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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.

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.

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-β-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 1.0 mg/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 selfgrooming. 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. KeywordsSelf-injurious behavior (SIB); N-methyl-β-carboline-3-carboxamide (FG7142); Anxiety

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 limbplacing 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.

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Acute Ischemic Stroke (AIS) is the second-leading cause of global mortality with an estimated 6.7 million victims dying each year. Our research has focused on a non-neuronal cell type, the astrocyte, and has demonstrated that GPCR receptor-mediated maintenance of astrocyte function enhances critical homeostatic mechanisms in the brain including protection against AIS-associated edema, glutamate excitotoxicity and oxidative stress. AST-004 is a small-molecule agonist of the GPCR Adenosine A3 receptor (ADORA3), demonstrating excellent pharmacokinetics and blood-brain barrier permeability in preclinical species. The efficacy and dose-response of AST-004 was assessed in rat and non-human primate stroke models of transient occlusion of the middle cerebral artery (tMCAO). In rats, a 1.5-hour tMCAO was conducted with a 24-hour steady-state intravenous infusion of vehicle or AST-004 initiated at time of reperfusion (vehicle or three AST-004 dose levels, n=12/group); neurological deficit and stroke lesion volume (TTC staining/image analysis) were assessed 24 hours post-reperfusion. Compared to vehicle, AST-004 reduced brain lesion volume by 50% (p=0.04) and improved neurological function by 36% (p=0.03). In non-human primates (cynomolgus macaque), a 4-hour tMCAO was conducted with a 22-hour steady-state intravenous infusion initiated 2 hours prior to reperfusion (vehicle or three AST-004 dose levels, n=4/group). Stroke lesion, perfusion deficits and penumbral endpoints were assessed by FLAIR, T2, MRA, DWI and ASL at multiple timepoints out to 5 days post-occlusion. Neurological deficit was assessed at 5-days post-occlusion. AST-004 treatment resulted in statistically significant improvements in outcome relative to vehicle, up to a 44% decrease in lesion volume (p=0.02) and a 72% decrease in percentage of lesion growth (p=0.0006) over the 5-day study period. AST-004 treatment during occlusion also reduced the slope of lesion evolution prior to reperfusion by 72% (p=0.05) relative to vehicle. Together, these studies indicate the potential of a non-neuronal approach to reducing stroke lesion damage via the ADORA3 receptor. AST-004 is a first-in-class candidate that warrants further evaluation in human clinical stroke trials.