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 γ-aminobutyric acid A (GABAA) 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 GABAA 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.
Footnotes
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Send reprint requests to: Sharon Rosenzweig-Lipson, Ph.D., Wyeth-Ayerst Research, CN-8000, Princeton, NJ 08543. E-mail:rosenzs{at}war.wyeth.com
- Abbreviations:
- K-channel
- potassium channel
- 4-AP
- 4-aminopyridine
- 3-AP
- 3-aminopyridine
- 2-AP
- 2-aminopyridine
- 2,3-DIAP
- 2,3-diaminopyridine
- 2,6-DIAP
- 2,6-diaminopyridine
- 3,4-DIAP
- 3,4-diaminopyridine
- 4-DMAP
- 4-dimethylaminopyridine
- tacrine
- 9-amino-1,2,3,4-tetrahydroacridine
- DS
- discriminative stimulus
- DA
- dopamine
- NE
- norepinephrine
- 5-HT
- serotonin
- ACh
- acetylcholine
- FR
- fixed-ratio
- KV channels
- voltage-gated potassium channels
- SB-200646
- N-(1-methyl-5-indolyl)-N′-(3-pyridyl)urea HCl
- BAY K 8644
- (±)-methyl-1,4,-dihydro-2,5-dimethyl-3-nitro-4-(2-trifluoromehtylphenyl)pyridine-5-carboxylate
- SCH-23390
- R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
- WAY-100635
- N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate
- mCPP
- meta-chlorophenylpiperazine
- 8-OH-DPAT
- 8-hydroxy-2-(di-n-propylamino)tetralin
- DOI
- 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane
- NMDA
- N-methyl-d-aspartate
- GABAA
- γ-aminobutyric acid A
- Received February 17, 2000.
- Accepted June 20, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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