sigma Receptor activation blocks potassium channels and depresses neuroexcitability in rat intracardiac neurons.
Zhang H, Cuevas J.
Department of Pharmacology and Therapeutics, University of South Florida College of Medicine, Tampa 33612, USA.
The sigma receptors have been implicated in the regulation of the cardiovascular system, and sigma-1 receptor transcripts have been found in parasympathetic intracardiac neurons. However, the cellular function of sigma-1 receptors in these cells remains to be determined. Effects of sigma receptor activation on voltage-activated K(+) channels and action potential firing were studied in isolated intracardiac neurons using whole-cell patch-clamp recording techniques. Activation of sigma receptors reversibly blocked delayed outwardly rectifying potassium channels, large conductance Ca(2+)-sensitive K(+) channels, and the M-current with maximal inhibition >80%. The inhibition of K(+) channels by sigma ligands was dose-dependent, and the rank order potency of (+)-pentazocine > ibogaine > 1,3-di-O-tolyguanidin (DTG) suggests that the effect is mediated by sigma-1 receptor activation. Preincubation of neurons with the irreversible sigma receptor antagonist metaphit blocked DTG-induced inhibition of K(+) channels, confirming that the effect is mediated by sigma receptor activation. Although bath application of sigma ligands depolarized intracardiac neurons, the number of action potentials fired by the cells in response to depolarizing current pulses was decreased in the presence of these drugs. Neither dialysis of the neurons nor application of intracellular 5'-O-(2-thiodiphosphate) trilithium salt inhibited the effect of sigma receptors on K(+) channels, which suggests that the signal transduction pathway does not involve a diffusible cytosolic second messenger or a G protein. Together, these data suggest that sigma-1 receptors are directly coupled to K(+) channels in intracardiac neurons. Furthermore, activation of sigma-1 receptors depresses the excitability of intracardiac neurons and is thus likely to block parasympathetic input to the heart.
Administration of a non-NMDA antagonist, GYKI 52466, increases excitotoxic Purkinje cell degeneration caused by ibogaine.
O'Hearn E, Molliver ME.
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. firstname.lastname@example.org
Ibogaine is a tremorigenic hallucinogen that has been proposed for clinical use in treating addiction. We previously reported that ibogaine, administered systemically, produces degeneration of a subset of Purkinje cells in the cerebellum, primarily within the vermis. Ablation of the inferior olive affords protection against ibogaine-induced neurotoxicity leading to the interpretation that ibogaine itself is not directly toxic to Purkinje cells. We postulated that ibogaine produces sustained excitation of inferior olivary neurons that leads to excessive glutamate release at climbing fiber terminals, causing subsequent excitotoxic injury to Purkinje cells. The neuronal degeneration induced by ibogaine provides an animal model for studying excitotoxic injury in order to analyze the contribution of glutamate receptors to this injury and to evaluate neuroprotective strategies. Since non-N-methyl-D-aspartate (NMDA) receptors mediate Purkinje cell excitation by climbing fibers, we hypothesized that 1-4-aminophenyl-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI-52466), which antagonizes non-NMDA receptors, may have a neuroprotective effect by blocking glutamatergic excitation at climbing fiber synapses. To test this hypothesis, rats were administered systemic ibogaine plus GYKI-52466 and the degree of neuronal injury was analyzed in cerebellar sections. The results indicate that the AMPA antagonist GYKI-52466 (10 mg/kg i.p. x 3) does not protect against Purkinje cell injury at the doses used. Rather, co-administration of GYKI-52466 with ibogaine produces increased toxicity evidenced by more extensive Purkinje cell degeneration. Several hypotheses that may underlie this result are discussed. Although the reason for the increased toxicity found in this study is not fully explained, the present results show that a non-NMDA antagonist can produce increased excitotoxic injury under some conditions. Therefore, caution should be exercised before employing glutamate antagonists to reduce the risk of neuronal damage in human clinical disorders. Moreover, the contribution of different glutamate receptors to excitotoxic injury is complex and merits further analysis.
Ibogaine is the most important alkaloid of the Central African
Iboga-shrub. It is the central drug in Gabonian initiation ceremonies in which it is used to cause a near-death experience. In Western countries it is used in private clinics to treat addiction. However, in the United States and most European countries it is classified as an illegal drug because at least eight persons have died after having taken Ibogaine. These fatalities occurred in most cases several days after ingestion or following the intake of very small doses. There is no conclusive explanation at the present time for these deaths. We hypothesize, that these deaths may be a result of cardiac arrhythmias, caused by a dysregulation of the autonomic nervous system. Ibogaine affects the autonomic nervous system by influencing several neurotransmitter-systems and the fastigial nucleus. The cerebellar nucleus responds to small doses with a stimulation of the sympathetic system, leading to a fight or flight reaction. High doses, however, lead to a vagal dominance: a "feigned death". The risk of cardiac arrhythmias is increased in situations of sympathetic stimulation or coincidence of a high parasympathetic tonus and a left-sided sympathetic stimulation. This could occur under influence of small doses of ibogaine and also at times of exhaustion with a high vagal tonus, when sudden fear reactions could cause a critical left-sided sympathetic stimulation. Gabonian healers prevent these risks by isolating their patients from normal life and by inducing a trance-state with right-hemispheric and vagal dominance for several days.
Chronic toxicity studies were done by H. Dhahir in his Ph.D. Thesis (1971), and his findings, as follows, are from his experiments with rats. Ibogaine was administered for 30 days at a dosage of 10 mg/kg intraperitoneally each day, with no damage found to the liver, kidneys, heart or brain. 40 mg/kg was administered each day for 12 days with no damage found to the liver, kidneys, heart or brain. Dhahir contrasted these results with the fact that serotonin is very toxic at dosages four times lower, causing severe kidney damage. He concluded that ibogaine was a relatively non-toxic alkaloid with a wide therapeutic range of 10-50mg as a stimulant and 300-1000mg as a psychotherapeutic agent (Dhahir, 1971).
There has only been one study conducted which has found toxicity or neurotoxicity of any form. This was done by O'Hearn and Molliver (1993) using repeated dosages of 100 mg/kg intraperitoneally on rats, which is near the LD50 for rats (i.p.), and above the LD50 for guinea pigs (i.p.). Also, since these doses were administered intraperitoneally, the drug is not subject to the first-pass effect, which I will discuss shortly, as it would be when given orally in a therapeutic setting. They found degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis. This was associated with loss of the microtubule-associated protein (MAP 2) and calbindin. However, similar neurotoxicity studies were done by Molinari, Maisonneuve and Glick (1996), in which no toxicity or neurotoxicity was found whatsoever. This supports the findings by Sanchez-Ramos and Mash (1994), who conducted Pre-Clinical studies in which African Green monkeys were given 5-25 mg/kg orally for four consecutive days and no neurotoxicity was found.
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