Antagonism of 5‐HT2A receptors attenuates the effects of amphetamine and 3,4‐methylenedioxymethamphetamine on wakefulness and dopamine overflow

Abstract

The neuropharmacology of the sleep and arousal systems involves a complex interplay between multiple neurotransmitter systems. Previous work has downplayed the role of dopamine in sleep and wakefulness, at least in part, because dopamine neurons do not appear to change their firing rates across arousal states. In the present study, we examined the wake promoting effects of amphetamine and 3,4‐methylenedioxymethamphetamine (MDMA) in rhesus monkeys using noninvasive telemetric monitoring. To evaluate the importance of dopamine, we used in vivo microdialysis targeting the caudate nucleus and pretreatment experiments with the selective 5‐HT2A receptor antagonist M100907. We targeted 5‐HT2A receptors because previous studies found that antagonizing this receptor attenuates some of the behavioral and neurochemical effects of amphetamine and MDMA. We found that amphetamine and MDMA significantly and dose‐dependently increased wakefulness. The effects of amphetamine were more pronounced than those of MDMA, but this may have been the result of different durations of action. Antagonism of 5‐HT2A receptors attenuated the effects of amphetamine and MDMA on both wakefulness and dopamine overflow. These findings suggest that increased dopamine neurotransmission may be necessary for the wake promoting effects of amphetamines. These studies were supported by USPHS grants (DA 00517 and RR 00165).