Cocaine facilitates dopamine transmission from ventral tegmental area (VTA) neurons that project to nucleus accumbens (NAcc), and previous experiments suggest that serotonin-1B (5-HT1B) receptors are involved in this effect. Specifically, activation of 5-HT1B receptors in VTA during cocaine exposure increases dopamine release in NAcc and enhances cocaine-induced locomotor activity, reward, and reinforcement. Thus, it is reasonable to hypothesize that blocking 5-HT1B activity may have the opposite effect. To investigate this hypothesis, SB 224289, a highly selective 5-HT1B antagonist, was used to block this receptor. In an open field/novel object exploration test, SB 224289 reduced cocaine-induced locomotion. However, SB 224289 also increased anxiety-like behavior, both alone and in combination with cocaine. This experiment gives evidence that 5-HT1B antagonists may reduce some of the behavioral effects of cocaine, but may have negative effects on anxiety as well.