The abuse of psychomotor stimulants such as cocaine and methamphetamine is a continuing and very serious problem. In our program to synthesize and evaluate a number of 5-HT agonists and their antagonists, we recently developed a practical nonchromatographic chemical synthesis of the 5-HT2A receptor antagonist MDL100,907 that is providing multigram amounts of this critical research tool. We have also studied the discriminative stimulus effects of MDL100,907 several other drugs in order to gain further insight into their 5-HT receptor subtype(s) selectivity and the possible receptor role in certain neuropsychiatric disorders. It is well established that the dopamine and serotonin (5-HT) receptor systems are involved in the regulation of impulsive behavior in animals and humans. Cocaine abuse has been shown to increase impulsive behavior and prior studies have implicated the 5HT2A receptor subtype in the behavioral effects of cocaine. We used the 5HT2A receptor antagonist MDL100907 synthesized earlier by our novel methodology to examine the question of whether this drug would suppress cocaine-induced impulsivity in two established rat models of impulsive behavior. MDL100907 attenuated impulsivity in the differential reinforcement of low rate (DRL) task and the one-choice serial reaction time (1-CSRT) task. Our results suggest that 5-HT2A receptor antagonists will be useful in further study of cocaine-induced impulsivity and may be may be therapeutically useful in the treatment of cocaine abuse and other impulse-control disorders.
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