Evidence for dissociable mechanisms of amphetamine- and stress-induced behavioral sensitization: effects of MK-801 and haloperidol pretreatment.

The present study examined the ability of pretreatment with MK-801 or haloperidol to block the induction of behavioral sensitization to amphetamine challenge by repeated immobilization stress in male Sprague-Dawley rats. Fifteen minutes before each of ten 30-min restraint sessions, rats were administered saline, MK-801 (0.01, 0.10 or 0.25 mg/kg i.p.) or haloperidol (0.10 or 0.25 mg/kg i.p.). Control rats received the same injection regimen without restraint. An additional experiment examined the ability of MK-801 to block the induction of sensitization by repeated d-amphetamine. In this experiment, rats were administered saline or MK-801 (0.25 mg/kg i.p.) 15 min before each of ten amphetamine injections (1.0 mg/kg i.p., administered under the same regimen as immobilization stress). Four days after the final immobilization or amphetamine injection, rats were tested for locomotor response to novelty, saline and d-amphetamine (1.5 mg/kg i.p.). Exposure to repeated immobilization stress significantly enhanced the locomotor response to amphetamine challenge but not to saline challenge whether rats were pretreated with saline, MK-801 or haloperidol. Secondary analysis of dose effects in each pretreatment group revealed that at 0.25 mg/kg, repeated MK-801 in itself induced sensitization to the response to amphetamine in control rats and potentiated stress-induced sensitization in restrained rats. In contrast, the sensitization induced by repeated amphetamine was attenuated by MK-801 pretreatment. Neither dose of haloperidol affected the locomotor response to saline or amphetamine in control or stressed rats. These results indicate that the effects of MK-801 on the induction of sensitization are complex and suggest that amphetamine- and stress-induced behavioral sensitization may arise through different mechanisms.