Actions of methoxylated amphetamine hallucinogens on serotonergic neurons of the brain

1. Previous studies of phenethylamine hallucinogenic drugs have reported that intravenous injection of DOI or similar compounds produce an inhibition of the firing rate of serotonergic dorsal raphe neurons of the rat; potentially lowering levels of 5-HT throughout the brain. 2. Direct application by iontophoresis demonstrated only weak non-specific effects, but injection into the nucleus produced slowing of cell firing possibly due to the reduction of on-going synaptic excitation. 3. The literature concerning phenethylamine hallucinogens is discussed in the context of new results obtained from acutely isolated raphe neurons. The effect of DOI (10 microM) was tested on isolated DR neurons that responded to 5-HT with the activation of an inwardly rectifying K+ current but it was without effect. Under conditions that isolated inward Ca2+ current in raphe neurons that was inhibited by 5-HT, DOI was similarly without effect, neither blocking nor mimicking the action of 5-HT. Brief applications of glutamate produced an inward current similar to those produced by synaptic excitation in a slice preparation, but DOI failed to influence the size or duration of these responses. 4. These results suggest that DOI does not directly influence the cell bodies of DR neurons. 5. Further studies using raphe slices subject to synaptic influences will be required to reveal any indirectly mediated mechanism that may underlie the effects of DOI on DR neurons. Alternative indirect mechanisms of DR neuronal inhibition by i.v. DOI and DOM are suggested.