Pharmacological characterization of the discriminative stimulus effects ofthe potassium channel blocker 4-aminopyridine in rats

The discriminative stimulus (DS) effects of 4-aminopyridine (4-AP) were eva luated in 36 male Sprague-Dawley rats that were trained to discriminate 4-A P from saline in a standard two-lever food reinforced drug discrimination p rocedure. 4-AP along with its structural analogs 3-aminopyridine (3-AP), 2- aminopyridine (2-AP), and 2,3-diaminopyridine (2,3-DIAP) produced dose-depe ndent 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 t he 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 indire ct dopamine, norepinephrine, serotonin, and acetylcholine agonists, and gam ma-aminobutyric acid A (GABA(A)) agonists and antagonists. The norepinephri ne reuptake inhibitor tomoxetine, but not nisoxetine or imipramine, produce d dose-dependent increases in the percentage of responses on the 4-AP-assoc iated lever and partially substituted for 4-AP. In addition, antagonism stu dies were conducted using indirect dopamine, norepinephrine, serotonin, ace tylcholine antagonists, and GABA(A) agonists as pretreatments to the traini ng dose of 4- AP. The benzodiazepine agonists chlordiazepoxide and diazepam dose dependently attenuated the DS effects of 4-AP. The present results de monstrate that the K-channel blocker 4-AP can be trained as a DS in rats an d the DS effects of 4-AP are likely mediated through blockade of voltage-de pendent K-channels. The results also demonstrate a novel interaction betwee n benzodiazepines and K-channels.