ABSTRACT
The discriminative stimulus (DS) effects of 4-aminopyridine (4-AP) were evaluated in 36 male Sprague-Dawley rats that were trained to discriminate 4-AP from saline in a standard two-lever food reinforced drug discrimination procedure. 4-AP along with its structural analogs 3-aminopyridine (3-AP), 2-aminopyridine (2-AP), and 2,3-diaminopyridine (2,3-DIAP) produced dose-dependent increases in the percentage of responses on the 4-AP-associated lever with full substitution at one or more doses. 2,6-Diaminopyridine (2, 6-DIAP) and 3,4-diaminopyridine (3,4-DIAP) produced dose-dependent increases in the percentage of responses on the 4-AP-associated lever but only partially substituted for 4-AP. Neither 4-dimethylaminopyridine (4-DMAP) nor pyridine substituted for 4-AP. Substitution studies were also conducted with indirect dopamine, norepinephrine, serotonin, and acetylcholine agonists, and gamma-aminobutyric acid A (GABA(A)) agonists and antagonists. The norepinephrine reuptake inhibitor tomoxetine, but not nisoxetine or imipramine, produced dose-dependent increases in the percentage of responses on the 4-AP-associated lever and partially substituted for 4-AP. In addition, antagonism studies were conducted using indirect dopamine, norepinephrine, serotonin, acetylcholine antagonists, and GABA(A) agonists as pretreatments to the training dose of 4-AP. The benzodiazepine agonists chlordiazepoxide and diazepam dose dependently attenuated the DS effects of 4-AP. The present results demonstrate that the K-channel blocker 4-AP can be trained as a DS in rats and the DS effects of 4-AP are likely mediated through blockade of voltage-dependent K-channels. The results also demonstrate a novel interaction between benzodiazepines and K-channels.
Subject(s)
4-Aminopyridine/pharmacology , Discrimination Learning/drug effects , Potassium Channel Blockers , Animals , Cholinergic Agents/pharmacology , Dopamine Agents/pharmacology , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/pharmacology , Male , Pinacidil/pharmacology , Prazosin/pharmacology , Rats , Rats, Sprague-Dawley , Serotonin Agents/pharmacologyABSTRACT
The behavioral effects of the competitive N-methyl-D-aspartate (NMDA) antagonist 2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoate (NPC 17742) were compared with those of its parent compound, 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoate (NPC 12626), and other reference agents in a variety of operant-based tasks in rodents. In mice trained to lever press under a fixed-ratio (FR) 20 reinforcement schedule, NPC 17742 was 6.2 times more potent than NPC 12626 and equipotent with the competitive NMDA antagonist [E]-2-amino-4-methyl-5-phosphono-3-penteneoic acid (CGP 37849) in reducing rates of responding. NPC 17742 was also 3.5 and 4.5 times more potent than [+-]cis-4-phosphonomethyl-2-piperidine carboxylate (CGS 19755) and [+-] 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), respectively, and half as potent as 3SR, 4aRS, 6SR, 8aRS-6-(phosphonomethyl)-1,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylate (LY 274614) in this paradigm. In rats trained to discriminate 4.0 mg/kg NPC 17742 from saline, NPC 17742 was 5.7 times more potent than NPC 12626 in substituting for NPC 17742. CGS 19755 also substituted for NPC 17742, but a maximum of only 50% NPC 17742 lever responding was observed after LY 274614 administration. In rats trained to lever press in a modified Geller-Seifter procedure, NPC 17742 and NPC 12626, like the benzodiazepine chlordiazepoxide, increased rates of punished responding. Neither tolerance nor sensitization to the anti-punishment effects were observed upon administration of NPC 17742 for 5 consecutive days. The results are consistent with NPC 17742 being a potent, systemically active compound whose behavioral effects are mediated through interaction with the NMDA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
