Mixed-acting sympathomimetic amines, when used clinically as anorectic agents, have produced untoward cardiovascular and behavioral effects as a consequence of the doses required to significantly affect food intake. Long-term therapy with some of these agents has resulted in the development of tolerance, necessitating the need to increase drug dosage and the risk of untoward effects. Enhancing the release of neurotransmitter from catecholamine-containing neurons with mixed- or indirect-acting sympathomimetics produces a decrease in the concentration of tyrosine, the precursor of catecholamine synthesis. In vitro and in vivo studies document tyrosine's ability to sustain catecholamine release following repeated stimulation or drug administration. Preliminary results show that tyrosine potentiates the anorectic activity of various mixed-acting sympathomimetics in a hyperphagic rat model; other amino acids tested were without effect. Tyrosine also failed to potentiate the direct-acting sympathomimetics and serotoninergically active anorexiant tested. Further studies indicated no potentiation of cardiovascular activity by tyrosine. We propose to further characterize the ability of tyrosine to alter acute pharmacological actions of the mixed-acting sympathomimetics by determining their effects on: 1) food intake in insulin- and tail-pinch-induced hyperphagic and freely feeding rats, 2) heart rate and blood pressure, and 3) behavioral parameters (locomotor activity and stereotypy). The effects of chronic administration of such combinations on food intake in freely rats and cardiovascular parameters will also be determined. In tyrosine is effective in potentiating the anorectic activity of the drugs while not altering their cardiovascular and behavioral effects, decreased drug exposure to patients via this combination would offer significant clinical and commercial advantages over existing products.
