Behavioral Arousal Research Articles

A Noradrenergic Mechanism Functions to Couple Motor Behavior with Arousal State

Appropriate levels of skeletal muscle tone are needed to support routine motor behaviors. But, the brain mechanisms that function to couple muscle tone with waking behaviors are unknown. We addressed this question by studying mice with cataplexy--a condition caused by a decoupling of motor and arousal behaviors. Cataplexy is characterized by involuntary loss of muscle tone during wakefulness, which results in postural collapse during otherwise normal consciousness. Cataplexy is caused by loss of hypocretin (orexin) cells, but it is unknown how this loss triggers motor inactivity during cataplexy. Here, we used hypocretin knockout mice to identify the neurochemical cause of cataplexy and to determine the biochemical mechanisms that normally function to couple arousal and motor systems. Using genetic, behavioral, electrophysiological, and pharmacological approaches, we show that the noradrenergic system acts to synchronize motor and arousal systems. Specifically, we show that an excitatory noradrenergic drive maintains postural muscle tone during wakefulness by activating α1 receptors on skeletal motoneurons. Loss of this normal excitatory drive triggers motor inactivity during cataplexy by reducing motoneuron excitation. However, loss of this drive does not affect arousal since mice remain awake during cataplexy, suggesting the noradrenergic system is not required for maintaining wakefulness. Artificial restoration of noradrenergic drive to motoneurons prevents motor inactivity and rescues cataplexy. We conclude that hypocretin deficiency causes cataplexy by short-circuiting the noradrenergic drive to skeletal motoneurons. We suggest that the noradrenergic system functions to couple the brain systems that control postural muscle tone and behavioral arousal state.

Orexins (hypocretins) contribute to fear and avoidance in rats exposed to a single episode of footshocks

Orexins (hypocretins) are peptides that have been shown to regulate behavioral arousal and wakefulness. Recent evidence indicates that orexin neurons are activated by stress and that orexins play a role in anxiety. The present paper describes a series of experiments that examined whether orexins are involved in the anxiety that resulted from exposing rats to an acute episode of footshocks (5×2s of 1.5mA shocks). We found that prepro-orexin (ppOX) mRNA was elevated in rats at 6 and 14days after exposure to footshock and that ppOX mRNA levels were correlated with fear at 14days post-shock. Systemic injections of the non-selective dual orexin receptor antagonist TCS-1102 (10 and 20mg/kg, i.p.) were found to decrease fear and anxiety in rats 14days after exposure to footshock. We also found that rats that exhibited a high level of immobility to a novel tone the day after the footshock episode (high responders, HR) showed significantly elevated levels of ppOX mRNA at 14days post-shock compared to control rats. Furthermore, TCS-1102 (10mg/kg, i.p.) was found to have anxiolytic effects that were specific for HR when tested in the elevated T-maze. This study provides evidence linking the orexin system to the anxiety produced by exposure of rats to a single episode of footshocks. It also provides preclinical evidence in support of the use of orexin antagonists for the treatment of anxiety in response to an acute episode of stress.

Neuropeptide W increases mean arterial pressure as a result of behavioral arousal

Neuropeptide W (NPW), an endogenous ligand for G protein-coupled receptors NPBWR1 (GPR7) and NPBWR2 (GPR8), has been detected in neurons in limbic and reticular activating system areas known to be important in arousal, as well as hypothalamic nuclei known to be important in food and water intake and the neuroendocrine response to stress. In rat, central administration of NPW increased mean arterial pressure (MAP) and behaviors associated with locomotion and grooming. We hypothesized that the NPW-induced increase in MAP was secondary to those increases in physical activity. Since peptides that stimulate arousal have been shown to increase sympathetic activity (e.g., orexin), we tested the ability of the mixed α1- and α2-adrenergic antagonist, phentolamine, to block the NPW-23-induced rise in MAP. Phentolamine pretreatment abrogated the NPW-induced MAP increase. However, we noticed the animals no longer exhibited NPW-associated behavioral arousal when pretreated with phentolamine. Anesthesia also blocked the NPW-induced increase in MAP, although the animals still were able to respond with an increase in MAP to centrally administered ANG II. Additionally, pretreatment with an orexin type 1 receptor antagonist significantly reduced the behavioral action of NPW-23 and completely blocked the peptide's action to increase MAP, suggesting that orexin neurons are downstream targets of NPW. Our results suggest that NPW increased MAP secondary to increased behavioral arousal.

Evaporative water loss, spatial distributions, and survival in white-nose-syndrome-affected little brown myotis: a model

Many temperate bat species deal with harsh winter conditions by hibernating. Brief periods of arousal from torpor occur at regular intervals throughout hibernation, although energetically costly. Factors that increase arousal frequency, such as the recently discovered white-nose syndrome (WNS), can thereby greatly decrease survival rates of overwintering bats. Evidence increasingly suggests that evaporative water loss (EWL) may be an important driver of arousal behavior in infected bats. We examined the role that EWL could play in torpor arousals and energy expenditures by developing an individual-based energetics model using EWL as the stimulus for arousal in populations of healthy and WNS-affected little brown myotis (Myotis lucifugus). Our model also examined how EWL could affect spatial distributions of healthy and infected bats within a cave throughout winter. We calculated mean torpor bout duration and survival of populations that inhabited 2 modeled caves typical of both northern and midrange hibernacula. In a northern cave, the mean torpor bout duration was 19.97 days 6 5.49 SD between arousals for healthy bats and 8.60 6 2.11 days for WNS-affected bats, accompanied by survival rates of 0.80 6 0.07 SD (healthy) and 0.04 6 0.02 (infected). In a midrange cave, the mean torpor bout duration was 20.88 6 6.22 days for healthy bats and 8.88 6 2.47 for infected bats, and survival rates were 0.98 6 0.02 (healthy) and 0.55 6 0.05 (infected). When bats clustered, survival rates increased in both healthy and diseased populations; however, slight changes in relative humidity or the rate of EWL from infected skin counteracted these advantages. We show that, by causing an increase in arousal rates, EWL could play an important role in the pathology of WNS. Additionally, populations experiencing shorter southern winters could persist longer than their northern counterparts when faced with WNS, a fact that could be critical in maintaining viable populations for WNS-vulnerable species.

Analysis of NPR-1 Reveals a Circuit Mechanism for Behavioral Quiescence in C. elegans

Animals undergo periods of behavioral quiescence and arousal in response to environmental, circadian, or developmental cues. During larval molts, C. elegans undergoes a period of profound behavioral quiescence termed lethargus. Locomotion quiescence during lethargus was abolished in mutants lacking a neuropeptide receptor (NPR-1) and was reduced in mutants lacking NPR-1 ligands (FLP-18 and FLP-21). Wild-type strains are polymorphic for the npr-1 gene, and their lethargus behavior varies correspondingly. Locomotion quiescence and arousal were mediated by decreased and increased secretion of an arousal neuropeptide (PDF-1) from central neurons. PDF receptors (PDFR-1) expressed in peripheral mechanosensory neurons enhanced touch-evoked calcium transients. Thus, a central circuit stimulates arousal from lethargus by enhancing the sensitivity of peripheral mechanosensory neurons in the body. These results define a circuit mechanism controlling a developmentally programmed form of quiescence.

Psychometric properties of the Adolescent Sleep Hygiene Scale

This study evaluated the psychometric properties of the Adolescent Sleep Hygiene Scale (ASHS), a self-report measure assessing sleep practices theoretically important for optimal sleep. Data were collected on a community sample of 514 adolescents (16-19; 17.7±0.4years; 50% female) participating in the late adolescent examination of a longitudinal study on sleep and health. Sleep hygiene and daytime sleepiness were obtained from adolescent reports, behavior from caretaker reports, and sleep-wake estimation on weekdays from wrist actigraphy. Confirmatory factor analysis indicated the empirical and conceptually based factor structure were similar for six of the eight proposed sleep hygiene domains. Internal consistency of the revised scale (ASHSr) was α=0.84; subscale alphas were: physiological: α=0.60; behavioural arousal: α=0.62; cognitive/emotional: α=0.81; sleep environment: α=0.61; sleep stability: α=0.68; daytime sleep: α=0.78. Sleep hygiene scores were associated positively with sleep duration (r=0.16) and sleep efficiency (r=0.12) and negatively with daytime sleepiness (r=-0.26). Results of extreme-groups analyses comparing ASHSr scores in the lowest and highest quintile provided further evidence for concurrent validity. Correlations between sleep hygiene scores and caretaker reports of school competence, internalizing and externalizing behaviours provided support for convergent validity. These findings indicate that the ASHSr has satisfactory psychometric properties for a research instrument and is a useful research tool for assessing sleep hygiene in adolescents.

Probabilistic models of expectation violation predict psychophysiological emotional responses to live concert music

We present the results of a study testing the often-theorized role of musical expectations in inducing listeners' emotions in a live flute concert experiment with 50 participants. Using an audience response system developed for this purpose, we measured subjective experience and peripheral psychophysiological changes continuously. To confirm the existence of the link between expectation and emotion, we used a threefold approach. (1) On the basis of an information-theoretic cognitive model, melodic pitch expectations were predicted by analyzing the musical stimuli used (six pieces of solo flute music). (2) A continuous rating scale was used by half of the audience to measure their experience of unexpectedness toward the music heard. (3) Emotional reactions were measured using a multicomponent approach: subjective feeling (valence and arousal rated continuously by the other half of the audience members), expressive behavior (facial EMG), and peripheral arousal (the latter two being measured in all 50 participants). Results confirmed the predicted relationship between high-information-content musical events, the violation of musical expectations (in corresponding ratings), and emotional reactions (psychologically and physiologically). Musical structures leading to expectation reactions were manifested in emotional reactions at different emotion component levels (increases in subjective arousal and autonomic nervous system activations). These results emphasize the role of musical structure in emotion induction, leading to a further understanding of the frequently experienced emotional effects of music.

Partial antagonism of propofol anaesthesia by physostigmine in rats is associated with potentiation of fast (80–200 Hz) oscillations in the thalamus

Positron emission tomography studies in human subjects show that propofol-induced unconsciousness in humans is associated with a reduction in thalamic blood flow, suggesting that anaesthesia is associated with impairment of thalamic function. A recent study showed that antagonism of propofol-induced unconsciousness by the anticholinesterase physostigmine is associated with a marked increase in thalamic blood flow, supporting the implication of the thalamus. The aim of the present study was to assess the role of the thalamus in the antagonistic effects of physostigmine during propofol anaesthesia using electrophysiological recordings in a rat model. Local field potentials were recorded from the barrel cortex and ventroposteromedial thalamic nucleus in 10 chronically instrumented rats to measure spectral power in the gamma/high-gamma range (50-200 Hz). Propofol was given i.v. by target-controlled infusion at the lowest concentration required to abolish righting attempts. Physostigmine was given during anaesthesia to produce behavioural arousal without changing anaesthetic concentration. Compared with baseline, gamma/high-gamma power during anaesthesia was reduced by 31% in the cortex (P=0.006) and by 65% in the thalamus (P=0.006). Physostigmine given during anaesthesia increased gamma/high-gamma power in the thalamus by 60% (P=0.048) and caused behavioural arousal that correlated (P=0.0087) with the increase in power. Physostigmine caused no significant power change in the cortex. We conclude that partial antagonism of propofol anaesthesia by physostigmine is associated with an increase in thalamic activity reflected in gamma/high-gamma (50-200 Hz) power. These findings are consistent with the view that anaesthetic-induced unconsciousness is associated with impairment of thalamic function.

Enhanced Avoidance Habits in Obsessive-Compulsive Disorder

BackgroundObsessive-compulsive disorder (OCD) is a psychiatric condition that typically manifests in compulsive urges to perform irrational or excessive avoidance behaviors. A recent account has suggested that compulsivity in OCD might arise from excessive stimulus-response habit formation, rendering behavior insensitive to goal value. We tested if OCD patients have a bias toward habits using a novel shock avoidance task. To explore how habits, as a putative model of compulsivity, might relate to obsessions and anxiety, we recorded measures of contingency knowledge, explicit fear, and physiological arousal.MethodsTwenty-five OCD patients and 25 control subjects completed a shock avoidance task designed to induce habits through overtraining, which were identified using goal-devaluation. The relationship between habitual behavior, erroneous cognitions, and physiological arousal was assessed using behavior, questionnaires, subjective report, and skin conductance responses.ResultsA devaluation sensitivity test revealed that both groups could inhibit unnecessary behavioral responses before overtraining. Following overtraining, OCD patients showed greater avoidance habits than control subjects. Groups did not differ in conditioned arousal (skin conductance responses) at any stage. Additionally, groups did not differ in contingency knowledge or explicit ratings of shock expectancy following the habit test. Habit responses were associated with a subjective urge to respond.ConclusionsThese data indicate that OCD patients have a tendency to develop excessive avoidance habits, providing support for a habit account of OCD. Future research is needed to fully characterize the causal role of physiological arousal and explicit fear in habit formation in OCD.

Development × environment interactions control tph2 mRNA expression

Adverse early life experience is thought to increase an individual’s susceptibility to mental health disorders, including anxiety and affective disorders, later in life. Our previous studies have shown that post-weaning social isolation of female rats during a critical period of development sensitizes an anxiety-related serotonergic dorsal raphe nucleus (DR) system in adulthood. Therefore, we investigated how post-weaning social isolation, in combination with a challenge with the anxiogenic drug, N-methyl-beta-carboline-3-carboxamide (FG-7142; a partial inverse agonist at the benzodiazepine allosteric site on the GABAA receptor), affects home cage behavior and serotonergic gene expression in the DR of female rats using in situ hybridization histochemistry. Juvenile female rats were reared in isolation or groups of three for a 3-week period from weaning (postnatal day (PD) 21 to mid-adolescence (PD42)), after which all rats were group-reared for an additional 16days until adulthood. Among vehicle-treated rats, isolation-reared rats had decreased rodent tryptophan hydroxylase 2 (tph2) mRNA expression in ventral and ventrolateral subdivisions of the DR, a pattern observed previously in a rat model of panic disorder. Isolation-reared rats, but not group-reared rats, responded to FG-7142 with increased duration of vigilance and arousal behaviors. In addition, FG-7142 decreased tph2 expression, measured 4h following treatment, in multiple subregions of the DR of group-reared rats but had no effect in isolation-reared rats. No treatment effects were observed on 5-HT1A receptor or serotonin transporter gene expression. These data suggest that adolescent social isolation alters tph2 expression in specific subregions of the DR and alters the effects of stress-related stimuli on behavior and serotonergic systems.

Adenosine A1 Receptors in Mouse Pontine Reticular Formation Depress Breathing, Increase Anesthesia Recovery Time, and Decrease Acetylcholine Release

Clinical and preclinical data demonstrate the analgesic actions of adenosine. Central administration of adenosine agonists, however, suppresses arousal and breathing by poorly understood mechanisms. This study tested the two-tailed hypothesis that adenosine A1 receptors in the pontine reticular formation (PRF) of C57BL/6J mice modulate breathing, behavioral arousal, and PRF acetylcholine release. Three sets of experiments used 51 mice. First, breathing was measured by plethysmography after PRF microinjection of the adenosine A1 receptor agonist N-sulfophenyl adenosine (SPA) or saline. Second, mice were anesthetized with isoflurane and the time to recovery of righting response (RoRR) was quantified after a PRF microinjection of SPA or saline. Third, acetylcholine release in the PRF was measured before and during microdialysis delivery of SPA, the adenosine A1 receptor antagonist 1, 3-dipropyl-8-cyclopentylxanthine, or SPA and 1, 3-dipropyl-8-cyclopentylxanthine. First, SPA significantly decreased respiratory rate (-18%), tidal volume (-12%), and minute ventilation (-16%). Second, SPA concentration accounted for 76% of the variance in RoRR. Third, SPA concentration accounted for a significant amount of the variance in acetylcholine release (52%), RoRR (98%), and breathing rate (86%). 1, 3-dipropyl-8-cyclopentylxanthine alone caused a concentration-dependent increase in acetylcholine, a decrease in RoRR, and a decrease in breathing rate. Coadministration of SPA and 1, 3-dipropyl-8-cyclopentylxanthine blocked the SPA-induced decrease in acetylcholine and increase in RoRR. Endogenous adenosine acting at adenosine A1 receptors in the PRF modulates breathing, behavioral arousal, and acetylcholine release. The results support the interpretation that an adenosinergic-cholinergic interaction within the PRF comprises one neurochemical mechanism underlying the wakefulness stimulus for breathing.

The motor cortex: a network tuned to 7-14 Hz

The neocortex or six layer cortex consists of at least 52 cytoarchitectonically distinct areas in humans, and similar areas can be distinguished in rodents. Each of these areas has a defining set of extrinsic connections, identifiable functional roles, a distinct laminar arrangement, etc. Thus, neocortex is extensively subdivided into areas of anatomical and functional specialization, but less is known about the specialization of cellular and network physiology across areas. The motor cortex appears to have a distinct propensity to oscillate in the 7–14 Hz frequency range. Augmenting responses, normal mu and beta oscillations, and abnormal oscillations or after discharges caused by enhancing excitation or suppressing inhibition are all expressed around this frequency range. The substrate for this activity may be an excitatory network that is unique to the motor cortex or that is more strongly suppressed in other areas, such as somatosensory cortex. Interestingly, augmenting responses are dependent on behavioral state. They are abolished during behavioral arousal. Here, I briefly review this evidence.

Have we missed that neural vasodilator mechanisms may contribute to exercise hyperemia at onset of voluntary exercise?

Whether neurally-mediated vasodilatation may contribute to exercise hyperemia has not been completely understood. Bülbring and Burn (1935) found for the first time the existence of sympathetic cholinergic nerve to skeletal muscle contributing to vasodilatation in animals. Blair et al. (1959) reported that atropine-sensitive vasodilatation in skeletal muscle appeared during arousal behavior or mental stress in humans. However, such sympathetic vasodilator mechanism for muscle vascular bed in humans is generally denied at present, because surgical sympathectomy, autonomic blockade, and local anesthesia of sympathetic nerves cause no substantial influence on vasodilatation in muscle not only during mental stress but also during exercise. On the other hand, neural mechanisms may play an important role in regulating blood flow to non-contracting muscle. Careful consideration of the neural mechanisms may lead us to an insight about a possible neural mechanism responsible for exercise hyperemia in contracting muscle. Referring to our recent study measuring muscle tissue blood flow with higher time resolution, this review has focused on whether or not central command may transmit vasodilator signal to skeletal muscle especially at the onset of voluntary exercise.

Abstract: Modeling Change in a Correlation Over Time Within an SEM Framework

Many theoretical frameworks concerning romantic couples suggest that partners' behavior, mood, and physiological arousal will align as they interact. Evidence for these notions is typically provide...

Conflicted Emotions Following Trust-Based Interaction

We observed reports of conflicted (concurrent positive and negative) emotions activated after interactions in the Trust game. Our analyses reveal that activation of 20 emotional states following trust-based interaction is better explained by predictions derived from a multi-dimensional Recalibrational perspective than by predictions derived from two-dimensional Valence and Arousal perspectives. The Recalibrational perspective proposes that emotions are activated according to their functional features – for example, emotions help people achieve short or long-sighted goals by up or down-regulating behavioral propensities, whereas Valence and Arousal perspectives consider simpler hedonic dimensions lacking functional specificity. The Recalibrational perspective is also distinguished from the Valence and Arousal perspectives in that it predicts the possibility of conflicted emotions. We discuss the theoretical implications of having conflicted goals and the economic implications of having conflicted emotions.

Situationally appropriate behavior: translating situations into appetitive behavior modes

If an organism's responding to its present location or more abstract situation is similar to its responding to discrete motivationally salient stimuli, then principles of stimulus-response relationships and their acquisition may apply to the organization of behavior that appears to be sensitive and appropriate to the organism's external context. Locations or situations become motivationally salient, insofar as they acquire the ability to compel the organism to obtain a specific type of reward through more or less constrained exploratory or foraging behavior. The ventral hippocampus is proposed to play a key role in linking a salient situation or location with an appropriate mode of behavior, whereas allocentric information predicted and updated by the dorsal hippocampus may be associated with, or translated into, a sequence of orienting and locomotor actions. The impact of ventral hippocampal representations of salient situations on behavior is mediated by the ventral subiculum, ventromedial prefrontal cortex, and ventral striatum. Projecting via the ventral subiculum to the ventromedial prefrontal cortex and ventral striatum, the ventral hippocampus maps motivationally salient environmental information, as well as emotional information reflective of the internal physiological milieu, onto an instrumental or emotional behavior mode that represents a specialized, more or less purposeful, state of behavioral arousal and global locomotor activation.

Pre-treatment of BALB/c mice with a centrally acting serotonin antagonist (Cyproheptadine) reduces mortality from Boophone Disticha poisoning

Introduction. Crude extracts of Boophone disticha are used in Southern African traditional medical practice for the management of various illnesses and conditions and have also been abused for their claimed euphoric and hallucinogenic effects. Unfortunately, ingestion of Boophone disticha has resulted in toxicity and death. The results of a recent acute toxicity study in a rat model insinuated that central nervous system (CNS) serotonin overdrive could be the cause of toxicity in B. disticha poisoning. The present work sought to test that hypothesis by investigating whether pre-treatment of B. disticha poisoned BALB/c mice with the CNS acting serotonin antagonist, cyproheptadine, has a dose-dependent protective effect on toxicity and mortality. Methods. A hydroethanolic extract of B. disticha was used in all the experiments. Five groups each with 10 animals were constituted as follows; a negative control group (received 10 ml/kg Normal Saline), a positive control group (received 375 mg/kg of the B. disticha extract), and three test groups each receiving 10 mg/kg, 15 mg/kg and 20 mg/kg cyproheptadine intraperitoneally 15 minutes before oral gavage administration of 375 mg/kg B. disticha extract respectively. The Functional Observational Battery was used to evaluate neurobehavioral and physiological changes resulting from toxicity of the plant extract. The mice were then placed in an open field for another five minutes and the number of rearings and border crossings were counted and recorded. Gait abnormalities, involuntary motor movements, mobility, arousal and stereotypical behavior were also scored according to predefined criteria. All open field investigations were recorded electronically using a LABTEC Webcam® and results were later analysed and recorded by one of the group members. All results were entered on data collection forms. Time to death (survival time) was considered as the time period from dosage with Boophone disticha to time of death. The study follow up period was 7 days and those mice that were alive at the end of the 7 day follow-up period were considered as having survived the poisoning episode. The Kaplan Meier plot and Log-rank test were used to compare differences in mortality and median time to death for mice in the 5 treatment groups. Results. We found that cyproheptadine pre-treatment led to a dose-dependent decrease in mortality from 80% in the group not pre-treated with cyproheptadine, to 30% in the 15 and 20 mg/kg cyproheptadine pre-treated groups (n = 10 per group, p < 0.05). There was also a dose-dependent increase in median survival times amongst the groups (p < 0.0001). Pre-treatment with cyproheptadine also resulted in a decrease of other toxic symptoms associated with Boophone disticha. Conclusions. We conclude that cyproheptadine has a dose-dependent protective effect on mortality and toxicity produced by exposure to Boophone disticha in our mouse model of toxicity.

Antagonism of the neuropeptide S receptor with RTI-118 decreases cocaine self-administration and cocaine-seeking behavior in rats

Neuropeptide S (NPS) is a neuromodulatory peptide, acting via a G-protein-coupled receptor to regulate sleep, anxiety and behavioral arousal. Recent research has found that intracerebroventricular NPS can increase cocaine and alcohol self-administration in rodents, suggesting a key role in reward-related neurocircuitry. It is hypothesized that antagonism of the NPS system might represent a novel strategy for the pharmacological treatment of cocaine abuse. To this end, a small-molecule NPSR antagonist (RTI-118) was developed and tested in animal models of cocaine seeking and cocaine taking. Male Wistar rats (n=54) trained to self-administer cocaine and food under a concurrent alternating FR4 schedule exhibited specific dose-dependent decreases in cocaine intake when administered RTI-118. RTI-118 also decreased the reinstatement of extinguished cocaine-seeking behavior induced by conditioned cues, yohimbine and a priming dose of cocaine. These data support the hypothesis that antagonism of the neuropeptide S receptor may ultimately show efficacy in reducing cocaine use and relapse.

SEB‐3, a CRF receptor‐like GPCR, regulates locomotor activity states, stress responses and ethanol tolerance in Caenorhabditiselegans

The CRF (corticotropin-releasing factor) system is a key mediator of the stress response. Alterations in CRF signaling have been implicated in drug craving and ethanol consumption. The development of negative reinforcement via activation of brain stress systems has been proposed as a mechanism that contributes to alcohol dependence. Here, we isolated a gain-of-function allele of seb-3, a CRF receptor-like GPCR in Caenorhabditis elegans, providing an in vivo model of a constitutively activated stress system. We also characterized a loss-of-function allele of seb-3 and showed that SEB-3 positively regulates a stress response that leads to an enhanced active state of locomotion, behavioral arousal and tremor. SEB-3 also contributed to acute tolerance to ethanol and to the development of tremor during ethanol withdrawal. Furthermore, we found that a specific CRF(1) receptor antagonist reduced acute functional tolerance to ethanol in mice. These findings demonstrate functional conservation of the CRF system in responses to stress and ethanol in vertebrates and invertebrates.

147. Neural correlates of persistent fatigue-like behavior in cancer chemotherapy-treated rats

Reduced behavioral activity during acute illness in rats, likely indicative of fatigue, is dependent upon signaling from brainstem catecholamine neurons in the ventrolateral medulla (VLM) and nucleus of the solitary tract (NTS) that can drive hypothalamic and midbrain arousal systems. Cancer chemotherapy induces mood and behavior/activity disturbances similar to those seen in acute illness, and acute chemotherapy-induced fatigue and mood disturbance shares common neurological substrates with immune challenges such as LPS. Fatigue persists in many patients, and we hypothesized that persistent fatigue may be associated with persistent activation of the brainstem catecholamine pathway and suppression of arousal. To explore whether brainstem catecholamine neurons could be involved in persistent fatigue associated with cancer chemotherapy, we treated middle-aged female rats with six injections of cancer chemotherapy (Cytoxan/Doxirubicin). Four weeks after cessation of chemotherapy, 50% of the rats showed evidence of persistent fatigue, based in decreased voluntary wheel running and reduced behavior in the open field and elevated plus maze, in line with the 30–40% of human cancer patients reporting symptoms of persistent fatigue. Like acutely immune challenged animals, fatigue symptoms following cancer chemotherapy were associated with activation of brainstem catecholamine neurons, which was absent in rats that did not show evidence of “fatigue”. These findings suggest that fatigue symptoms may follow from persistent drive on brainstem neurons that modulate brain arousal systems and behavior.