strychnine and nipecotic-acid

The specific role of gamma-aminobutyric acid (GABA) and glycine receptors in respiratory rhythm generation and pattern formation was investigated in in vitro brainstem preparations from adult lampreys by analyzing the changes in respiratory activity induced by bath application of specific antagonists, agonists, and uptake blockers. GABAA receptor blockade by bicuculline or picrotoxin increased both the frequency and amplitude of respiratory bursts. Similar effects were observed after glycine receptor blockade by strychnine. Combined bath application of bicuculline and strychnine markedly increased the frequency and amplitude of respiratory activity. These responses were associated, especially at the higher concentrations of the two drugs, with the appearance of tonic activity and irregular, high-frequency bursts followed by transient depression of respiratory activity. GABAA and glycine receptor agonists suppressed respiratory activity. These effects were prevented by bath application of the corresponding specific antagonists. GABAB receptor blockade by 2-hydroxysaclofen reduced the respiratory frequency but increased the peak amplitude of respiratory bursts. Activation of GABAB receptors suppressed respiratory activity. These responses were prevented by 2-hydroxysaclofen. Neither GABAC receptor agonist nor antagonist had any effects on respiration. Depression of both the frequency and amplitude of respiratory bursts was induced by blockades of GABA and glycine uptake using, respectively, nipecotic acid and sarcosine. The results suggest that GABA- and glycine-mediated inhibition is not essential for respiratory rhythm generation in the adult lamprey, although it appears to exert potent influences on respiratory activity and to have a role in maintaining a stable and regular breathing pattern.

Topics: Action Potentials; Animals; Brain Stem; Efferent Pathways; GABA Agonists; GABA Antagonists; gamma-Aminobutyric Acid; Glycine; Glycine Agents; Nerve Net; Neural Inhibition; Neurons; Nipecotic Acids; Petromyzon; Receptors, GABA-A; Receptors, GABA-B; Receptors, Glycine; Respiratory Center; Respiratory Physiological Phenomena; Sarcosine; Strychnine; Synaptic Transmission

Local circuits in the spinal cord that generate locomotion are termed central pattern generators (CPGs). These provide coordinated bilateral control over the normal limb alternation that underlies walking. The molecules that organize the mammalian CPG are unknown. Isolated spinal cords from mice lacking either the EphA4 receptor or its ligand ephrinB3 have lost left-right limb alternation and instead exhibit synchrony. We identified EphA4-positive neurons as an excitatory component of the locomotor CPG. Our study shows that dramatic locomotor changes can occur as a consequence of local genetic rewiring and identifies genes required for the development of normal locomotor behavior.

Topics: Animals; Axons; Bicuculline; Carrier Proteins; Electrophysiology; Ephrin-B3; Gait; In Vitro Techniques; Interneurons; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Neurons; Nipecotic Acids; Receptor, EphA4; Sarcosine; Signal Transduction; Spinal Cord; Spinal Nerve Roots; Strychnine; Vesicular Glutamate Transport Protein 1; Vesicular Glutamate Transport Protein 2; Vesicular Transport Proteins; Walking

We have investigated the contribution of GABA(A) receptor activation to swimming in Xenopus tadpoles during the first day of postembryonic development. Around the time of hatching stage (37/8), bicuculline (10-50 microM) causes a decrease in swim episode duration and cycle period, suggesting that GABA(A) receptor activation influences embryonic swimming. Twenty-four hours later, at stage 42, GABA(A) receptor activation plays a more pronounced role in modulating larval swimming activity. Bicuculline causes short, intense swim episodes with increased burst durations and decreased cycle periods and rostrocaudal delays. Conversely, the allosteric agonist, 5beta-pregnan-3alpha-ol-20-one (1-10 microM) or the uptake inhibitor, nipecotic acid (200 microM) cause slow swimming with reduced burst durations and increased cycle periods. These effects appear to be mainly the result of GABA release from the spinal terminals of midhindbrain reticulospinal neurons but may also involve spinal GABAergic neurons. Intracellular recordings were made using KCl electrodes to reverse the sign and enhance the amplitude of chloride-dependent inhibitory postsynaptic potentials (IPSPs). Recordings from larval motoneurons in the presence of strychnine (1-5 microM), to block glycinergic IPSPs, provided no evidence for any GABAergic component to midcycle inhibition. GABA potentials were observed during episodes, but they were not phase-locked to the swimming rhythm. Bicuculline (10-50 microM) abolished these sporadic potentials and caused an apparent decrease in the level of tonic depolarization during swimming activity and an increase in spike height. Finally, in most larval preparations, GABA potentials were observed at the termination of swimming. In combination with the other evidence, our data suggest that midhindbrain reticulospinal neurons become involved in an intrinsic pathway that can prematurely terminate swim episodes. Thus during the first day of larval development, endogenous activation of GABA(A) receptors plays an increasingly important role in modulating locomotion, and GABAergic neurons become involved in an intrinsic descending pathway for terminating swim episodes.

Topics: Animals; Bicuculline; GABA Antagonists; GABA Modulators; gamma-Aminobutyric Acid; Glycine Agents; Larva; Neurons; Nipecotic Acids; Pregnanolone; Proline; Receptors, GABA-A; Rhombencephalon; Spinal Cord; Strychnine; Swimming; Synapses; Xenopus laevis

The relative ability of the enantiomers of the ethyl and m-nitrophenyl esters of nipecotic acid to block convulsions induced by bicuculline and pentylenetetrazol, as well as to block the uptake of GABA into whole brain mini-slices, was studied in mice. Neither (+)ethyl nipecotate hydrogen tartrate [(+)E.Tartrate], which is hydrolyzed to (-)nipecotic acid, nor (-)ethyl nipecotate hydrogen tartrate [(-)E.Tartrate], which is hydrolyzed to (+)nipecotic acid, provided protection against challenge with bicuculline. Both (+)E.Tartrate and (-)ethyl nipecotate hydrochloride [(-)E.HCl], which are hydrolyzed to (-)nipecotic acid, blocked seizures induced by pentylenetetrazol. However, neither (-)E.Tartrate nor (+)ethyl nipecotate hydrochloride [(+)E.HCl], which are hydrolyzed to (+)nipecotic acid, provided significant protection against challenge with pentylenetetrazol. These results agree with the relative ability of these compounds to inhibit the uptake of GABA, where (-)nipecotic acid was more potent than (+)nipecotic acid and (+)E.Tartrate was more potent than (-)E.Tartrate. The enantiomers of m-nitrophenyl-3-piperidinecarboxylate hydrochloride, (+)MNPC.HCl and (-)MNPC.HCl, were almost equi-effective in preventing seizures induced by bicuculline. This lack of significant difference in anticonvulsant activity is in contrast with the ability to inhibit the uptake of GABA, where (-)MNPC.HCl was significantly more potent than (+)MNPC.HCl. Changing the route of administration from subcutaneous to intraperitoneal injection reduced the onset of time of the peak effect and the anticonvulsant potency of (+/-)MNPC.HCl. Cholinergic effects were observed with the administration of (+)E.Tartrate and (-)E.HCl, but not with (-)E.Tartrate, (+)E.HCl, (+)MNPC.HCl or (-)MNPC.HCl.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anticonvulsants; Bicuculline; Esters; GABA Antagonists; Male; Mice; Nipecotic Acids; Parasympathomimetics; Pentylenetetrazole; Pharmaceutical Preparations; Prodrugs; Proline; Seizures; Strychnine

Pipecolic acid (PA) is an alicyclic amino acid and putative neurotransmitter which may modulate GABAergic transmission in the central nervous system. The present study was designed to investigate the anticonvulsant effect of intrathecally (i.t.) injected PA on picrotoxin- and bicuculline-induced convulsions which are thought to be produced by interactions with GABAergic systems. Intrathecal injections of picrotoxin and bicuculline in mice produced convulsions which were characterized by a rapid onset and short duration. Coadministration of GABA with either bicuculline or picrotoxin, but not strychnine, attenuated the severity of the convulsions. Coadministration of PA also protected against bicuculline- and picrotoxin-induced convulsions. Intrathecal injections of PA produced a dose-related increase in the latency to the onset of these convulsions as well as a decrease in their duration, however PA failed to inhibit the duration of strychnine-induced seizures. The D isomer of PA was found to be more effective than the L isomer as an anticonvulsant in this study. When administered in a high dose (500 micrograms i.t.), the D isomer produced flaccid paralysis while injection of high doses (100-500 micrograms i.t.) of the L isomer actually elicited convulsions. These results further support an interaction between PA and GABAergic activity.

Topics: Animals; Bicuculline; gamma-Aminobutyric Acid; Injections, Spinal; Male; Mice; Nipecotic Acids; Picrotoxin; Pipecolic Acids; Proline; Receptors, GABA-A; Seizures; Strychnine