Drug dependence study of the new cognition-enhancing agent nefiracetam in rats.
The new cognition-enhancing agent nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7) was assessed for dependence liability in rats using the DAF (drug admixed food) method and an intravenous self-administration system. In the physical dependence test, nefiracetam and codeine phosphate were administered to rats mixed with food for 43 days in a gradually increasing dosage schedule, followed by feeding a drug-free normal diet to detect signs of withdrawal. After the withdrawal, rats in the nefiracetam treated groups showed no withdrawal symptoms (e.g. body weight loss) and exhibited greater body weight gains than control. On the other hand, rats in the codeine phosphate treated group showed overt withdrawal symptoms (e. g. soft stool, diarrhea, vocalization) and a significant body weight loss, suggesting development of physical dependence on the drug. It was concluded that nefiracetam did not possess physical dependence liability in rats. In the reinforcement liability test, through an indwelling cannula implanted into the right jugular vein rats were allowed to self-administer nefiracetam, morphine hydrochloride or pentobarbital for 14 days. Saline was administered to negative control animals for the same period. The daily frequency of self-administration increased progressively with time in rats of the morphine hydrochloride and pentobarbital groups. In the nefiracetam groups, it remained comparable to or was even lower than that in the saline control group. When compared with the saline control, the group mean frequency of self-administration showed a tendency to be small for nefiracetam, whereas the morphine hydrochloride and pentobarbital showed greater frequencies.(ABSTRACT TRUNCATED AT 250 WORDS)
Fujikawa
K
K
Drug Safety Research Center, Developmental Research Laboratories, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Akiyama
Y
Y
Takayama
S
S
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003061:Codeine / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000633:toxicity*; D011760:Pyrrolidinones / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D019966:Substance-Related Disorders / Q000523:psychology*
D011619:Psychotropic Drugs; D011760:Pyrrolidinones; C058876:nefiracetam; D009020:Morphine; D010424:Pentobarbital; D003061:Codeine