Abstract
D-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT1 and 5-HT2 receptors. Little is known about its potential interactions with the dopamine (DA) neurons of the ventral tegmental area (VTA). Using in-vivo electrophysiology in male adult rats, we evaluated the effects of cumulative doses of LSD on VTA DA neuronal activity, we compared these effects to those produced on 5-HT neurons in the dorsal raphe nucleus (DRN), and we attempted to identify the mechanism of action mediating the effects of LSD on VTA DA neurons. We confirmed that low doses of LSD (5–20 µg/kg, i.v.) induce a significant decrease of DRN 5-HT firing activity, but at these doses, it did not alter VTA DA neuronal activity. On the contrary, higher doses of LSD (30–120 µg/kg, i.v.) dose-dependently decreased VTA DA firing activity. The depletion of 5-HT synthesis with p-chlorophenylalanine did not modulate the effects of LSD on DA firing activity. The inhibitory effects of LSD on VTA DA firing activity were prevented by the D2 receptor antagonist haloperidol (50 µg/kg, i.v.) and by the 5-HT1A receptor antagonist WAY-100,635 (500 µg/kg, i.v.). Notably, pretreatment with the novel synthetized trace amine-associate receptor 1 (TAAR1) antagonist EPPTB (5 mg/kg, i.v.) blocked the inhibitory effect of LSD on VTA DA neurons. These results suggest that LSD at high doses strongly affects DA mesolimbic neuronal activity in a 5-HT independent manner and with a pleiotropic mechanism of action involving 5-HT1A, D2 and TAAR1 receptors.