There is increasing evidence that genetic factors can influence individual differences in vulnerability to drugs of abuse(1,2). Serotonin (5-hydroxytryptamine, 5-HT), acting through many receptors can modulate the activity of neural reward pathways and thus the effects of various drugs of abuse(3-8). Here we examine the effects of cocaine in mice lacking one of the serotonin-receptor subtypes, the 5-HT1B receptor(9). We show that mice lacking 5-HT1B display increased locomotor responses to cocaine and that they are more motivated to self-administer cocaine. We propose that even drug-naive 5-HT1B-knockout mice are in a behavioural and biochemical state that resembles that of wild-type mice sensitized to cocaine by repeated exposure to the drug. This altered state might be responsible for their increased vulnerability to cocaine.