Modelling asthma in macaques: longitudinal changes in cellular and molecular markers.

The aim of the present study was to determine whether systemic sensitisation and chronic aeroallergen challenge in macaques replicate the classical and emerging immunology and molecular pathology of human asthma. Macaques were immunised and periodically challenged over 2 yrs with house dust mite allergen. At key time-points, serum, bronchoalveolar lavage (BAL) and bronchial biopsies were assayed for genes, proteins and lymphocyte subpopulations relevant to clinical asthma. Immunisation and periodic airway challenge induced changes in immunoglobulin E, airway physiology and eosinophilia consistent with chronic, dual-phase asthma. Sensitisation increased interleukin (IL)-1ß and -6 concentrations in serum, and IL-13 expression in BAL cells. Airway challenge increased: early expression of IL-5, -6, -13 and -19, and eotaxin; and variable late-phase expression of IL-4, -5 and -13, and thymus- and activation-regulated chemokine in BAL cells. CD4+ lymphocytes comprised 30% of the CD3+ cells in BAL, increasing to 50% in the late phase. Natural killer T-cells represented <3% of the CD3+ cells. Corticosteroid treatment reduced serum histamine levels, percentage of CD4+ cells and monocyte-derived chemokine expression, while increasing CD3+ and CD8+ cells in BAL. Sensitisation and periodic aeroallergen challenge of cynomolgus macaques results in physiological, cellular, molecular and protein phenotypes, and therapeutic responses observed in human asthma, providing a model system useful in target and biomarker discovery, and translational asthma research.

Behavioral and neurochemical effects of the serotonin (5-HT)1A receptor ligand spiroxatrine.

The effects of spiroxatrine, a putative antagonist with selectivity for the serotonin (5-HT)1A receptor, were compared with compounds believed to function as agonists at the 5-HT1A receptor. Schedule-controlled responding of pigeons was maintained under a multiple 30-response fixed-ratio (FR), 3-min fixed-interval (FI) schedule or under a schedule in which responding was suppressed by electric shock ("conflict" procedure). Under the multiple schedule, spiroxatrine (0.3-1.0 mg/kg) decreased FR responding but did not affect FI responding; responding was decreased in both schedule components at 3.0 mg/kg. When administered alone, buspirone, a compound believed to produce its anxiolytic effects through 5-HT1A agonist actions, produced effects similar to those of spiroxatrine; in combination, the two drugs produced greater effects than when either was administered alone. As with 5-HT1A agonists such as buspirone and 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) in the pigeon, spiroxatrine (0.01-1.0 mg/kg) increased punished responding. Spiroxatrine and buspirone were potent inhibitors of [3H]8-OH-DPAT binding to pigeon cerebral membranes with IC50 values in the nM range. Neurochemical analyses of metabolite changes produced by spiroxatrine in pigeon cerebrospinal fluid showed buspirone-like effects, with increases in MHPG, DOPAC and HVA at doses that decreased 5-HIAA levels. Spiroxatrine dose-dependently blocked the behavioral effects of the dopamine agonist piribedil indicating that, like buspirone, it also is a potent dopamine antagonist. Spiroxatrine most likely functions as an agonist at the 5-HT1A receptor. As with buspirone, however, spiroxatrine has a prominent dopamine antagonist component.