Tolerance to and dependence on MK-801 (dizocilpine) in rats

Rats were trained to respond under a fixed-ratio 30 schedule for food presentation during four daily 0.5-h sessions occurring every 6 h. After stable baseline response was established, osmotic minipumps were implanted that infused vehicle or (+)-5 methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine; MK-801), SC. Behavioral sessions continued to be conducted daily. After 10 days the infusion pumps were removed. Vehicle and 0.10 mg/kg per day MK-801 did not affect behavior during infusions or after cessation of dosing. Dosing with 0.32 and 0.56 mg/kg per day initially suppressed responding, but tolerance developed to these effects. After the infusions were stopped, a dose-dependent disruption of operant behavior occurred. Response rates for the 0.32 and 0.56 mg/kg per day infusion groups were suppressed to 41 and 27% of preinfusion control response rates, respectively, the day after dosing stopped; however, no physical signs of abstinence were observed. Response rates recovered toward control over the next 2–4 days. In a separate experiment, the suppression of response produced by abstinence from 0.32 mg/kg per day of MK-801 (SC) for 10.5 days was reversed by readministration of MK-801 (IP). These results demonstrate that MK-801 produces dependence, as evidenced by the emergence of a behavioral abstinence syndrome after cessation of dosing.