POTENTIATION OF 5-METHOXY-N,N-DIMETHYLTRYPTAMINE-INDUCED HEAD-TWITCHES BY DIAZEPAM - EVIDENCE FOR INVOLVEMENT OF ADENOSINE UPTAKE INHIBITION

Previous work shows that benzodiazepines potentiate head-twitches indu ced by 5-HT agonists and that this action is not mediated via the GABA receptor complex. In the present study the involvement of adenosinerg ic mechanisms in this effect has been examined, as in addition to thei r actions at the GABA receptor, benzodiazepines also inhibit adenosine uptake. The adenosine antagonists caffeine (0.3-30 mg/kg ip) and 1,3- dipropyl-8-(2-amino-4-chlorophenyl)xa thine (0.03-1 mg/kg ip) dose-dep endently inhibited the ability of diazepam (4 mg/kg ip) to potentiate head-twitches induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 2 .5 mg/kg ip) without affecting head-twitches induced by 5-MeODMT alone at a higher dose (10 mg/kg), which induced a similar number of head-t witches to the combination of 5-MeODMT and diazepam. The adenosine upt ake inhibitors papaverine, mioflazine, and dilazep all potentiated hea d-twitches induced by 5-MeODMT, but this effect was seen at only a sin gle dose of each compound. The benzodiazepine antagonist flumazenil di d not inhibit the potentiation of head-twitches by diazepam but did it self potentiate head-twitches at 30 mg/kg, consistent with its ability to inhibit adenosine uptake. In contrast, the adenosine uptake inhibi tor dipyridamole and the peripheral-type benzodiazepine receptor antag onist Ro 5-4864, which also inhibits adenosine uptake, failed to poten tiate head-twitches. The adenosine agonists N-6-cyclohexyladenosine, 5 '-(N-ethylcarboxamido-adenosine, and (-)-N-6-(R-phenylisopropyl)adenos ine were similarly without effect. These results confirm previous find ings that the potentiation of head-twitches by benzodiazepines is not mediated via an action at benzodiazepine receptors and suggest that in hibition of adenosine uptake is an important component of the mechanis m involved. (C) 1993 Wiley-Liss, Inc.