Different effects of methylxanthines on central serotonergic postsynaptic neurons in a mouse behavioral model

Effects of the four methylxanthines (100 mg/kg, IP)--caffeine, theophylline, theobromine, and pentoxifylline--on the central serotonergic neuron were studied in mice using a behavioral model, the head-twitch response. The four methylxanthines potentiated the head twitches induced by 5-hydroxytryptophan (5-HTP) in pargyline-pretreated mice; pentoxifylline was the most potent. The potentiating effect of pentoxifylline was increased by paroxetine, the selective inhibitor of uptake of 5-hydroxytryptamine (5-HT), but those of the other drugs were not. In nontreated animals, caffeine directly induced head-twitch responses, which were not affected by pargyline pretreatment but were increased by prior treatment with 5,7-dihydroxytryptamine (5,7-DHT). The number of head twitches produced by caffeine in 5,7-DHT-treated mice was increased twofold by p-chlorophenylalanine (p-CPA), the tryptophan hydroxylase inhibitor. In mice treated with both 5,7-DHT and p-CPA, theophylline induced the responses, although much less potently than caffeine. Theobromine and pentoxifylline produced even fewer responses. From the results of the present study, it may be concluded that the methylxanthines possess qualitatively different actions on the central serotonergic neuron; caffeine and theophylline appear to have direct effects on the postsynaptic neuron, but theobromine and pentoxifylline do not.