LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT2A receptor

Lysergic acid diethylamide (LSD) and its congener lisuride both disrupt prepulse inhibition (PPI), a measure of sensorimotor gating, in male Sprague-Dawley rats, but through different receptor mechanisms. LSD reduced PPI via activation of the 5-HT(2A) receptor, an effect blocked by the selective 5-HT(2A) antagonist MDL 11,939. Lisuride also reduced PPI, but its effect was not blocked by 5-HT(2A) or 5-HT(1A) antagonists; instead, it was prevented by the dopamine D(2)/D(3) receptor antagonist raclopride. These results indicate that lisuride disrupts PPI through dopamine receptors, supporting its classification as a non-hallucinogenic 5-HT(2A) agonist.

Study at a glance

Abstract

RATIONALE: Compounds that activate the 5-HT(2A) receptor, such as lysergic acid diethylamide (LSD), act as hallucinogens in humans. One notable exception is the LSD congener lisuride, which does not have hallucinogenic effects in humans even though it is a potent 5-HT(2A) agonist. LSD and other hallucinogens have been shown to disrupt prepulse inhibition (PPI), an operational measure of sensorimotor gating, by activating 5-HT(2A) receptors in rats. OBJECTIVE: We tested whether lisuride disrupts PPI in male Sprague-Dawley rats. Experiments were also conducted to identify the mechanism(s) responsible for the effect of lisuride on PPI and to compare the effects of lisuride to those of LSD. RESULTS: Confirming a previous report, LSD (0.05, 0.1, and 0.2 mg/kg, s.c.) reduced PPI, and the effect of LSD was blocked by pretreatment with the selective 5-HT(2A) antagonist MDL 11,939. Administration of lisuride (0.0375, 0.075, and 0.15 mg/kg, s.c.) also reduced PPI. However, the PPI disruption induced by lisuride (0.075 mg/kg) was not blocked by pretreatment with MDL 11,939 or the selective 5-HT(1A) antagonist WAY-100635 but was prevented by pretreatment with the selective dopamine D(2)/D(3) receptor antagonist raclopride (0.1 mg/kg, s.c). CONCLUSIONS: The effect of LSD on PPI is mediated by the 5-HT(2A) receptor, whereas activation of the 5-HT(2A) receptor does not appear to contribute to the effect of lisuride on PPI. These findings demonstrate that lisuride and LSD disrupt PPI via distinct receptor mechanisms and provide additional support for the classification of lisuride as a non-hallucinogenic 5-HT(2A) agonist.