The abuse of psychomotor stimulants such as cocaine and methamphetamine is a continuing and very serious problem worldwide. In our program to synthesize and evaluate a number of 5-HT agonists and their antagonists, we earlier 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 and 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. Relapse to cocaine self-administration is a major obstacle to overcome in the successful treatment of human cocaine addicts. Such relapse can be triggered by impulsivity or cue reactivity. 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 and prior studies have implicated the 5HT2A receptor subtype. We used the 5HT2A receptor antagonist MDL100907 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. Preclinical studies have now shown that impulsivity and cocaine seeking behavior can be suppressed by relatively large doses of either a selective 5-HT2A antagonist or a selective 5HT2C agonist. We evaluated the possibility that low doses (to avoid side effects) of both a 5-HT2A antagonist MDL100907 and a 5HT2C agonist WAY163909 be effective and offer advantages over single drug treatment in preventing relapse. Our results showed that low doses of both drugs in combination was effective when the same doses separately had no effect. The drug mixture suppressed cocaine-induced inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. This is an important finding that suggests that a single drug showing both profiles in the optimum ratio could constitute a valuable medication for the prevention of cocaine relapse.
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