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.

[1]  J. Barrett,et al.  Attenuation of the locomotor activating effects of D-amphetamine, cocaine, and scopolamine by potassium channel modulators , 1997, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[2]  L. Schechter The potassium channel blockers 4-aminopyridine and tetraethylammonium increase the spontaneous basal release of [3H]5-hydroxytryptamine in rat hippocampal slices. , 1997, Journal of Pharmacology and Experimental Therapeutics.

[3]  J. Vry,et al.  Stimulus properties of the L—type calcium channel agonist BAY k 8644 in rats , 1996, Behavioural pharmacology.

[4]  C. Routledge,et al.  Differential effects of potassium channel blockers on extracellular concentrations of dopamine and 5‐HT in the striatum of conscious rats , 1995, British journal of pharmacology.

[5]  J. Barrett,et al.  K-Channel blockers attenuate the presynaptic effects of the D2 D3 agonist quinpirole in monkeys , 1995, Pharmacology Biochemistry and Behavior.

[6]  L. Schrama,et al.  4-Aminopyridine differentially affects the spontaneous release of radiolabelled transmitters from rat brain slices in vitro , 1995, Brain Research.

[7]  Randolph M. Johnson,et al.  Linopirdine (DuP 996) improves performance in several tests of learning and memory by modulation of cholinergic neurotransmission , 1994, Pharmacology Biochemistry and Behavior.

[8]  E. Wong,et al.  Cholinergic agents and delay-dependent performance in the rat , 1994, Pharmacology Biochemistry and Behavior.

[9]  A. Brown,et al.  Function and structure of voltage‐dependent potassium channels , 1994 .

[10]  G A Gutman,et al.  Pharmacological characterization of five cloned voltage-gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines. , 1994, Molecular pharmacology.

[11]  S. Yoshida,et al.  Antiamnesic and cholinomimetic side-effects of the cholinesterase inhibitors, physostigmine, tacrine and NIK-247 in rats. , 1993, European journal of pharmacology.

[12]  T. Zetterström,et al.  Quinine and 4-aminopyridine inhibit the stimulatory output of dopamine in nucleus accumbens and the behavioural activity produced by morphine. , 1993, European journal of pharmacology.

[13]  A. Nordberg,et al.  Effect of in vivo microdialysis of 1,2,3,4-tetrahydro-9-aminoacridine (THA) on the extracellular concentration of acetylcholine in the striatum of anesthetized rats. , 1993, The Journal of pharmacology and experimental therapeutics.

[14]  R. Tapia,et al.  NMDA receptor antagonists protect against seizures and wet-dog shakes induced by 4-aminopyridine. , 1992, European journal of pharmacology.

[15]  B. Fredholm,et al.  4‐Aminopyridine‐induced increase in basal and stimulation‐evoked [3H]‐NA release in slices from rat hippocampus: Ca2+ sensitivity and presynaptic control , 1991, British journal of pharmacology.

[16]  M. Häusser,et al.  Activation by cromakalim of pre- and post-synaptic ATP-sensitive K+ channels in substantia nigra. , 1991, Biochemical and biophysical research communications.

[17]  A. Hunter,et al.  The cholinergic pharmacology of tetrahydroaminoacridine in vivo and in vitro , 1989, British journal of pharmacology.

[18]  J. C. Stoof,et al.  Restricted usefulness of tetraethylammonium and 4‐aminopyridine for the characterization of receptor‐operated K+ ‐channels , 1989, British journal of pharmacology.

[19]  B. Rudy,et al.  Diversity and ubiquity of K channels , 1988, Neuroscience.

[20]  G. Damsma,et al.  Differential effects of 4-aminopyridine and 2,4-diaminopyridine on the in vivo release of acetylcholine and dopamine in freely moving rats measured by intrastriatal dialysis. , 1988, European journal of pharmacology.

[21]  Kitzman Jv,et al.  Antagonism of xylazine sedation by 4-aminopyridine and yohimbine in cattle. , 1982 .

[22]  T. Narahashi,et al.  3,4-diaminopyridine. A potent new potassium channel blocker. , 1978, Biophysical journal.

[23]  T. Narahashi,et al.  Dynamics of aminopyridine block of potassium channels in squid axon membrane , 1976, The Journal of general physiology.

[24]  M. Rogawski,et al.  Induction of seizures by the potent K+ channel-blocking scorpion venom peptide toxins tityustoxin-K(alpha) and pandinustoxin-K(alpha). , 1999, Epilepsy research.

[25]  A. Mathie,et al.  Voltage-activated potassium channels in mammalian neurons and their block by novel pharmacological agents. , 1998, General pharmacology.

[26]  R. Hoffman,et al.  Characterization of 4-aminopyridine in overdose. , 1994, Journal of Toxicology Clinical Toxicology.

[27]  C. L. Cramer,et al.  Kainic acid and 4-aminopyridine seizure models in mice: evaluation of efficacy of anti-epileptic agents and calcium antagonists. , 1994, Life sciences.

[28]  P. Lavoie,et al.  Mechanism of aminopyridine-induced release of [3H]dopamine from rat brain synaptosomes. , 1991, General pharmacology.

[29]  H. Kuriyama,et al.  Pinacidil opens the ATP-sensitive and Ca-dependent K channel in smooth muscle cells of the rat and rabbit portal veins , 1990 .

[30]  N. S. Cook,et al.  The pharmacology of potassium channels and their therapeutic potential. , 1988, Trends in pharmacological sciences.

[31]  Laura Gladstein,et al.  Preliminary analysis of the discriminative stimuli induced by the calcium channel “agonist” BAY K 8644 , 1987 .

[32]  B. Wallner,et al.  Antagonism of xylazine sedation by 4-aminopyridine and yohimbine in cattle. , 1982, American journal of veterinary research.

[33]  W. E. Glover The aminopyridines. , 1982, General pharmacology.