Potentiation of 5‐methoxy‐n,n‐dimethyltryptamine‐induced head‐twitches by diazepam: Evidence for involvement of adenosine uptake inhibition

Abstract

AbstractPrevious work shows that benzodiazepines potentiate head‐twitches induced by 5‐HT agonists and that this action is not mediated via the GABA receptor complex. In the present study the involvement of adenosinergic mechanisms in this effect has been examined, as in addition to their 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)xanthine (0.03‐1 mg/kg ip) dose‐dependently 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‐twitches to the combination of 5‐MeODMT and diazepam. The adenosine uptake inhibitors papaverine, mioflazine, and dilazep all potentiated head‐twitches induced by 5‐MeODMT, but this effect was seen at only a single dose of each compound. The benzodiazepine antagonist flumazenil did not inhibit the potentiation of head‐twitches by diazepam but did itself potentiate head‐twitches at 30 mg/kg, consistent with its ability to inhibit adenosine uptake. In contrast, the adenosine uptake inhibitor dipyridamole and the peripheraltype benzodiazepine receptor antagonist Ro 5‐4864, which also inhibits adenosine uptake, failed to potentiate head‐twitches. The adenosine agonists N6‐cyclohexyladenosine, 5'‐(N‐ethylcarboxamido‐adenosine), and (–)‐N6‐(R‐phenylisopropyl)adenosine were similarly without effect. These results confirm previous findings that the potentiation of head‐twitches by benzodiazepines is not mediated via an action at benzodiazepine receptors and suggest that inhibition of adenosine uptake is an important component of the mechanism involved. © 1993 wiley‐Liss, Inc.