 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl]-N,N-diethylbenzamide] and oxymorphindole (17-methyl-6,7-dehydro-4,5-epoxy-3,14-dihydroxy-6,7,2',3'-indolomorphinan), also modified amphetamine-induced activity levels. SNC80 pretreatment enhanced the stimulatory effects of the dopamine/norepinephrine transporter ligands cocaine and nomifensine (1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-isoquinolinanmine maleate salt), but not the direct dopamine receptor agonists SKF81297 [R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide] and quinpirole [trans-(-)-(4alphaR)-4,4a, 5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g] quinoline monohydrochloride]. In conclusion, SNC80 enhanced the locomotor-stimulating effects of monoamine transporter ligands suggesting that delta-opioid receptor activation might alter the functional activity of monoamine transporters or presynaptic monoamine terminals.

Comparison of preferences for object properties in the rat using paired- and free-choice paradigms

A common method for testing preference for objects is to determine which of a pair of objects is approached first in a paired-choice paradigm. In comparison, many studies of preference for environmental enrichment (EE) devices have used paradigms in which total time spent with each of a pair of objects is used to determine preference. While each of these paradigms gives a specific measure of the preference for one object in comparison to another, neither method allows comparisons between multiple objects simultaneously. Since it is possible that several EE objects would be placed in a cage together to improve animal welfare, it is important to determine measures for rats’ preferences in conditions that mimic this potential home cage environment. While it would be predicted that each type of measure would produce similar rankings of objects, this has never been tested empirically. In this study, we compared two paradigms: EE objects were either presented in pairs (paired-choice comparison) or four objects were presented simultaneously (simultaneous presentation comparison). We used frequency of first interaction and time spent with each object to rank the objects in the paired-choice experiment, and time spent with each object to rank the objects in the simultaneous presentation experiment. We also considered the behaviours elicited by the objects to determine if these might be contributing to object preference. We demonstrated that object ranking based on time spent with objects from the paired-choice experiment predicted object ranking in the simultaneous presentation experiment. Additionally, we confirmed that behaviours elicited were an important determinant of time spent with an object. This provides convergent evidence that both paired choice and simultaneous comparisons provide valid measures of preference for EE objects in rats.

Behavioral phenotyping of mice lacking the K ATP channel subunit Kir6.2

ATP-sensitive potassium (K ATP) channels are expressed in various tissues and cell-types where they act as so-called metabolic sensors that couple metabolic state to cellular excitability. The pore of most K ATP channel types is built by Kir6.2 subunits. Analysis of a general Kir6.2 knockout (KO) mouse has identified a variety of different functional roles for central and peripheral K ATP channels in situations of metabolic demand. However, the widespread distribution of these channels suggests that they might influence cellular physiology and animal behavior under metabolic control conditions. As a comprehensive behavioral description of Kir6.2 KO mice under physiological control conditions has not yet been carried out, we subjected Kir6.2 KO and corresponding wild-type (WT) mice to a test battery to assess emotional behavior, motor activity and coordination, species-typical behaviors and cognition. The results indicated that in these test situations Kir6.2 KO mice were less active, had impaired motor coordination, and appeared to differ from controls in their emotional reactivity. Differences between KO and WT mice were generally attenuated in test situations that resembled the home cage environment. Moreover, in their home cages KO mice were more active than WT mice. Thus, our results suggest that loss of Kir6.2-containing K ATP channels does affect animal behavior under metabolic control conditions, especially in novel situations. These findings assign novel functional roles to K ATP channels beyond those previously described. However, according to the widespread expression of K ATP channels, these effects are complex, being dependent on details of test apparatus, procedure and prior experience.

Involvement of protein kinase A in ethanol-induced locomotor activity and sensitization

Rationale Mutant mice lacking the RIIβ subunit of protein kinase A (regulatory subunit II beta −/−) show increased ethanol preference. Recent evidence suggests a relationship between heightened ethanol preference and susceptibility to ethanol-induced locomotor sensitization. It is currently unknown if protein kinase A signaling modulates the stimulant effects and/or behavioral sensitization caused by ethanol administration. To address this question, we examined the effects of repeated ethanol administration on locomotor activity RIIβ −/− and littermate wild-type (RIIβ +/+) mice on multiple genetic backgrounds. Methods Over three consecutive days, mice were given single i.p. saline injections and immediately placed in a locomotor activity apparatus to establish a composite baseline for locomotor activity. Next, mice maintained on a hybrid 129/SvEv×C57BL/6J or pure C57BL/6J genetic background were given 10 i.p. ethanol injections before being placed in the activity apparatus. Each ethanol injection was separated by 3–4 days. To determine if changes in behavior were specific to ethanol injection, naïve mice were tested following repeated daily saline injections. The effects of ethanol injection on locomotor behavior were also assessed using an alternate paradigm in which mice were given repeated ethanol injections in their home cage environment. Results Relative to RIIβ +/+ mice, RIIβ −/− mice, regardless of genetic background, consistently showed significantly greater ethanol-induced locomotor activation. RIIβ −/− mice also showed increased sensitivity to ethanol-induced locomotor sensitization resulting from repeated administration, an effect that was dependent on genetic background and testing paradigm. Increased locomotor activity by RIIβ −/− mice was specific to ethanol injections, and was not related to altered blood ethanol levels. Conclusions These data provide novel evidence implicating an influence of protein kinase A signaling on ethanol-induced locomotor activity and behavioral sensitization. The observation that RIIβ −/− mice are more sensitive to the effects of repeated ethanol administration suggests that normal protein kinase A signaling limits, or is protective against, the stimulant effects of ethanol and the plastic alterations that underlie behavioral sensitization.

Behavioral Phenotyping of Transgenic and Knockout Mice: Practical Concerns and Potential Pitfalls

New technologies in molecular genetics have dramatically increased the number of targeted gene mutations available to the biomedical research community. Many mutant mouse lines have been generated to provide animal models for human genetic disorders, offering insights into anatomical, neurochemical, and behavioral effects of aberrant gene expression. A variety of assays have been developed to identify and characterize phenotypic changes. In the behavioral domain, our phenotyping strategy involves a comprehensive standardized methodological approach that assesses general health, reflexes, sensory abilities, and motor functions. This assessment is followed by a series of complementary tasks in the specific behavioral domain(s) hypothesized to reveal the function(s) of the gene. Our multitiered approach minimizes intersubject variability by standardizing the experimental history for all animals, improves interlaboratory reliability by providing a clearly defined experimental protocol, and minimizes artifactual interpretations of behavioral data by careful preliminary assessments of basic behaviors, followed by multiple tests within the behavioral domain of interest. Despite meticulous attention to experimental protocol, attention to environmental factors is essential. Differences in noise, light, home cage environment, handling, and diet can dramatically alter behavior. Baseline differences in the behaviors of inbred strains used to generate targeted mutant mouse lines can directly influence the behavioral phenotype of the mutant line. Strategies aimed at minimizing environmental variability and contributions of background genes will enhance the robustness of mouse behavioral phenotyping assays.

Home cage observations following acute and repeated IV cocaine in intact and gonadectomized rats

The purpose of the present experiment was to examine the effects of acute and repeated intravenous (IV) cocaine on rat behavior in the home cage environment. An observational sampling method was used. Pair-housed, male, female, castrated (CAST), and ovariectomized (OVX) rats were administered daily IV cocaine injections (3.0 mg/kg/injection) in the home cage for 13 consecutive days, and observations occurred after the 1st and 13th injections. The incidence, i.e., occurrence or nonoccurrence of a behavior, was recorded according to a behavioral profile comprised of 11 behaviors. Data were analyzed as locomotor composite and orofacial composite scores. Behaviors not amenable for combination into a composite incidence score were evaluated independently (e.g., still behavior). Females exhibited more locomotor incidence scores than males following acute injection and more still behavior after repeated cocaine administration. Females exhibited more locomotor activity than OVX rats following acute, but not repeated, cocaine injection. There were no differences between the male and CAST rats on days 1 or 13. CAST rats exhibited more still behavior than OVX following only acute cocaine administration. This study indicates that IV cocaine-induced sex differences and the effects of gonadectomy can be measured in the home cage, and furthermore, describes a simple method to screen changes in cocaine-induced locomotor behaviors in the absence of automated equipment.

Comparison of c-Fos induction in the brain by the mGlu2/3 receptor antagonist LY341495 and agonist LY354740: Evidence for widespread endogenous tone at brain mGlu2/3 receptors in vivo

LY341495 and LY354740 are potent and selective antagonist and agonist, respectively, for Group II metabotropic glutamate (mGlu2/3) receptors. Here we demonstrate that LY341495 (3 mg/kg) significantly increased c-Fos expression in almost all brain regions analyzed (44 out of 52 regions) in animals that were prehandled and kept in home-cage environment to minimize stress. Robust c-Fos induction was observed in all cortical regions, hippocampal CA1 and CA3 subregions, amygdala and several other subcortical nuclei. In contrast to LY341495, changes in c-Fos expression following LY354740 were more modest and not generally widespread (decreased in 1 region, dentate gyrus; and increased in 13 out of 52 regions). Interestingly, although LY354740 is anxiolytic in animals, LY341495 did not increase c-Fos expression in the paraventricular nucleus of the hypothalamus which is usually activated by stress/fear and several anxiogenic compounds. To further investigate the behavioral consequences of mGlu2/3 receptor antagonism, LY341495 was administered to prehandled animals that were placed in the elevated plus maze test under low light (low stress) conditions. Here LY341495 increased mouse elevated plus maze (EPM)-anxiety in a dose-dependent manner, significantly decreasing the time spent in open arms, but not affecting total ambulations. The behavioral consequences and associated widespread pattern of brain neuronal activations following blockade of mGlu2/3 receptors suggest that there is considerable endogenous glutamate tone throughout the brain at negative feedback peri-synaptic mGlu2/3 receptors, even under low stress conditions where synaptic glutamate release spillover would be expected to be minimized.

Differential effects of the selective orexin-1 receptor antagonist SB-334867 and lithium chloride on the behavioural satiety sequence in rats

Recent studies have shown that acute systemic administration of the selective orexin-1 receptor antagonist SB-334867 significantly reduces food intake in rats. Although this anorectic action of orexin-1 receptor blockade is associated with an acceleration in the transition from eating to resting, it is widely recognised that the behavioural indices of satiety are not dissimilar to those of illness. In this context, Experiment 1 confirmed a significant anorectic effect of 90 (but not 60) mg/kg lithium chloride (LiCl) in male rats presented with palatable mash in the home-cage environment. Experiment 2 employed a continuous monitoring technique to contrast the effects of LiCl (90 mg/kg) and SB-334867 (10 and 30 mg/kg) on food intake and behaviour during a 1-h test with palatable mash. SB-334867 dose-dependently inhibited food intake, with the higher dose producing a comparable degree of appetite suppression (approximately 40%) to that seen with LiCl. Despite equivalent anorectic action, the two compounds produced very different effects on behaviour. LiCl reduced active behaviours (locomotion, rearing, grooming and sniffing), slowed the rate of eating and disrupted the behavioural satiety sequence (BSS). In contrast, SB-334867 (30 mg/kg) decreased the duration of feeding and grooming, and modestly accelerated the transition between eating and resting. Furthermore, whereas LiCl failed to alter posttreatment bodyweight gain, SB-334867 (30 mg/kg) produced a significant weight loss in the 24-h period immediately following injection. Overall, the divergent profiles obtained with equianorectic doses of LiCl and SB-334867 provide convincing evidence for the behavioural selectivity of SB-334867-induced anorexia.

Training Nonhuman Primates to Cooperate With Scientific Procedures in Applied Biomedical Research

This report provides a brief overview of aspects of training nonhuman primates who have been, and continue to be, used in this laboratory. The research context involves applied behavioral studies in which animals are trained to perform complex operant behavioral sequences, often in their homecage environment. In such studies, animals have freedom to choose whether to engage in appetitively reinforced behavioral tests that employ neither food deprivation nor fluid management. This background of operant conditioning has provided an insight to, and a context for, animal training both as an adjunct to general laboratory management and as a way to expedite scientific procedures. Thus, training has potential implications for both well-being and scientific quality, although it must be considered an adjunct to the provision of socialization with conspecifics in high quality diverse housing systems and not as an alternative to such provision. The importance of discussion and consideration of alternative procedures cannot be overemphasized.

Environmental stimulation increases survival in mice transgenic for exon 1 of the Huntington's disease gene.

Mice transgenic for the first exon of the human Huntington's disease (HD) gene carrying an expanded CAG repeat expansion (R6/2 line) develop a progressive neurologic phenotype with symptoms resembling those seen in HD. The overt symptoms of R6/2 mice worsen with age, resulting in a rapid decline in health and premature death between 13 and 18 weeks of age. In this study, we characterized the onset and progression of the overt phenotype in R6/2 mice and examined factors that affect the phenotype and life expectancy of these mice. In particular, the effects of altering home cage environment, through changing feeding regimes and providing environmental stimulation, were investigated. We show that changes in feeding regimes significantly improved the general well-being and life expectancy of R6/2 mice. Furthermore, we find that various forms of environmental stimulation, including regular behavioral testing, significantly improved the survival of R6/2 mice over and above that resulting from the enhanced feeding regime. The fact that environmental stimulation improves the health and life expectancy in R6/2 mice not only enables the mice to serve as more useful research tools, but also suggests that environmental stimulation may have a beneficial impact on the progression of HD in patients.

Locomotor sensitization to quinpirole: environment-modulated increase in efficacy and context-dependent increase in potency.

This study examines whether behavioural sensitization to the dopamine agonist, quinpirole, reflects an increase in the drug's potency and/or efficacy to induce locomotion, and how these parameters are influenced by environmental context. Three experiments were conducted in which animals received either chronic quinpirole (10 x 0.5 mg/kg, twice weekly) or saline injections in either the home cage environment, an alternate environment or the testing environment (activity monitors), followed by a dose-response test for the expression of sensitization in the activity monitors. Compared to the acute dose-response relationship, chronic quinpirole increased the maximum response. This increase in efficacy was significantly higher in animals treated with quinpirole in a non-home cage environment compared to those that received chronic treatment in the home cage. A leftward shift in the dose-effect function was observed only in animals with prior drug experience in the testing environment. Results indicate that locomotor sensitization to quinpirole reflects an environment-modulated increase in the drug's efficacy, and an environment-dependent increase in drug potency. Efficacy and potency may be subject to sensitization by non-associational and associational mechanisms, respectively.

The influence of restraint on blood pressure in the rat

We examined the influence of procedures used in blood pressure measurement on blood pressure and the effects of antihypertensive agents. Subjects were spontaneously hypertensive rats (SHR) and their Wistar/Kyoto (WKY) controls. Blood pressure was recorded by telemetry. Twenty-four h baseline pressure were measured, and the effect of minor handling on blood pressure and heart rate was examined. The influence of restraint such as is used for tail-cuff blood pressures was examined. The effects of three different antihypertensive drugs was also examined in the SHR. In the home-cage environment, the SHRs showed higher systolic blood pressures, but had similar hypertensive responses to minor handling as the WKYs. Both strains had elevated heart rate and blood pressure when restrained in the manner used for tain-cuff readings. The antihypertensive effects of captopril and losartan in the SHR were unchanged when the animals were restrained but the hypotensive effect of hydralazine was greater. These results confirm that significant changes in heart rate and blood pressure can occur as a result of the minor procedures frequently used in blood pressure recording in both SHR and WKY rats. This suggests that telemetry may have significant advantages as a method for continous blood pressure monitoring. The pharmacological profile of antihypertensive drugs may well be different in animals where telemetry is employed and are not subject to the stresses involved in previous methods of monitoring blood pressure.

Effects of bromocriptine on self-administration of sweetened ethanol solutions in rats

The effect of bromocriptine (BRO), a D2 receptor agonist, on chronic oral ethanol (ETOH) self-administration was tested in a home-cage environment. Male Wistar rats (n = 77) were food deprived for 24 h. Then, a period of 15 days of limited-access (1 h/day) to food and to a sweetened ETOH solution was started [3% w/v of glucose and several concentrations of ETOH depending upon the group: 0% (control group). 1.5%, 5% or 10% v/v]. Later, another period started in which rats were maintained in a free-choice, two-bottle situation with food, tap-water and the sweetened solution available for 24 h/day, for 14 days. Following this period, BRO (5 mg/kg, SC) was administered, once daily, for 5 days, in the same continuous free-access conditions. ETOH consumption was also studied for 4 days after the last BRO injection. BRO increased ETOH self-administration throughout the 5-day period, regardless of the ETOH concentration available, in the rats with previous higher ETOH intake, without effect in the control animals. In the control rats, water intake was increased, whereas in the group that had access to the lowest ETOH concentration a decrease in water consumption was found. The enhanced ETOH drinking was maintained after BRO treatment for the animals with previous higher ETOH intake. BRO effects on water consumption were also maintained. These data suggest that BRO can potentiate ETOH intake and provide further support for the role of dopamine (DA) systems in mediating volitional oral intake of ETOH.

Group Selection for Adaptation to Multiple-Hen Cages: Behavioral Responses ,

Three stocks of White Leghorns were compared for behavioral traits when kept in single-bird (1H) and 12-hen (12H) layer-house cages. Genetic stocks consisted of a commercial strain (X), a randombred control (C), and a stock derived from C and selected on the basis of kin's group performance information for increased survival and egg production over seven generations (S). Experimental units consisted of four consecutive 1H cages or a single 12H cage. All birds within a unit had intact beaks and were of the same stock. Each stock was represented by hens in 48 units of both 1H and 12H cages, and by 48 males (C and S stocks only) in 1H cages. Birds that died were replaced. Observations involved hens in their home cages except for tonic immobility (TI) and pair contests.Observations carried out soon after birds were placed in layer-house cages indicated that avoidance of the observer was essentially absent after pullets were observed on the 1st and 2nd d. Behavioral profile frequencies differed for nearly all behaviors compared in 1H and 12H environments. Following initially high crouching and low feeding frequencies, apparently normal levels were present by Days 15 and 16 posthousing. During the initial adaptation phase, genetic stock differences were not found within 1H cages and were present in only 2 of 10 categories in 12H cages. Young adult profiles also indicated no differences among stocks in 1H cages, but stock differences were found in 6 of 12 categories in 12H cages. In those cases, X strain hens differed from hens of the C and S stocks, but C and S hens did not differ from each other. Comparisons carried out between hens in 1H and 12H cages revealed that fearfulness was greater in 12H cages.Genetic stock comparisons, involving relative fearfulness and feeding and movement in a frustrating situation indicated that the X stock frequently differed from both C and S, but C and S did not usually differ from each other. However, observations of hens’ agonistic activity in the 12H home cage environment revealed that the S stock had fewer agonistic acts than the C stock from which it was derived, and both C and S had less agonistic activity than the X stock. Pair contests carried out within and between C and S stocks in both sexes yielded results inconsistent with those for agonistic activity in 12H cages. The C and S hens did not differ, but S males were more aggressive and, in between-strain contests, were more dominant.

Unsignaled morphine delivery does not disrupt the development of associative morphine tolerance in the rat

When morphine administration is paired with a distinctive context, tolerance to morphine's analgesic effects comes readily under the associative control of the drug-paired context. These associative tolerance effects are eliminated when a relatively short (i.e., 6 h) interdose interval (IDI) is used for conditioning. Contemporary models of learned tolerance explain the absence of learning at short IDIs by positing that residual morphine effects from a recent drug exposure disrupt the formation of drug-context associations. The present studies examined the impact of Unsignaled morphine injections given 6 h prior to drug-context pairings on the development of associative tolerance. Analgesia was measured by the tail-flick method, and tolerance levels were assessed by dose-response curve methodology. Morphine preexposure had no detectable influence on the acquisition of associative tolerance when rats were tested immediately after conditioning, after a 30-day rest interval, or after a 30-day period of daily saline injections in their home-cage environment. These data suggest disruption of associative tolerance effects at short IDIs is not attributable to residual effects of morphine from the immediately preceding trial.

Social confrontation and tumor metastasis in rats: Defeat and β-adrenergic mechanisms

The effect of social confrontation on the susceptibility to metastatic development was studied in rats. An intruder male Fischer 344 (F344) was introduced to a male-female Long-Evans pair and the behavior was recorded during the first 30 min of a 7-h confrontation session. Mammary tumor cells (MADB106), syngeneic to the inbred F344 rat, were injected IV to the intruder 1 h after the beginning of the confrontation session, and the lung retention of tumor cells was determined 24 h later. In this tumor model, metastases develop only in the lungs. Retention of tumor cells and the consequent development of lung colonies are known to be highly controlled by the activity levels of natural killer cells during the first 24 h after tumor inoculation but not later. Twenty of the 21 intruders were attacked by resident males and 19 displayed submissive behavior. A significant increase in lung tumor retention was evident in intruders compared to both control groups: home cage and new environment. The magnitude of this increase was higher in intruders that frequently displayed submissive behavior (indicating social defeat). Pretreatment with the β-adrenergic antagonist, butoxamine, reduced the effects of social confrontation by approximately 50%, and adrenal demedullation almost abolished it without significantly affecting the social interaction. These findings suggest that the nature of intruder-resident interaction, rather than being subdominant or exposure to an unfamiliar environment, has a marked influence on the intruder's susceptibility to metastatic development. These effects of social confrontation seem to be mediated by adrenergic mechanisms, possibly via adrenergic influence on NK function and distribution.

Cocaine preexposure sensitizes conditioned fear in a potentiated acoustic startle paradigm

The consequences of chronic cocaine administration on fear-potentiated startle were evaluated in two experiments. Cocaine treatment (40 mg/kg) for 7 days prior to fear acquisition (light + shock pairings) had an attenuating influence on the ability of the conditioned stimulus (CS) to increase acoustic startle. When cocaine was administered in the context of the CS, following fear conditioning, a marked enhancement of potentiated startle was observed. In contrast, an extinction of the fear response was seen in saline and procaine animals repeatedly exposed to the nonreinforced CS. The results from control subjects injected with cocaine either in the shock chambers (contextual cues) or in their home cage environment, suggest that the systemic effects of this stimulant served to intensify the fear-eliciting properties acquired by the CS during fear conditioning. These findings demostrate a cocaine sensitization of conditioned fear, and were related to the emotional and psychological disturbances associated with long-term cocaine use.