Continuous infusion of selective dopamine uptake inhibitors or cocaine produces time-dependent changes in rat locomotor activity

Chronic continuous cocaine treatment produces a unique pattern of locomotor activation over time. An initial, progressive increase in locomotion is indicative of sensitization. Unlike intermittent cocaine, this increase is subsequently reversed during the continuous exposure, and activity returns to pre-sensitization levels within days. To study the pharmacological mechanisms that underlie this phenomenon, osmotic minipumps containing cocaine or selective uptake inhibitors of dopamine (GBR 12909 or RTI-117), serotonin (fluoxetine), or norepinephrine (nisoxetine) were implanted into rats. Locomotor activity was measured for 1 h each day, beginning 4 h after pumps were implanted. In the cocaine group, activity was significantly elevated on the first day, peaked between the second and third days, then decreased to a plateau which remained significantly above control levels through 14 days. Peak activity in the GBR 12909 and RTI-117 animals occurred on the first day, followed by a significant decrease 24-48 h later, but not complete tolerance. Neither fluoxetine nor nisoxetine altered locomotor activity. The selective dopamine uptake inhibitors produced some of the effects of cocaine. The possibilities that cocaine interacts with the dopamine transporter in a qualitatively different manner from that of these selective dopamine uptake inhibitors, or that other monoamine systems are involved, are discussed.