Aerobic physical activity and salivary cortisol levels among women with a history of breast cancer.

BACKGROUND: Physical activity (PA) helps reduce cancer-related symptoms and improves overall functioning for women with and without a history of breast cancer (BC). Few researchers have examined the associations between PA and physiological stress measures. The aim of this study was to determine whether aerobic PA was associated with diurnal and reactive cortisol patterns, and whether these associations differed for women with and without a history of BC. METHODS: Participants were 25 women with a history of BC and 23 women without a history of BC who self-reported aerobic PA frequency. To assess diurnal cortisol patterns, participants provided five saliva samples collected on two consecutive days at the following times: upon awakening, 30 min after waking, 12 PM, 4 PM, and 9 PM. To measure reactive cortisol patterns, participants provided seven saliva samples collected before, during, and after doing the Trier Social Stress Test. RESULTS: Cortisol patterns differed statistically based on women's cancer history, whereby women without a history of BC had significantly higher overall cortisol reactivity to an acute stressor, and a marginally significant (p = .05) cancer experience by aerobic PA interaction was observed when analyzing diurnal cortisol data. CONCLUSIONS: Findings suggest that PA may not have the same effect on women with and without a history of BC.

Measuring neuropsychological change following breast cancer treatment: an analysis of statistical models.

This article considers the quantitative techniques currently in use in the evaluation of cognitive impairments associated with chemotherapy treatment for breast cancer. To illustrate differences among analytical approaches, all analyses were applied to baseline and posttreatment scores on neuropsychological tests obtained from Stages I and II breast cancer patients receiving either chemotherapy or hormonal therapy; a healthy control group with similar demographics to those of the treatment groups was also included. Conventional group analyses were compared with individual-based analyses (standardized regression-based and reliable change methods). Both univariate and multivariate techniques with and without covariates produced negligible effects. In contrast, results of the individual-based analyses identified a subset of participants in the chemotherapy group who experienced a severe decline in function on two or more tests. Differences between the control and treatment groups were greater than differences between the treatment groups alone. The standardized regression-based approach was more sensitive than the reliable change index in detecting chemotherapy and hormonal therapy subjects whose performance was different from baseline scores on two or more tests (roughly 80% vs. 50% of participants). From a clinical perspective, the degree of impairment determined on the basis of the individual-based methodologies could have a major impact on quality of life for those affected. On the whole, we argue that the standardized regression-based approach, allowing for the assessment of individual practice effects and evaluation of moderator variables, is the method of choice in this context.

The effects of rewarding ventral tegmental area stimulation and environmental enrichment on lipopolysaccharide-induced sickness behavior and cytokine expression in female rats.

Responding for rewarding brain stimulation has been used to track hedonic status in animals. In addition to neurochemical alterations, stimulation of the lateral hypothalamus or ventral tegmentum has been shown to influence immunological processes, including elevation of peripheral natural killer cell activity. In the present study, we examined whether ventral tegmental area (VTA) stimulation or environmental enrichment altered the severity of lipopolysaccharide (LPS)-induced sickness behaviors and the provocation of cytokine expression induced by the endotoxin. Accordingly, rats received either trials of brain stimulation reward or exposure to an enriched environment and subsequently challenged with 150 ug/kg i.p. of LPS. Groups receiving LPS and saline injections without further manipulation were also included. Using the real-time RT-PCR and a multiplex bead assay, mRNA and protein levels for several cytokines and their receptors were determined to evaluate how these may vary as a consequence of reward. Both brain stimulation and environmental enrichment similarly diminished sickness behaviors associated with the endotoxin. Receptor gene levels were generally stable across groups. Levels of IL-6 within the VTA were increased in the group receiving LPS challenge alone and environmental enrichment was associated with modestly reduced IL-6 levels within this brain region. Taken together, these data suggest that rewarding brain stimulation and environmental enrichment buffer against malaise provoked by endotoxin challenge. Moreover, IL-6 expression within the VTA may influence the development of sickness behavior following inflammatory stimuli.

Influence of housing on the consequences of chronic mild stress in female rats.

The chronic mild stress (CMS) paradigm was developed to model anhedonia in animals. The repeated administration of a series of unpredictable, mild stressors attempts to mimic the daily stress associated with the onset of clinical depression in humans. Male animals are predominantly used in these investigations despite significant, well-documented sex differences in human depression. In this study, the CMS procedure was modified to be more ecologically relevant to female animals. The effects of stress on sucrose preference, social interaction, rate of weight gain, and regularity of the estrous cycle in female Sprague-Dawley (SD) rats were evaluated in both single- and paired-housed rats, during 3 weeks each of baseline, CMS, and post-CMS phases. The results indicate that only single-housed rats exposed to stressors have a reduced rate of weight gain, significantly attenuated sucrose preference levels, and increased social interaction scores during the CMS phase of the study. Housing condition more than exposure to stress appeared to contribute to the disruption of estrous cycling in some animals. These data suggest that housing affords some protection from the negative consequences of CMS, at least in female rats, and that lack of social interaction in the single-housing condition may render females more vulnerable to stress-related illnesses. The development of paradigms that model human depression should emphasize sex-specific differences.

Behavioral and physiological effects of a single injection of rat interferon-alpha on male Sprague-Dawley rats: a long-term evaluation.

Interferon-alpha (IFN-alpha) is a cytokine used as a first line of defense against diseases such as cancer and hepatitis C. However, reports indicate that its effectiveness as a treatment is countered by central nervous system (CNS) disruptions in patients. Our work explored the possibility that it may also cause long-term behavioral disruptions by chronicling the behavioral and physiological disturbances associated with a single injection of vehicle, 10, 100, or 1,000 units of IFN-alpha in male Sprague-Dawley rats (n = 5/dose). Following 1 day of locomotor baseline collection, we monitored sickness behaviors (ptosis, piloerection, lethargy, and sleep), food and water intake, body weight, temperature, and motor activity. Observations were recorded 4 days prior to and 4 days following the IFN-alpha injection. Temperature and sickness behaviors were recorded three times daily at 9:00, 15:00, and 21:00 h, and all other indices, once daily. On the injection day, temperature values were highest in the animals receiving the 10-unit IFN-alpha dose 15 min and 13 h post-injection. In the case of sickness behaviors, a significant increase was observed in piloerection in all IFN-alpha groups at each time point measured, while the scores of the rats in the vehicle condition remained unchanged between pre- and post-injection days. Analyses of overall sickness behaviors during morning and night observation periods indicated increased scores in all IFN-alpha groups following injection. Cumulatively, these data suggest that a single IFN-alpha exposure may elicit long-term behavioral disruptions and that its consequences should be thoroughly investigated for its use in clinical populations.

Short- and long-term effects of interleukin-2 on weight, food intake, and hedonic mechanisms in the rat.

In the present work, we investigated the short- and long-term effects of a single systemic injection of rat recombinant interleukin-2 on weight, food intake, and brain stimulation reward thresholds elicited from the ventral tegmental area. An inverted U-shaped dose-function was obtained with 0.5 microg producing the greatest increases in the threshold for rewarding brain stimulation which were sustained during the month long tests. No differences between groups in terms of maximum response rates, a measure of performance, were observed. Although all injected groups showed a minor decline in the rate of weight gain over time, percent efficiency of food utilization (percent weight gain/food intake) was the same across groups, suggesting that metabolic function was not affected by the cytokine. In animals with bilateral ventral tegmental area implants, there was no consistent correspondence between the threshold change obtained from ipsilateral stimulation and that associated with the contralateral site; side-to-side differences ranged from 0 to 100%, suggesting a specific interaction between cytokine activity and the locus of rewarding brain stimulation. These data suggest that peripheral IL-2 significantly modifies hedonic processes arising from medial forebrain bundle stimulation in a long-term manner. We further suggest that since this modulation appears to be notably site-specific, IL-2 receptors or its metabolites may not be evenly distributed within the medial forebrain bundle.

Strain and gender specific effects in the forced swim test: effects of previous stress exposure.

The chronic mild stress (CMS) procedure was developed in rodents to target anhedonia, the core symptom of depressive melancholia. Stress exposure has been shown to induce a variety of physiological, biochemical and behavioral alterations associated with depression, although its anhedonic consequences as indexed by either sucrose intake and preference or thresholds for brain stimulation reward are less reliably observed. In the present study, we assessed the effects of six weeks of CMS on the latter measure in two strains of male and female rats subsequently challenged with an acute psychophysical stressor, forced swimming; their behavior in the swimming cylinder was evaluated on two consecutive days. While brain stimulation reward thresholds and response rates were unchanged by CMS exposure, significant differences in forced swim behaviors were observed between male control and CMS groups. In particular, male Long Evans rats with a history of CMS showed the largest decrease in the duration of active behaviors on the second test day, a pattern less evident in the Sprague-Dawley strain of rats, or in any of the female groups. The results suggest that the effects of depressogenic manipulations are strain and gender dependent, with male Long Evans rats most susceptible, as demonstrated by the selective reduction of struggling behaviors. Inclusion of multiple measures, including the forced swim test, would provide a better understanding of the psychopathological profile engendered by chronic exposure to mild stressors and its genetic specificity.

Chronic paroxetine infusion influences macronutrient selection in male Sprague-Dawley rats.

Decreased intake and weight loss are among the side effects frequently reported with chronic selective serotonin reuptake inhibitor (SSRI) use in both humans and animals. In an earlier study, we documented that paroxetine administered for several weeks induced a weight loss of greater than 10% in some male Sprague-Dawley rats (Pharmacol. Biochem. Behav. 63 (1999) 435). As a follow-up to that work, we investigated in this study whether such treatment influenced dietary macronutrient selection. Animals were first habituated to foods containing principally either proteins, fats, or carbohydrates in a self-selection paradigm, after which they were implanted intraperitoneally with osmotic minipumps that delivered either paroxetine (7.5 mg/kg/day) or vehicle (50:50 ethanol:water) for 28 days; food intake and weight changes were documented during this period. No acute effects of the drug were apparent. By the fifth day of treatment, significant differences in weight gain between groups were observed and thereafter generally maintained for the remainder of the study, with animals receiving paroxetine showing about an 8% decrease in weight gain overall. Carbohydrate and fat intakes were significantly reduced, whereas preference was unchanged in fats and proteins and initially decreased in carbohydrates; in the latter, this pattern reversed and exceeded vehicle animals for the second half of the study. Several hypotheses are discussed with respect to specific and nonspecific effects of paroxetine on feeding and macronutrient selection.

The effects of chronic mild stress on male Sprague-Dawley and Long Evans rats: I. Biochemical and physiological analyses.

The chronic unpredictable mild stress (CMS) is a paradigm developed in animals to model the relatively minor and unanticipated irritants that lead to a state of anhedonia in some individuals. However, the effectiveness of CMS is sometimes difficult to establish, for which unique strain sensitivities has been attributed as one contributing factor. These considerations led us to design the present study, which was an investigation of the corticosterone response to CMS in two outbred rat strains--Sprague-Dawley and Long Evans. Animals were exposed to one of two conditions--control or CMS--for 3 weeks during which body weight and fecal count were regularly monitored. At the end of this period, blood was sampled at a variety of time intervals following induction of a brief restraint stressor. First, a significant effect of CMS on corticosterone levels was evident at time 0 (prior to the application of the acute restraint stressor) in both strains. Second, the typical quadratic pattern of stressor-elicited fluctuations in this measure was similar in both Sprague-Dawley and Long Evans rats, with consistently elevated levels for the first hour following exposure to the acute stressor; near baseline values were observed at 2 h. However, only in the Long Evans strain were CMS related values much less than that observed in the control group after restraint stress. Third, both strains showed a reduced weight gain in the CMS groups relative to control groups. Fourth, spleen and adrenal weights were similar across all groups. Fifth, fecal counts remained stable across weeks of treatment in all groups with the exception of the Long Evans rats exposed to CMS; in this group, average counts were systematically reduced over the treatment period. We conclude that a history of chronic stress significantly blunts corticosterone levels in Long Evans but not Sprague-Dawley rats following exposure to an acute stressor. Physiological indices however are less influenced by this experience, at least when the exposure is limited to 3 weeks.

Measuring threshold shifts for brain stimulation reward using the method of limits.

Thresholds determined from the frequency of pulses and the current for rewarding brain stimulation were obtained from rats with lateral hypothalamic electrodes. The threshold, defined as the frequency or current corresponding to one-half the maximum response rate, was interpolated from reward summation functions. Daily trials of both ascending and descending sequences of frequency and current yielded no significant difference between order of presentation. While there was more variability in the maximum response rates across the sessions, neither frequency- nor current-based threshold evaluations yielded significant rate effects. Our findings suggest that the threshold procedure is generally not influenced by the sequence of delivery of stimulus values and, thus, may be regarded as a reliable measure of the reinforcing properties of brain-stimulation reward.

The substrate for brain-stimulation reward in the lateral preoptic area: III. Connections to the lateral hypothalamic area.

Double-pulse tests were used to estimate the refractory periods and anatomical linkage of the reward-relevant fibers that course between the lateral preoptic and lateral hypothalamic areas. In the 1st study, pairs of conditioning and test pulses were delivered to each site, and the interval between pulses varied; recovery from refractoriness was similar at both sites, with the curves generally rising from 0.6 to 2.0 ms. In the 2nd study, the pairs of pulses were delivered to both sites. Six of 7 rats showed evidence of axonal collision, with estimates of conduction velocity that ranged from 0.48 to 8.95 m/s across rats. These results suggest that a wide spectrum of fiber types characterizes the reward-relevant axons that course uninterruptedly between these 2 regions.

Factors that influence the persistence of stimulation-induced aversion.

Brain stimulation reward in certain regions has been shown to produce analgesia to externally applied painful stimuli. In the present experiments, we studied how electrical self-stimulation of the dorsal raphe (DR) nucleus modifies the aversive effects of electrical stimulation of the nucleus reticularis gigantocellularis (Gi) or of the dorsal tegmentum (DTg). In the first study, the threshold for latency to escape aversive Gi stimulation was tracked before and after exposure to rewarding DR stimulation. Only a few sessions of DR self-stimulation were required to produce a complete and long-lasting inhibition of Gi aversion. In the second study, the aversion induced by DTg stimulation rapidly disappeared following a few test sessions at that site. Unlike our previous experience with Gi aversion that required either pairing with rewarding lateral hypothalamic (LH) or ventral tegmental area (VTA) pulses in order to increase the threshold for latency to escape Gi aversion, in this study, simply brief experience with rewarding DR stimulation in unpaired trials was sufficient to entirely suppress Gi-induced aversion. Even more surprising was the finding that unlike the Gi, aversion obtained from activation of the DTg does not persist, its threshold for escape quickly increases, and within a few sessions is no longer evident. One interpretation of these findings is that the aversion mechanisms associated with the Gi and DTg are differentially susceptible to analgesic processes.

Dynamic changes in cytochrome oxidase activity in the amygdala following lesions of rewarding sites in the lateral hypothalamus.

The aim of this study was to evaluate neural changes in oxidative metabolism in amygdaloid sub-nuclei following unilateral electrolytic lesions of lateral hypothalamic sites that supported brain stimulation reward. A histochemical analysis of cytochrome oxidase activity, comparing lesioned to non-lesioned sides in the amygdala, revealed a significant reduction of oxidative metabolism in the cortical nucleus and, to a lesser degree, in the adjacent piriform cortex; this effect was observed 2-4 weeks after the lesion, with complete recovery by the eighth week in the case of the cortical nucleus only. No particular pattern in cytochrome oxidase activity was detected in other amygdaloid sub-nuclei that were examined, including the basolateral and medial nucleus. Within both structures, the most pronounced decreases in metabolic activity were observed at roughly the same level, corresponding to the posterolateral and posteromedial levels of the cortical nucleus and just anterior to the amygdalopiriform transition. These results suggest that within the amygdaloid complex, the cortical sub-nuclei and possibly the neighbouring piriform cortex contribute more to modulating lateral hypothalamic self-stimulation than components of the central extended amygdala.

Interactions between rewarding lateral hypothalamic and aversive nucleus reticularis gigantocellularis stimulation.

The interaction between rewarding and aversive consequences of brain stimulation were assessed in two studies. In the first, the frequency threshold for 300 ms trains of combined lateral hypothalamic (LH) and nucleus reticularis gigantocellularis (Gi) stimulation, in which each LH pulse was followed 2 ms later by the Gi one, was determined for one month. Compared to the threshold for trains of single LH pulses, combined LH-Gi stimulation initially increased the frequency threshold; however, this effect reversed within one session and was subsequently maintained for the duration of the study. The aversion produced by Gi stimulation, as measured by latency to escape, was abolished following a single session of LH-Gi pairs. In the second study, a subset of animals received both presentations of combined pulses, LH followed by Gi, and the reverse; the interval between pulses was varied from 0.2 to 6.4 ms. The effectiveness of combined stimulation, determined by the ratio of LH frequency thresholds to that of the LH-Gi ranged from 0 to 50% across animals but the individual effectiveness functions within animals did not vary with different intervals. In addition, the order of presentation of pulses was of no consequence. Thus, not only did exposure to LH stimulation appear to obliterate Gi aversion, but the combination of LH and Gi pulses added to the rewarding effect produced by LH stimulation alone.

The substrate for brain-stimulation reward in the lateral preoptic area. I. Anatomical mapping of its boundaries.

Given the putative role of the lateral preoptic area as a primary contributor of the cell bodies of origin of the descending pathway linking a subset of lateral hypothalamic and ventral tegmental area reward neurons, the distribution of self-stimulation sites in this structure was mapped in 22 animals using moveable electrodes and threshold procedures. Ninety-seven electrode sites were evaluated with placements ranging from just rostral to the midline convergence of the anterior commissure back to the transition zone between the lateral preoptic and lateral hypothalamic areas; of these, roughly 2/3 supported self-stimulation which was widely observed throughout the lateral preoptic area and medial forebrain bundle. In general, self-stimulation thresholds obtained from lateral sites were most stable, and progressively so approaching more caudal regions. Examination of the slopes of the period/current trade-off functions revealed a tendency for higher values in lateral and caudal sites; in contrast, dorsoventral excursions did not influence these estimates. Taken together, these data provide support for the notion that the substrate for brain-stimulation reward in the lateral preoptic area has a relatively homogeneous distribution that is more diffusely organized than that found in reward sites activated further caudally in the medial forebrain bundle.

The substrate for brain-stimulation reward in the lateral preoptic area. II. Connections to the ventral tegmental area.

This experiment investigated the existence of a direct anatomical connection between lateral preoptic and ventral tegmental areas that mediate brain stimulation reward using the behavioral adaptation of the collision test. This test is a double-pulse, two-electrode technique based on the axonal conduction failure that occurs when two separate sites in the same axon bundle are concurrently stimulated. This anatomical arrangement is inferred from the shape of the function relating the effectiveness of double-pulse stimulation to the interval between pulses. In this study, nine rats with a total of 44 pairs of sites were examined. In two pairs only was there a profile suggestive of an axonal collision effect, while the double-pulse effectiveness curve consistent with the properties of transynaptic collision was apparent for a single pair of sites; the remaining 93% were associated with relatively flat effectiveness curves. While electrode misalignment could be responsible for these results, there was adequate sampling to suggest that the preponderance of first stage signals that give rise to the rewarding effects mediated by the lateral preoptic and ventral tegmental areas do not travel along the same fiber bundle. However, stimulation applied to both sites concurrently produces a summation that is roughly 40% greater than stimulation at either site alone, suggesting reasonable integration of the reward signals generated by lateral preoptic and ventral tegmental area stimulation.

The effects of cholecystokinin on stimulation-induced feeding and self-stimulation.

Cholecystokinin (CCK) is a peptide hormone which controls a number of important functions during the process of digestion. It is present in the gut and the central nervous system, although its exact role in the latter is not yet clear. Our interest was in the effects of intraperitoneal and intracerebral injections of CCK on brain stimulation reward and stimulation-induced feeding. Period thresholds for rewarding stimulation were unaffected by either route of peptide administration, whereas stimulation-induced feeding thresholds were weakly increased by centrally injected CCK. In addition, we evaluated stimulation-induced feeding using a more resolved measure and found it to provide clearer results. By actually measuring the amount of food eaten during a stimulation-induced feeding session, and not only the occurrence of feeding, CCK was shown to systematically decrease the total intake as a function of dose in an inverse manner. The efficiency of food utilization was calculated for each animal during the different phases of the experiment in order to monitor the effects of CCK on the animals' overall health. Centrally administered CCK appeared to increase the animals' efficiency and, furthermore, this level was sustained for the entire post-injection phase, about 2 weeks, suggesting a relatively enduring increase in metabolic rate. While the functional role of central CCK and other gastric peptides requires clarification, analyses which exploit the stimulation-induced feeding paradigm need to make use of more clearly defined microstructural variables.

Control of motor seizures by brotizolam with maintenance of stable refractory periods for self-stimulation.

In recent years, we have been pursuing our mapping investigations of the substrate for brain-stimulation reward in regions of the anterior hypothalamic and lateral preoptic areas. However, one problem is that stimulation of these sites often generates overt seizures so that their suppression via a pharmacological means would be very useful. The sedative-hypnotic benzodiazepine, brotizolam, is reportedly a long-lasting anticonvulsant. Hence, its effects on motor seizures elicited from stimulation of the lateral preoptic area were evaluated in the first experiment. Both tested doses (5.0 and 7.5 mg/kg) of the drug were shown to significantly decrease the number, and marginally, the severity of stimulation-induced seizures; furthermore, this effect was relatively long lasting, up to about 3 h. The higher dose of brotizolam did not alter the single-pulse thresholds for self-stimulation, a requirement for evaluations of poststimulation excitability, the purpose of the second experiment. Here, our interest was in documenting whether the membrane properties of the stimulated neurons, as assessed by refractory periods, were altered by brotizolam. No differences in the time course of recovery were observed; refractoriness began between 0.4 and 0.8 ms, and reached 50% recovery by 2.0 ms, which is consistent with the pattern of poststimulation excitability typically measured at these sites. Thus, in addition to its long-lasting suppression of motor seizures in rats, brotizolam does not alter the time course of recovery from refractoriness of the neurons that mediate brain-stimulation reward in the lateral preoptic area.

Feeding and reward interactions from chronic paroxetine treatment.

The self-stimulation paradigm was used to evaluate threshold changes following acute and chronic administration of the selective serotonergic reuptake inhibitor paroxetine; stimulation sites were located in medial forebrain bundle structures. Rats received daily systemic injections of one of three doses of paroxetine (2.5, 5, or 7.5 mg/kg), either with or without stimulation, while the last group received the same number of vehicle injections with stimulation. Frequency thresholds were collected over a period of 6 h on day 1 (acute phase); no marked difference in the values were observed over this time span. Thereafter, the animals were tested every third day (chronic phase), for a total of 11 sessions or roughly 31 days. Commencing around day 10 of the drug treatment, the higher dose of paroxetine produced a significant and persistent facilitation in self-stimulation thresholds, mimicking the delay in clinical response in humans that is well documented. We also monitored on a daily basis the animals' weights and food intake. A large difference in the percent efficiency of food utilization, measured by calculating the ratio of weight change to food intake, was observed between the animals receiving stimulation and those that were not, exclusive to the higher dose of paroxetine. The percent efficiency of food utilization remained low in the animals only receiving the drug treatment, whereas they returned to baseline levels and above in subjects receiving both paroxetine and stimulation. Two findings emerge from these data: 1) the paradigm appears to model the human response to this class of antidepressants, and 2) rewarding stimulation seems to counteract the drug-induced weight loss.

Influence of bombesin on threshold for feeding and reward in the rat.

Bombesin's purported role in satiety mechanisms prompted this investigation of its effects on thresholds for stimulation-induced feeding and self-stimulation in the rat. Single electrodes were implanted in the lateral hypothalamus and the ability of each electrode to support self-stimulation and stimulation-induced feeding was evaluated at four current levels between 80 and 320 microA. The frequency thresholds associated with each current value were assessed following four intraperitoneal doses of bombesin, 2, 4, 8, and 16 micrograms/kg, as well as a saline dose. Bombesin increased the thresholds for stimulation-induced feeding at doses known to reduce food intake without influencing self-stimulation thresholds. From these findings we conclude that (1) the effects of peripheral bombesin on stimulation-induced feeding are analogous to its effects on normal feeding and (2) the data provide additional evidence for a pharmacological dissociation between stimulation-induced feeding and reward.