Dalfampridine improves sensorimotor function in rats with chronic deficits after middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: Stroke survivors often have permanent deficits that are only partially addressed by physical therapy. This study evaluated the effects of dalfampridine, a potassium channel blocker, on persistent sensorimotor deficits in rats with treatment initiated 4 or 8 weeks after stroke. METHODS: Rats underwent permanent middle cerebral artery occlusion. Sensorimotor function was measured using limb-placing and body-swing symmetry tests, which normally show a partial recovery from initial deficits that plateaus ≈4 weeks after permanent middle cerebral artery occlusion. Dalfampridine was administered starting at 4 or 8 weeks after permanent middle cerebral artery occlusion in 2 blinded, vehicle-controlled studies. Plasma samples were collected and brain tissue was processed for histologic assessment. RESULTS: Dalfampridine treatment (0.5-2.0 mg/kg) improved forelimb- and hindlimb-placing responses and body-swing symmetry in a reversible and dose-dependent manner. Plasma dalfampridine concentrations correlated with dose. Brain infarct volumes showed no differences between treatment groups. CONCLUSIONS: Dalfampridine improves sensorimotor function in the rat permanent middle cerebral artery occlusion model. Dalfampridine extended-release tablets (prolonged release fampridine outside the United States) are used to improve walking in patients with multiple sclerosis, and these preclinical data provide a strong rationale for examining the potential of dalfampridine to treat chronic stable deficits in stroke patients. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01605825.

Fenfluramine challenge, self-injurious behavior, and aggression in rhesus monkeys.

Self-injurious behavior (SIB) and aggression have been linked to reduced serotonergic (5-HT) functioning in both humans and nonhuman primates. The present study examined serum prolactin and cortisol responses to the 5-HT releasing agent D,L-fenfluramine (FEN) in 24 individually housed rhesus monkeys (Macaca mulatta), 15 of which carried a veterinary record of self-wounding (SW). Subjects received two doses of FEN, 4 and 2 mg/kg, separated by an interval of at least 2 months. For control purposes, monkeys were given an intramuscular saline injection 1 week prior to each FEN challenge. The relationship between the hormonal responses to FEN, wounding history, the rates of self-directed biting and aggression were determined for each animal based on 100 five-minute observations conducted over a period of 12 months surrounding the challenge procedures. Prolactin and cortisol responses to FEN were unrelated either to wounding history or to rates of self-directed biting. However, there were significant inverse correlations between levels of aggression and the prolactin response to both doses of FEN. The present findings provide no evidence for reduced 5-HT system function in rhesus monkeys with SIB under the present challenge conditions. However, the results are consistent with a previously reported inverse relationship between serotonergic activity and aggression. Moreover, a dose-dependent response to FEN was observed only for prolactin, suggesting that this variable is more appropriate than cortisol as an endpoint for FEN challenge in monkeys.

The anxiogenic drug FG7142 increases self-injurious behavior in male rhesus monkeys (Macaca mulatta).

AIMS: Self-injurious behavior (SIB), which is deliberate infliction of self-injury without suicidal intent, is a significant human health problem. SIB is not unique to humans but is also manifested in a small percentage of captive macaques, typically as self-directed biting. Although the onset and maintenance of SIB have been linked to increased anxiety in both humans and nonhuman primates, no previous studies have directly tested the anxiety-SIB hypothesis. Here, we determined whether rhesus monkeys increase their self-directed biting following a challenge with the anxiogenic compound N-methyl-beta-carboline-3-carboxamide (FG7142). MAIN METHODS: Ten rhesus monkeys (Macaca mulatta) with a veterinary record of self-wounding (SIB) as well as six age- and weight-matched non-wounding control monkeys were given intramuscular injections of 0.1, 0.3, or 1.0mg/kg FG7142. Behavior was observed following drug administration with special attention to displacement behaviors (scratching, self-grooming, and yawning), locomotor stereotypy, and self-directed biting. Plasma cortisol and ACTH were also measured as physiological indices of stress. KEY FINDINGS: Self-directed biting rates dose-dependently increased in a subset of SIB monkeys, but did not change in control animals. Furthermore, administration of FG7142 led to an increase in scratching, yawning, and locomotor stereotypy in all monkeys, but did not affect the frequency self-grooming. Additionally, there was a dose-dependent increase in plasma cortisol concentrations, but not ACTH, in all animals. SIGNIFICANCE: The present findings indicate that self-biting is anxiety-related in some but not all SIB monkeys, suggesting that this behavioral pathology is heterogeneous as has previously been suggested for SIB in humans.

A rhesus monkey model of self-injury: effects of relocation stress on behavior and neuroendocrine function.

BACKGROUND: Self-injurious behavior (SIB), a disorder that afflicts many individuals within both clinical and nonclinical populations, has been linked to states of heightened stress and arousal. However, there are no published longitudinal data on the relationship between increases in stress and changes in the incidence of SIB. This study investigated the short- and long-term behavioral and neuroendocrine responses of SIB and control monkeys to the stress of relocation. METHODS: Twenty adult male rhesus macaques were exposed to the stress of relocation to a new housing arrangement in a newly constructed facility. Daytime behavior, sleep, and multiple measures of hypothalamic-pituitary-adrenocortical (HPA) axis function were investigated before and after the move. RESULTS: Relocation induced a complex pattern of short- and long-term effects in the animals. The SIB animals showed a long-lasting increase in self-biting behavior, as well as evidence of sleep disturbance. Both groups exhibited elevated cortisol levels in saliva, serum, and hair, and also an unexpected delayed increase in circulating concentrations of corticosteroid binding globulin (CBG). CONCLUSIONS: Our results indicate that relocation is a significant stressor for rhesus macaques and that this stressor triggers an increase in self-biting behavior as well as sleep disturbance in monkeys previously identified as suffering from SIB. These findings suggest that life stresses may similarly exacerbate SIB in humans with this disorder. The HPA axis results underscore the potential role of CBG in regulating long-term neuroendocrine responses to major stressors.

Analysis of endogenous cortisol concentrations in the hair of rhesus macaques.

Short-term changes in activity of the hypothalamic-pituitary-adrenocortical (HPA) system are routinely assessed by measuring glucocorticoid or metabolite concentrations in plasma, saliva, urine, or feces. However, there are no current methods for determining long-term (i.e., weeks or months) activity of this system. Herein, we describe the development and validation of a simple procedure for measuring cortisol concentrations in the hair of rhesus macaques. This procedure involves two brief isopropanol washes of the hair strands to remove surface contaminants, subsequent powdering of the washed and dried hair, a 24-h methanol extraction followed by evaporation of the solvent and reconstitution of the extract in assay buffer, and finally analysis of the extracted cortisol by a sensitive and specific enzyme immunoassay. Our results confirm the specificity of the procedure for cortisol, show that proximal and distal segments of hair do not differ in their cortisol concentration, and demonstrate that a significant and prolonged stressful experience produces a significant increase in hair cortisol. This new procedure should be valuable for assessing baseline HPA activity in nonhuman primates (and, with appropriate validation, in other species as well) over relatively long periods of time, and also for monitoring chronic stress that might be associated with various experimental manipulations.

Disinhibition of female sexual behavior by a CRH receptor antagonist in Syrian hamsters.

Several conditions that inhibit female sexual behavior are thought to be associated with altered corticotropin-releasing hormone (CRH) activity in the brain. The present experiments examined the hypothesis that endogenous CRH receptor signaling mediates the inhibition of estrous behavior by undernutrition and in other instances of sexual dysfunction. Intracerebroventricular (ICV) infusion of CRH or urocortin inhibited estrous behavior in ovariectomized steroid-primed hamsters. Conversely, ICV infusion of the CRH receptor antagonist astressin prevented the suppression of estrous behavior by food deprivation or by ICV administration of neuropeptide Y. Astressin treatment also induced sexual receptivity in nonresponders, animals that do not normally come into heat when treated with hormones, and this effect persisted in subsequent weekly tests in the absence of any further astressin treatment. Activation of the hypothalamo-pituitary-adrenocortical axis was neither necessary nor sufficient to inhibit estrous behavior, indicating that this phenomenon is due to other central actions of CRH receptor agonists. This is the first direct evidence that CRH receptor signaling may be a final common pathway by which undernutrition and other conditions inhibit female sexual behavior.