Chapter 42 Behavioral Intervention
Physiologic Translation of Stress into Gastrointestinal Signs in Dogs
Moberg states that the term stress has been used so broadly in biology that no clear definition of stress has emerged.1 Stress is defined as the biologic response elicited when an individual perceives a threat to its homeostasis. Threats may be real (physical) or perceived (psychological),2 and may originate from the outside world or from within. Interoceptive stressors (e.g., gut infection, mucosal inflammation, or internal hemorrhage) may be seen as simple reflex responses, mediated at a subcortical level by the system involved in the processing of visceral information. Exteroceptive stressors (psychological), on the other hand, engage circuits in the limbic forebrain including the lateral and medial prefrontal cortex, hippocampus, and amygdala.2 These responses are adaptive and serve to maintain the stability of the internal environment and ensure the survival of the organism. In the healthy individual, the physiologic response systems are rapidly turned on and off, synchronizing the physiologic stress response to the duration of the stressor, and limiting exposure time of the organism to potentially harmful effects of the stress response.2 There are situations, however, in which the severity or duration of the stressor and resulting physiologic responses can cause damage, exacerbate existing disease processes, or predispose the individual to acquire new disease. These responses become maladaptive.
Researchers have relied on a variety of endocrine, behavioral, autonomic nervous system, and immunologic parameters to assess stress.3–11 In fasted dogs, 90-dB music produces inhibition of gastric motility along with increases in heart rate and plasma cortisol,12 and is therefore considered an example of acoustic stress. One hour of acoustic stress, associated with a fourfold increase in plasma cortisol, delays the appearance of the next gastric, but not jejunal, migrating motor complex (MMC) by 75%. Acoustic stress–induced inhibition of the gastric MMC is completely abolished with prior administration of diazepam (0.2 to 0.5 mg/kg IM) or muscimol (10 µg/kg IV) and partially abolished with lower doses of diazepam (0.1 mg/kg). Gastric MMC inhibition is unaffected by naloxone (0.1 mg/kg IM), phentolamine (0.2 mg/kg IV), or propranolol (0.1 mg/kg IV) treatment. Muscimol, a GABAergic receptor agonist, and diazepam (a benzodiazepine that interacts at the receptor level and potentiates the effects of endogenous γ-aminobutyric acid [GABA]) may act at the central or peripheral level to block the effect of noise on gastric motility. In a different study,13 intracerebroventricular administration of ovine corticotropin-releasing factor (CRF) (100 ng/kg) in dogs also delayed the appearance of gastric MMC without affecting jejunal motility and this effect was not antagonized by previous administration of diazepam or muscimol. The effects of acoustic stress and CRF on gastric motility were both abolished after bilateral thoracic vagotomy. Consequently, the suppressive action of diazepam and muscimol on noise-induced gastric hypomotility may be related to blockade of the acoustic stress–induced CRF release.
A high prevalence of gastric lesions have been reported in racing Alaskan sled dogs.14 Endoscopic examination of 70 dogs that participated in the 2001 Iditarod race revealed that 34 dogs (48.5%) had gastric ulceration, erosion, hemorrhage, or some combination of these findings. Gastric disease in racing sled dogs has been attributed to bacterial pathogens, ingested foreign bodies, ulcerogenic drugs (usually banned during races), exercise-induced ischemia (although mesenteric blood flow was unchanged during vigorous exercise in one study15), and stress. Exercise on a treadmill at low and high intensity (4.2 miles/h with a 6% or 20% incline) has been shown to increase serum cortisol concentrations in dogs.16
Interaction of Corticotropin-Releasing Factor and Monoaminergic Systems
CRF is the principal neuroendocrine substance regulating adrenocorticotropic hormone secretion, and is involved in inflammatory responses of the gut via vagal and peripheral pathways.17 CRF mediates stress influences on the gastrointestinal (GI) tract either centrally (hypothalamic–pituitary–adrenal [HPA] axis) or peripherally via local CRF-based paracrine activity. CRF is also implicated in many behavioral responses. Physiologic and behavioral responses observed during stress can be induced by exogenous administration of CRF and α1-adrenergic agonists.18 Psychological stress triggers sympathetic activation and favors inflammatory reactions, which is associated with concurrent activation of the HPA axis. To date, it is unclear whether stress is the cause or consequence of inflammatory bowel disease development in humans.17
CRF immunoreactivity has been demonstrated in the raphe nuclei and the locus coeruleus, two areas of origin of the major serotonergic and noradrenergic pathways in the brain. Thus CRF may play a role in modulating these monoaminergic systems that have been implicated in the pathophysiology of depression and anxiety.19 Dysregulation of signaling by CRF may contribute to the etiology and pathophysiology of stress-related neuropsychiatric disorders in people. Activation of serotonergic systems plays an important role in several behaviors that are influenced by CRF, including behavioral arousal, motor activity, and facilitation of anxiety-related behaviors. In a recent study in rats,20 intracerebroventricular injections of CRF (1 µg) increased several measures of behavioral activity, including total activity, locomotion, and spontaneous nonambulatory motor activity such as visual scanning of the environment, head movements associated with sniffing, shifts in body position, and lateral or vertical movements of the forelimbs. Treatment with fluoxetine,20 a selective serotonin reuptake inhibitor (SSRI), prevented CRF-induced increases in spontaneous nonambulatory motor activity at all doses (0.1 mg/kg; 1 mg/kg; 10 mg/kg). These effects were most apparent during a 40- to 70-minute time period when CRF-induced behavioral activity was most pronounced. The data of this study support an interaction between CRF and serotonergic systems in the regulation of emotional behavior. These data do not exclude a role of other brainstem neuromodulatory systems such as the noradrenergic systems. Given that the behavioral consequences of CRF are similar to the behavioral consequences of anxiogenic drugs,21 therapeutic effects of fluoxetine and other SSRIs may involve attenuation or prevention of the effects of aversive or anxiogenic stimuli on CRF-induced stress- or anxiety-related emotional states and behavior.20