Tricyclic antidepressant drugs: Attenuation of excitatory effects of d-lysergic acid diethylamide (LSD) on acoustic startle response

At a dose of 5 mg/kg, the tricyclic antidepressant drugs chlorimipramine (CIMI), desipramine (DMI), imipramine (IMI), and chlordesipramine (C-DMI) all blocked the excitatory effects of a low dose (30 μg/kg) of LSD on the acoustic startle response in the rat. Over a dose range from 1–5 mg/kg, CIMI and DMI were about equally potent in blocking the LSD effect, despite the fact that both drugs actually increased brain levels of LSD. In contrast, α-methyl-p-tyrosine did not block the effect of LSD on startle. By themselves, DMI, IMI and C-DMI increased startle amplitude 20–30% whereas CIMI alone had no effect on startle. The ability of CIMI and IMI to block the excitatory effect of LSD on startle is consistent with the hypothesis that prior cessation of raphe cell firing caused indirectly by these drugs with no resultant change in 5-HT availability should pre-empt the ability of LSD to increase startle by directly inhibiting raphe cell firing and decreasing 5-HT availability. The finding that the other tricyclics also block the effect of LSD is not explained by that hypothesis. Results are discussed in terms of the serotonin hypothesis of the action of hallucinogenic drugs on behavior.