Monoamine release by compound 48/80 from nonmast cell compartments in mouse brain slices

In the present study we investigated the specificity of the releasing effects of compound 48/80 (48/80) for mast cell vs. neuronal histamine (HA) from hypothalamic slices. In addition, we investigated the selectivity of the releasing effects of 48/80 for HA compared to other neurotransmitters. Brain slices from W/W mice, a genetic mutant devoid of mast cells, and +/+ mice, its normal counterpart, were used. Hypothalamic slices were labeled with [3H]HA or [3H]histidine. 48/80 elicited similar degrees of release of [3H]HA from both mouse strains, irrespective of the label used. In addition, 48/80 produced marked increases in the efflux of dopamine (DA), serotonin (5-HT), norepinephrine (NE) and modest increases in the efflux of acetylcholine (ACh). These effects were concentration-dependent and the magnitude of release varied with the transmitter examined (DA > NE > 5-HT ≥ ACh = HA). Transmitter efflux induced by 48/80 was not altered by low calcium concentrations or by tetraethylammonium; whereas, release evoked by electrical stimulation was reduced and increased, respectively, by these treatments. In mouse striatal slices preloaded with [3H]DA, 48/80 induced an initial increase in [3H]DA efflux, followed by a marked increase in the efflux of its metabolite, [3H]-3,4-dihydroxyphenylacetic acid. Nomifensine failed to inhibit, whereas reserpine pretreatment reduced 48/80-induced efflux of 3H. In summary, these results indicate that the incubation of hypothalamic slices with [3H]HA or [3H]histidine labels HA neurons selectively and that 48/80 (10-100 μg/ml) releases HA from nonmast cell compartments. In addition, 48/80 is specific neither for mast cells nor for HA neurons, as it can induce the release of DA, NE and 5-HT. 48/80 appears to enter the nerve terminals by passive diffusion affecting transmitter storage and binding which leads to increases in intraneuronal metabolism and efflux of unchanged as well as metabolized transmitter.