Effects of anticonvulsants in a novel operant learning paradigm in rats: comparison of remacemide hydrochloride and FPL 15896AR to other anticonvulsant agents.
One of the primary undesired effects of anticonvulsant medication is an impairment in cognitive function, such as new learning ability. The purpose of the present study was to compare the effects of remacemide hydrochloride [(+/-)-2-amino-N-(1-methyl-1,2,-diphenylethyl)acetamide monohydrochloride] and FPL 15896AR [(+)-alpha-phenyl-2-pyridine-ethanamide] to a number of anticonvulsant agents on an operant acquisition baseline. Remacemide hydrochloride is currently in clinical trials for epilepsy and FPL 15896AR is under development. In the present procedure, fasted, experimentally naive rats were placed into operant chambers in which food pellets were initially available under a Fixed-Ratio 1 (FR1) schedule of food presentation, and as lever pressing progressed, the FR value incremented. All drugs were tested in multiples of three and ten times their respective ED50 values against maximal electroshock-induced seizure (MES) following p.o. administration. The drugs tested varied widely in their ability to disrupt acquisition of the lever-pressing task. Remacemide hydrochloride and a structurally related analog, FPL 15896AR, did not disrupt acquisition. Clonazepam, lamotrigine, MK-801, phenobarbital, felbamate, phenytoin, and carbamazepine increased the number of hours required to achieve FR3 (emit more than 100 responses) with respect to vehicle control performance. Of these, clonazepam, MK-801 and phenytoin produced robust enough disruption to result in significantly fewer reinforcers delivered over the 14-h operant session.
Department of Pharmacology, Astra Research Corporation, Rochester, NY 14602, USA.
T J
TJ
Hudzik
G C
GC
Palmer
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002998:Clonazepam / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects*; D008297:Male; D010672:Phenytoin / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats
D000081:Acetamides; D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; C096406:alpha-phenyl-2-pyridineethanamine dihydrochloride; D002998:Clonazepam; D010672:Phenytoin; D016291:Dizocilpine Maleate; C067553:remacemide