LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT(2A) receptor.
BACKGROUND
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.
Halberstadt
Adam L
AL
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA.
Geyer
Mark A
MA
D000161:Acoustic Stimulation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000494:pharmacology*; D008090:Lisuride / Q000494:pharmacology*; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D050637:Receptors, Dopamine D3 / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects*; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D006213:Hallucinogens; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C066169:alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol; D020891:Raclopride; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D008238:Lysergic Acid Diethylamide; D008090:Lisuride