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.
Wessinger
W D
WD
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205.
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D015918:Infusion Pumps, Implantable; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D019966:Substance-Related Disorders / Q000523:psychology*
D016291:Dizocilpine Maleate