MK-801 (dizocilpine): synergist and conditioned stimulus in bromocriptine-induced psychomotor sensitization

Intraperitoneal injections of the D2/D3 dopamine agonist bromocriptine (5.0 mg/kg, IP) induced locomotion that became progressively stronger on successive days of testing. The sensitized response developed twice as rapidly when the non-competitive NMDA antagonist MK-801 (0.25 mg/kg, IP) was given 30 min after bromocriptine (so that the peak effects of the two drugs overlapped). In a second group of animals, MK-801 was given 30 min prior to bromocriptine (the pretreatment regimen typical of studies where MK-801 is reported to block cocaine, amphetamine or morphine sensitization) and locomotion was monitored during the pretreatment period; in this case sensitization to the locomotor-stimulating effects of MK-801 alone (in the pretreatment period) as well as sensitization to the locomotor-stimulating effects of the drug combination (following the second injection) were observed. No sensitization to the effects of MK-801 alone (pretreatment) were seen in animals that received saline rather than bromocriptine as their second injection in this experiment. Thus MK-801 does not block but rather enhances bromocriptine sensitization; it appears to do so by a synergism with the locomotor effects of bromocriptine and by becoming a conditioned stimulus for the sensitized response. These findings confirm the earlier report that NMDA receptor activation is not critical to bromocriptine-induced sensitization, and they illustrate the importance of controls for conditioning and state-dependency phenomena in studies of drug interactions in psychomotor sensitization.