Milacemide, a glycine prodrug, enhances performance of learning tasks in normal and amnestic rodents.
The N-methyl-D-aspartate receptor complex appears to play an important role in processes of learning and memory. The presence of a glycine modulatory site at this complex has recently been established and suggests that glycinergic neurotransmission may influence these cognitive functions. Increasing glycine concentrations in the brain by administration of a glycine prodrug, milacemide, is shown here to enhance performance of a shock-motivated passive avoidance task in rats, and to reverse drug-induced amnesia in a spontaneous alternation paradigm in mice. Prevention of the metabolism of milacemide to glycine by pretreatment with MAO-B inhibitors not only prevents the memory-enhancing effects of the drug, but appears to have a deleterious effect on memory formation suggesting an action of the prodrug itself on the brain. These studies indicate a role of glycinergic neurotransmission in memory processes, and support the therapeutic potential of glycinergic drugs in memory impairment.
Handelmann
G E
GE
CNS Diseases Research, G. D. Searle and Co., St. Louis, MO 63198.
Nevins
M E
ME
Mueller
L L
LL
Arnolde
S M
SM
Cordi
A A
AA
D000081:Acetamides / Q000378:metabolism / Q000494:pharmacology*; D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D012642:Selegiline / Q000494:pharmacology
D000081:Acetamides; D001549:Benzamides; D008996:Monoamine Oxidase Inhibitors; D011355:Prodrugs; C039332:milacemide; D012642:Selegiline; C051040:Ro 16-6491; D005998:Glycine