Pharmacological characterization of the discriminative stimulus effects of the potassium channel blocker 4-aminopyridine in rats.
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.
Brandsgaard
R
R
Wyeth-Ayerst Research, Princeton, New Jersey, USA.
Barrett
J E
JE
Rosenzweig-Lipson
S
S
D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D018678:Cholinergic Agents / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D020110:Pinacidil / Q000494:pharmacology; D026902:Potassium Channel Blockers; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018490:Serotonin Agents / Q000494:pharmacology
D018678:Cholinergic Agents; D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D026902:Potassium Channel Blockers; D018490:Serotonin Agents; D020110:Pinacidil; D015761:4-Aminopyridine; D011224:Prazosin