Monoamines and the mechanisms of action of antitussive drugs in rats.

The influence of drugs which modify the concentration of brain monoamines on the size of the 50% antitussive dose (AtD50) of morphine (M), dihydrocodeine (DC) and dextromethorphan (DX) was investigated in male Sprague-Dawley rats. The puncture electrode-induced cough method was used for inducing cough. The AtD50 was calculated by the "up and down" method. All drugs were injected i.p. Concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the whole brain were measured by means of high performance liquid chromatography with electro-chemical detection. The values for the AtD50 of M, DC and DX were 1.22, 1.44, and 6.06 mg/kg, respectively. Reserpine (2.5 mg/kg/day, 2 days) produced depression of more than 80% in levels of NE, DA and 5-HT in the brain. This treatment resulted in a substantial reduction in the antitussive effect of the cough suppressants, as evidenced by an increase in the AtD50 of M, DC and DX. p-Chlorophenylalanine (PCPA; 300 mg/kg, 24 hr) specifically produced a reduction of more than 70% in the level of 5-HT in the brain. The PCPA-treated rats also displayed an inhibition of the antitussive effect. The AtD50 in reserpine- and PCPA-treated rats was 2- and 4-fold higher, respectively, than the AtD50 for normal rats. alpha-Methyl-p-tyrosine (300 mg/kg, 5 hr) produced a significant reduction in the levels of NE and DA in the brain, but the antitussive effects of M, DC and DX were not altered. These results suggest that 5-HT in the brain may play an important role in the mechanism of action of antitussive drugs.