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.

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.

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.

A comparison of glycogen phosphorylase a and cytochrome oxidase histochemical staining in rat brain.

The utility of metabolic markers that index functional neuronal circuits is widely appreciated. The present study asks whether patterns of the metabolic enzyme, active glycogen phosphorylase, parallel those of the neuronal marker, cytochrome oxidase. Fresh frozen rat brain sections (30 microns) were processed for either active glycogen phosphorylase or cytochrome oxidase at each of ten levels of the neuraxis. Although these metabolic markers predominate in different cellular compartments--glycogen phosphorylase in the astrocytic compartment and cytochrome oxidase in the neuronal compartment--the patterns of high, moderate, and low levels of activity for both enzymes were generally parallel. These similarities extended to detailed patterns of heterogeneous staining within structures, in particular, to laminated and modular distribution within cerebral and cerebellar cortical structures. The modular distribution was evident in barrel structures in the cerebral cortex and in parasagittal compartments in the vermis of the cerebellum. Conspicuous differences between the two patterns occurred in white matter, in subcortical grey matter regions such as the nucleus accumbens, diagonal band, amygdala, and globus pallidus, and in the superior olivary nuclei of the brainstem as well as in nonneural structures such as the choroid plexus and ependyma. Discrete patchiness was characteristic of active glycogen phosphorylase distribution in the limbic neuropil of the dentate gyrus and entorhinal cortex. The strong parallels between active glycogen phosphorylase and cytochrome oxidase distribution support the view that glycogen phosphorylase, despite its glial localization, can reflect neuronal metabolic demands.

Functional connections between medial prefrontal cortex and caudate-putamen in brain-stimulation reward of rats.

Rats were trained to self-stimulate for trains of cathodal pulses delivered via electrodes placed in the medial prefrontal cortex (MPFC) and caudate-putamen (CPu). When the pulses were delivered via 9 ipsilateral MPFC and CPu sites alternately, summation varied from 13% to 40%. However, the overall summation for 2 contralateral MPFC-CPu pairs was 5%, thus indicating a greater integration of ipsilateral than contralateral reward signals. When the interval between alternate pulses decreased in 4 of the 9 ipsilateral pairs, the summation also decreased, an outcome consistent with collision of action potentials passing between the MPFC and CPu sites. The size of the collision effect ranged from 15% to 33%. Estimates of conduction velocity varied between 0.4 to 5.4 m/s, with a 1.7 m/s average. According to these values, the neurons connecting the MPFC and CPu self-stimulation sites appear to be slower than the ones that have been shown to link reward fibers that course between posterior brain regions.

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.

Ventromedial hypothalamic regulation of brown adipose tissue.

The central control of brown fat thermogenesis was evaluated in seventeen rats with moveable electrodes implanted in the ventromedial hypothalamus (VMH) and adjacent structures. Brown adipose tissue and core body temperatures were monitored in response to VMH stimulation; sites which elicited a rise in brown fat temperature were observed in the dorsomedial and anterior ventromedial hypothalamus, with BAT temperature profiles varying widely in duration and peak values. Given the complexity of BAT responses to endogenous VMH signals, these varied profiles may be mediated by dissimilar VMH signals, which remain to be characterized.

Histochemical mapping of the substrate for brain-stimulation reward with glycogen phosphorylase.

Glycogen phosphorylase is the enzyme that regulates glycogenolysis and it appears that there is a relationship between central levels of glycogen and neuronal activity, which is influenced by a variety of neurotransmitters. In the present study, glycogen phosphorylase histochemistry was used to correlate changes in metabolic activity in response to rewarding lateral hypothalamic stimulation. Rats were allowed to self-stimulate for 1 h per day for ten consecutive days following which postmortem phosphorylase a activity was examined. Significant differences in optical density between the stimulated and contralateral hemispheres were found in three of the eight analyzed structures, two of which, the diagonal band of Broca and the caudate nucleus, showed a greater density of glycogen phosphorylase a on the stimulated side and the third, the habenula, had greater contralateral activity. In conclusion, our data suggest that glycogen phosphorylase activity is a viable but not weighty marker of energy alterations induced by chronic exposure to intracranial self-stimulation, and that it is generally consistent with the patterns revealed by other metabolic indices such as cytochrome oxidase and 2-deoxyglucose autoradiography.

Post-stimulation excitability of mediodorsal thalamic self-stimulation.

The post-stimulation excitability of the substrate for brain stimulation reward in the mediodorsal thalamus was assessed using equal- and unequal-pulse procedures. In 3 rats, refractory periods were found to begin no earlier than 1 ms and to end as late as 10 ms. Using test (T) pulses 1.5 times the amplitude of condition (C) pulses, the contribution of absolute and relative refractory periods was determined in one subject. No change in the slope of the recovery function was obtained in this condition, suggesting that several populations of neurons with different absolute refractory periods compose the behaviorally relevant substrate. A large supernormal contribution, evaluated by increasing the C amplitude to 1.5T, occurred between 3 and 10 ms with a peak at 7.5 ms. These results suggest that mediodorsal thalamic self-stimulation is mediated by a wide range of small, probably unmyelinated fibers.

Behaviourally derived estimates of excitability in striatal and medial prefrontal cortical self-stimulation sites.

The refractory periods of the substrate underlying brain-stimulation reward were investigated in three rats with moveable electrodes implanted in the rostral caudate-putamen and the medial prefrontal cortex. Acquisition of caudate-putamen self-stimulation occurred within the first session, while self-stimulation for medial prefrontal cortex was observed only after three sessions of caudate-putamen stimulation. The currents required for self-stimulation ranged from 300 to 800 microA (0.1 ms pulse duration) across animals; the maximum response rates averaged roughly 40 bar presses per minute for both structures. Refractory period estimates were obtained from ten caudate-putamen and four medial prefrontal cortex sites. The time course of recovery had the following profile: the curves began to rise at 0.65 ms and 0.95 ms for caudate-putamen and medial prefrontal cortex stimulation, respectively, thereafter increasing to approach an asymptote at 6.00 ms for the caudate-putamen and 6.25 ms for the medial prefrontal cortex. The mean effectiveness value corresponding to the asymptotic portion of the curves was 73% for the caudate-putamen and 69% for the medial prefrontal cortex. Like other forebrain structures, the behaviourally derived refractory periods underlying caudate-putamen and medial prefrontal cortex stimulation, at least at these particular sites, are significantly longer than those observed in most medial forebrain bundle areas, both beginning and ending later. One interpretation for the similarity in their refractory period profiles and the apparent facilitating effect of caudate-putamen stimulation on acquisition of medial prefrontal cortex self-stimulation is that these two regions form part of the same reward substrate.

Diazepam alters brain-stimulation reward thresholds in seizure-prone sites.

Studies of the effect of diazepam and related compounds on the rewarding properties of brain stimulation as measured by response rates have not yielded clear results, with self-stimulation performance reported to be potentiated, diminished, or unchanged following drug administration. In this study, the effect of two doses of diazepam (2.5 and 5.0 mg/kg) and its vehicle on self-stimulation thresholds was examined in eight rats with electrode placements scattered along a 4 mm length of the medial forebrain bundle. Stimulation of the lateral preoptic area and the anterior and mid-lateral hypothalamus produced overt seizures. Rate-period curves were generated for a wide range of currents and the resulting period-current trade-off functions were compared across doses. In seizure-prone sites upward shifts in period threshold were observed after 2.5 mg/kg of diazepam with little additional increases incurred by the 5.0 mg/kg dose. The majority of non-seizure sites showed no effects of diazepam upon period threshold. The results suggest that diazepam alters brain-stimulation reward thresholds by suppressing competing seizure activity.

Characteristics of stimulation-induced feeding sites in the sulcal prefrontal cortex.

Double pulse tests were used to infer the refractory periods of the substrate underlying stimulation-induced feeding in the sulcal prefrontal cortex of the rat. Eleven sites were examined, of which five supported the behaviour at currents of 250 to 400 microA; pulse duration was 100 microseconds. The average profile indicates a recovery function that begins at 0.5 ms and ends at 3.0 ms, with no apparent contribution from local potential summations. The mean effectiveness value corresponding to the asymptotic portion of the curves was 91%. These results suggest that there is substantial overlap in the excitability of neurons underlying stimulation-induced feeding in the sulcal prefrontal cortex and that reported for the medial forebrain bundle, but unlike the latter structure, there is no evidence of self-stimulation from the same sulcal prefrontal cortex placements. Response rates were collected for a maximum of 21 days from each of the cortical sites at which feeding was recorded and at the same currents used to evaluate the refractory periods underlying stimulation-induced feeding. The rates averaged between 0 and 3 responses per minute whether the current was available or not. These data represent the first demonstration of a site that supports stimulation-induced feeding in the absence of brain stimulation reward, at least at these specific placements and stimulation parameters.

The effect of pulse duration of refractory periods of neurons mediating brain-stimulation reward.

The post-stimulation excitability characteristics of neurons mediating the rewarding effects of electrical stimulation of the medial forebrain bundle were behaviorally assessed at 5 different pulse durations. Recovery from refractoriness was inferred from the results of double-pulse tests in which the interval between conditioning (C) and test (T) pulses of equal amplitude was varied. Pulses of 0.1-0.5 ms had little effect on the time course of recovery which ranged from 0.4 to about 1.5 ms in each animal. In some subjects, however, complete recovery from refractoriness was significantly delayed with 1- and 2-ms pulses, with as much as a tripling in the C-T interval at which recovery approached asymptotic levels. This effect appeared to be placement-specific and was well correlated with the threshold charge, which ranged from 0.5 to 1.3 microC. The highest charge values were obtained in those subjects in which longer pulses displaced the refractory period profile towards a slower recovery; the electrode tips in this group were located in more anterior positions than those subjects in which pulse duration had no effect on recovery from refractoriness. It appears that at some placements slowly recovering elements can contribute to the circuitry underlying brain-stimulation reward when suitable stimulation parameters are employed.

Task difficulty increases thresholds of rewarding brain stimulation.

The effect of increasing task difficulty on the threshold of rewarding, electrical brain stimulation was evaluated. Rats were trained to press a lever to obtain a brief burst of pulses to the lateral hypothalamus. The threshold was psychophysically scaled using a descending method of limits in which the pulse frequency was varied to yield a maximum to minimum range of self-stimulation rates. As expected, weighting the lever with 0, 15, 30, or 45 g produced progressive decreases in maximal rates, but it also caused a weight-related shift to the right of the rate-frequency ogives in each of the 7 rats. Although the degree of shift varied from rat to rat, it did not matter whether criterion performance was defined as half-maximum rate or as a constant rate of 5 responses. These results suggest that the effort required to make the operant response contributes to the position of rate-frequency curves and, further, that shifts in rate-frequency functions must be interpreted with caution when such shifts are obtained by CNS lesions or drug injections.

Factors that contribute to the reduced weight gain following chronic ventromedial hypothalamic stimulation.

This report follows up our earlier finding that chronic ventromedial hypothalamic stimulation caused an inhibition of weight gain. In this study we examined the contribution of stimulation-induced activity and brown adipose tissue thermogenesis to the reduced weight gain following three sessions of low-level stimulation delivered every other day to the ventromedial hypothalamus and adjacent areas. During stimulation trials, activity level was ranked on a dichotomous scale. Weight gain and food intake were subsequently monitored for an additional 4 weeks, after which the effects of a 60-s stimulation trial on the temperature of core and interscapular brown adipose tissue were evaluated. The highest activity was associated with the ventromedial hypothalamic sites and this factor contributed significantly to the difference in weight gain and food intake resulting from stimulation of the ventromedial hypothalamus and other areas. These differences largely disappeared during the follow-up period. With little exception, none of the sites elicited temperature changes in brown adipose tissue. As demonstrated in acute work, the contribution of stimulation-induced activity must be dissociated from the metabolic changes that occur in response to ventromedial hypothalamic stimulation.

Bicuculline microinjections into the ventral tegmental area of the rat: alteration of self-stimulation thresholds and of cytochrome oxidase activity in the brain.

Abuse of drugs that potentiate GABAergic neurotransmission, namely benzodiazepines, is difficult to understand because this potentiation should elicit, among other effects, a decrease in activity within the mesolimbic system. Abuse of benzodiazepines is difficult to understand since the opposite, namely an increase in mesolimbic activity, has been implicated in drug abuse as well as in the rewarding effect of direct mesolimbic stimulation. In order to evaluate how the activity of the mesolimbic system depends on mesolimbic GABAergic influence, a GABAA receptor antagonist, bicuculline methiodide, was unilaterally injected into the ventral tegmental area and its effect on self-stimulation thresholds derived from stimulations applied to the same area was evaluated. Microinjection of 15, 20 and 30 ng increased the stimulation threshold. This decrease in stimulation efficiency lasted no more than 15 min after which baseline levels were obtained. Such a decrease is paradoxical considering that the manipulation should have released the ventral tegmentum from a tonic inhibitory influence. The metabolic consequences of repeated injections of 30 ng bicuculline were furthermore evaluated by cytochrome oxidase histochemistry. The staining was found to be weak around the injection site and dense in the ipsilateral nucleus accumbens. Release of a tonic GABAergic inhibition added to some cytotoxic damage probably resulted in an increased metabolic activity of this system. The presently reported paradoxical response of the ventral tegmentum and mesolimbic system to a GABAergic challenge may account for the paradoxical relationship between some behavioral properties of the mesolimbic system and GABAergic drugs.

Refractoriness of neurons mediating intracranial self-stimulation in the anterior basal forebrain.

The post-stimulation excitability of neurons mediating electrical self-stimulation of the anterior basal forebrain was evaluated psychophysically in the rat. Rats with electrodes in the nucleus accumbens, caudate nucleus, lateral preoptic area, diagonal band, or anterior medial forebrain bundle pressed a lever to earn 0.5-s trains of conditioning (C) and test (T) pulse pairs. The C-T interval was systematically varied and the effectiveness of the T-pulse was estimated by measuring the frequency of pulse pairs required to sustain criterion responding. All sites tested demonstrated similar recovery; T-pulse effectiveness, normalized against the effect of the C-pulse, was lowest at delays of 0.4-0.8 ms and it rose monotonically until 5 ms when it achieved an effectiveness plateau of one. Increasing the current of the T-pulse by 50 or 60% failed to hasten recovery, suggesting that the recovery profiles primarily reflect the activation of neurons very soon after emergence from absolute refractoriness. Compared to lateral hypothalamic and ventral tegmental self-stimulation, the neurons that support self-stimulation in the ventral basal forebrain recover more slowly; recovery here is only about half done by the time lateral hypothalamic placements demonstrate complete recovery.

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.

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.