Strychnine Research Articles

Calcitonin gene-related peptide enhances substance P-induced behaviors via metabolic inhibition: in vivo evidence for a new mechanism of neuromodulation

The present study examined the effects of intrathecal (i.t.) injection of calcitonin gene-related peptide (CGRP) on caudally directed biting and scratching induced by i.t. substance P (SP), bombesin (BBS), strychnine (STR), and kainic acid (KA). CGRP alone (5.25, 10.5 and 21 nmol) had no effect on these behaviors, but CGRP pretreatment produced a dose-related enhancement of behaviors induced by SP or BBS, but not by KA or STR. 2-Amino-5-phosphonovaleric acid (APV, 25 nmol), a selective N-methyl- d-aspartate (NMDA) receptor antagonist, did not block the CGRP potentiation of SP and BBS induced behaviors. CGRP, however, failed to enhance scratching and biting induced by a SP analogue [pGlu 5-Mephe 8-MeGly 9]SP(5–11) (Dime-C7) that is resistant to enzymatic degradation by SP endopeptidase. These findings demonstrate that CGRP potentiates SP induced behavioral responses via inhibition of neuropeptide degradation and that this mechanism may serve as a physiological mechanism of SP modulation.

Differential blockade of bicuculline and strychnine on GABA- and glycine-induced responses in dissociated rat hippocampal pyramidal cells

The inhibitory effects of bicuculline (BIC) and strychnine (STR) on GABA- and glycine-induced responses were studied in the rat dissociated hippocampal CA1 pyramidal neurons in whole-cell mode by using the conventional patch-clamp technique. Both GABA and glycine elicited inward Cl − currents in a dose-dependent manner and had almost the same maximal responses. The half-maximum dose (K a) and Hill coefficient were 6.4 μM and 1.1 for the GABA response, and 74 μM and 1.5 for the glycine response. BIC and STR antagonized both GABA and glycine responses in a competitive manner. The blocking potency of BIC and STR on the GABA response was comparable. The half inhibition dose (IC 50) was 2.7 μM for BIC and 6.7 μM for STR. STR blocked the glycine response about 3000x more effectively than BIC. The IC 50 was 28 nM for STR and 100 μM for BIC. The BIC and STR did not have voltage-dependent blocking effects on either GABA or glycine responses. Neither GABA nor glycine showed outward rectification in their current-voltage relationships. The functional role of glycine in the rat hippocampal CA1 region is discussed.

The Effects of Spinal Gray Activation by Strychnine on the Motor Evoked Potential in the Rat

The Effects of Spinal Gray Activation by Strychnine on the Motor Evoked Potential in the Rat

Gamma-Aminobutyric acid-induced response in acutely isolated nucleus solitarii neurons of the rat

The gamma-aminobutyric acid (GABA)-induced macroscopic Cl- current (ICl) was investigated in acutely isolated nucleus tractus solitarii (NTS) neurons by a conventional patch-clamp technique combined with a rapid drug application method. The GABA- and muscimol-induced ICl increased in a concentration-dependent manner. The reversal potentials were close to the Cl- equilibrium potential. Pentobarbital sodium (PB) itself elicited a current. Bicuculline (BIC), strychnine (STR), picrotoxin, benzylpenicillin (PCG), Cd2+, and Zn2+ suppressed the GABA response in a concentration-dependent manner. Both BIC and STR shifted the concentration-response curve for GABA response to the right, whereas PCG suppressed the maximum response without affecting the threshold, indicating that BIC and STR antagonized competitively and PCG noncompetitively. The inhibitory action of PCG on GABA response was in a highly voltage-dependent manner. PB shifted the concentration-response curve for GABA response to the left. The augmentatory effect of PB was voltage dependent.

A strychnine-sensitive site is involved in dynorphin-induced paralysis and loss of the tail-flick reflex

Dynorphin A(1–13) administered intrathecally to rats induces a reversible hindlimb paralysis and permanent loss of the tail-flick reflex in a dose-dependent and all-or-none manner. The loss of the tail-flick reflex has been determined to result from neurotoxicity linked to theN-methyl- d-aspartate (NMDA) receptor. Recently, it has been reported that NMDA antagonists attenuate irreversible paralysis induced by dynorphin A(1–17) and dynorphin A(2–17). In the present studies, we examined whether repeated injections of dynorphin A(1–13) acetate salt could change the characteristics of the reversible paralysis. Injections repeated every 48 h resulted in hindlimb paralysis upon each injection which was not different in terms of magnitude or duration (P>0.60). Injections repeated at 2 h intervals resulted in desensitization of the paralytic effects (P<0.05). We also examined if strychnine sulfate, a glycine antagonist would alter the paralytic response to dynorphin. Strychnine protected rats from paralysis (P<0.01) and loss of the tail-flick reflex with an ED 50 of 7 nmol. We conclude that the reversible paralysis induced by dynorphin A(1–13) is repeatable which suggests that the paralysis results from nontoxic or subtoxic actions of dynorphin. Desensitization to the paralytic effects occurs with closely spaced injections by some unknown mechanism. In addition, we conclude that the spinal glycinergic inhibitory system may participate in the induction of the paralysis because strychnine antagonizes dynorphin-induced paralysis. Strychnine also antagonizes the loss of the tail-flick reflex, demonstrating that a strychnine-sensitive site is involved in both the paralysis and loss of the tail-flick reflex and this site may be linked to the NMDA receptor.

Static Responses of Artificial Membranes composed of a Mixture of Lipids to Taste Substances.

We have examined static responses of Millipore membranes infiltrated with only dioleyl phosphate (DOPH), DOPH and dioleoyl phosphatidylethanolamine (DOPE), and DOPH and cholesterol to a bitter (strychnine sulfate), a sour (HCl), a salty (NaCl) and a sweet (sucrose) substances. The DOPE-mixed membrane responded more sensitively to HCl. The cholesterol-mixed membrane responded more sensitively to strychnine, NaCl and sucrose. The present results are similar to the assumption that all sensory cells do not respond uniformly to a chemical substance in the biological system because of a difference of the membrane composition of sensory cells.

The effects of strychnine on the regulation of voltage-dependent calcium channels by dihydropyridines in brain and heart

The effects of strychnine (STR) were investigated on K +-stimulated 45Ca 2+-uptake into mouse brain neurons, the contractile activity of spontaneously beating rat atria and on [ 3H]nitrendipine and [ 3H]BAY K 8644 binding to dihydropyridine calcium channel antagonist and agonist binding sites on brain and cardiac membranes. STR (10 −6−10 −4 M) had no effect on neuronal 45Ca 2+-uptake. When combined at equimolar concentrations (10 −5 M), STR and nifedipine produced a potent (nM) inhibition (40%) of neuronal 45Ca 2+-uptake. In the spontaneously beating rat atria, STR produced a dose-dependent (10 −7−3 × 10 −4 M) decrease in chronotropy but did not affect inotropy. STR (10 −4 M) completely inhibited the positive chronotropic, but did not affect the positive inotropic effects of (−)-S-BAY K 8644. [ 3H]Nitrendipine and [ 3H]BAY K 8644 binding to brain and cardiac membranes was enhanced by STR in a concentration-dependent manner (EC 50 8 × 10 −6 M). Scatchard analysis revealed that STR increased the affinity (decreased the K d) of [ 3H]BAY K 8644 to a greater degree than that of [ 3H]nitrendipine for dihydropyridine binding sites. STR decreased the K d of [ 3H]nitrendipine binding by increasing and decreasing the microassociation and microdissociation constants respectively. STR enhanced [ 3H]nitrendipine binding to the same extent in the cerebral cortex, striatum, hippocampus, cerebellum, brainstem and spinal cord. The enhancement of [ 3H]nitrendipine binding in brain was completely inhibited by Ca 2+ and partially inhibited by Na + in a concentration-dependent manner. Glycine (10 −2 M) did not affect the STR enhancement of [ 3H]nitrendipine binding. Extensive rinsing of brain membranes increased (∼two-fold) the affinity of STR for enhancement of [ 3H]nitrendipine binding. The effects of STR on [ 3H]nitrendipine binding both resembled and were unique to those of phencyclidine. These findings suggest that STR interacts specifically with calcium channels in brain and cardiac tissues at a site similar, but not identical to that of phencyclidine and which is distinct from the dihydropyridine calcium channel regulatory site.

Taurine in deep cerebellar nuclei of the rat. In vivo comparison to GABA inhibitory effect

The sensitivity of neurons of the deep cerebellar nuclei to iontophoretic application of taurine (TAU) and γ-aminobutyric acid (GABA) has been studied in vivo in rats. Both TAU and GABA produced a dose-dependent depression of the firing rate. Both the inhibitory actions of TAU and GABA were antagonized by bicuculline (BIC) and picrotoxin (PIC) but not by strychnine (STRY) meaning that TAU had a ‘GABA-like’ effect in the deep cerebellar nuclei. Simultaneous application of TAU and GABA induced not an additive but a synergistic inhibitory effect on the discharge of the neurons of the interposed and dentate nuclei. These results indicate the involvement of TAU in the inhibitory processes acting on neurons of the deep cerebellar nuclei.

Comparison of the Anticonvulsant Activities of Ethosuximide, Valproate, and a New Anticonvulsant, Thiobutyrolactone

Anticonvulsant properties of alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone (alpha-EMTBL) were compared with those of the antiepileptic drugs ethosuximide (ESM) and valproate (VPA) by testing their ability to block seizures in mice caused by maximal electroshock (MES), pentylenetetrazol (PTZ), picrotoxin (PICRO), bicuculline (BIC), methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), N-methyl-D,L-aspartate (NMDA), aminophylline (AMPH), strychnine (STR), beta-ethyl-beta-methyl-gamma-thiobutyrolactone (beta-EMTBL), and t-butylbicyclophosphorothionate (TBPS). ESM was able to prevent PTZ-, PICRO-, DMCM-, and beta-EMTBL-induced seizures. In contrast, VPA and alpha-EMTBL blocked all of these plus MESTBPS-, and BIC-induced convulsions. Only VPA prevented AMPH-induced seizures. None of the anticonvulsants blocked STR or NMDA seizures. Rotorod testing for acute neurotoxicity demonstrated that ESM was the least toxic and alpha-EMTBL and VPA were equivalent. Animals treated daily with high doses of alpha-EMTBL for a 2-week period appeared healthier and had a higher survival rate than animals treated with VPA in the same manner. After a single intraperitoneal (i.p.) injection, the duration of anticonvulsant action of alpha-EMTBL was 1.3 and 4 times longer than that of ESM and VPA, respectively. These results indicate that alpha-EMTBL has a wide spectrum of anticonvulsant action like VPA but may be less toxic and longer acting. We suggest that alpha-EMTBL is a compound worthy of further testing and development as an antiepileptic drug (AED).

A Conductometric Study on the Phenylglyoxylic Acid–Strychnine Complex

Abstract In order to elucidate the mechanism by which phenylglyoxylic acid (PGA) is reduced electrochemically in the presence of strychnine (SC) to form mandelic acid (MA), which exhibits an optically active property, conductometric studies were carried out. The formation of a 1:1 complex between PGA (or MA) and SC was suggested from the results that equimolar mixture of PGA (or MA) and SC showed a maximum decrease of conductivity. Equilibrium constants of the 1:1 complex of PGA–SC or MA–SC were determined from the results of conductivity measurements at various temperatures. The thermodynamic data were calculated. ΔH and ΔS were found to be +22 kJ mol−1 and +1.1×102 J K−1 mol−1 for both the PGA–SC complex and MA–SC complex.

Anticonvulsant activity of MK-801 and Nimodipine alone and in combination against pentylenetetrazole and strychnine

The effects of the N-methyl-D-aspartate receptor antagonist MK-801 and the dihydropyridine calcium channel antagonist nimodipine were assessed for their anticonvulsant activity alone and in combination against clonic convulsions to pentylenetetrazole (PTZ) and strychnine (STR) in mice. Nimodipine (2–20 mg/kg) and MK-801 (0.1 and 0.5 mg/kg) did not affect the number of mice displaying clonic convulsions to PTZ. However, nimodipine in a dose-dependent manner increased (100%) the latency to clonic convulsions and lethality (mortality from tonic extension convulsions and respiratory failure) following PTZ. In contrast, MK-801 did not increase the latency to PTZ convulsions, but prevented the lethal effects of PTZ. When combined, MK-801 and nimodipine produced a significant reduction in the number of animals (40–60%) displaying PTZ convulsions and a greater increase in the latency to PTZ convulsions than did nimodipine alone. In contrast, MK-801 decreased the onset time, and increased the severity of STR convulsions. A combination of MK-801 and nimodipine which afforded significant protection against PTZ convulsions did not affect STR convulsions. These findings suggest that MK-801 and nimodipine, while possessing significant anticonvulsant activity on their own, produce a potent suggest that MK-801 and nimodipine, while possessing significant anticonvulsant activity on their own, produce a potent anticonvulsant synergism against PTZ but not STR.

Modulatory roles of GABAergic mechanisms in post-rotatory nystagmus in the rabbit

1. 1. To determine how the GABAergic mechanism operates in the generation of post-rotatory nystagmus, an experiment was performed with GABAergic drugs in rabbits. 2. 2. Subconvulsive doses of picrotoxin (0.3–0.6 mg/kg, i.v.) and bicuculline (0.1 mg/kg, i.v.) decreased the number of post-rotatory nystagmus beats, whereas strychnine sulphate, at a subconvulsive dose (0.1 mg/kg i.v.), increased it. 3. 3. Diazepam (1 mg/kg, i.v.) remarkably increased the number of post-rotatory nystagmus beats. Pretreatment with picrotoxin (0.45 mg/kg, i.v.), bicuculline (0.1 mg/kg, i.v.) or semicarbazide-HCl (180 mg/kg, i.v.) antagonized the effects of diazepam (1 mg/kg, i.v.). 4. 4. GABAergic mechanisms may play a modulatory role in the production of nystagmus rhythm. Strychnine-sensitive neurons involved in the vestibular mechanism may behave in a different manner from picrotoxin-sensitive neurons.

Electrical and chemical activation of the mesencephalic and subthalamic locomotor regions in freely moving rats

The locomotor activity of freely moving rats was increased by electrical stimulation of brainstem sites, including the pedunculopontine nucleus, a major component of the mesencephalic locomotor region region (MLR), and sites located in the subthalamic locomotor region (SLR), which is in the area of the zona incerta (ZI) dorsomedial to the subthalamic nucleus. Injections to the MLR of glycine, an inhibitory transmitter of the spinal cord and brainstem, had no effect on locomotion, nor did strychnine sulfate, a glycine antagonist. Unilateral injections of the excitatory amino acid, N-methyl- d-aspartic acid (NMDA), and kainic acid, a glutamate analogue, into the MLR produced an increase in locomotion not seen with glutamate, an excitatory amino acid, into the same area. A still greater response, having a later onset than NMDA but also a longer duration, was produced by administration of picrotoxin and bicuculline methiodide, GABA antagonists, to the MLR. Carbachol injections into the MLR produced two types of responses: either increased or decreased locomotion. Hypermotility resulted from microinjections of glutamate, and picrotoxin and bicuculline, into the ZI. The short latency, short duration response to glutamate resulted in a greater increase in locomotion than with picrotoxin or bicuculline when each was administered into the SLR. These results provide further evidence for the functional role of the MLR and SLR in the initiation of locomotor activity in the intact, freely behaving rat.

Possible role of inhibitory glycinergic neurons in the regulation of lordosis behavior in the rat

Strychnine sulfate (3, 9 or 27 μg in 0.5 μl saline) was bilaterally infused into the ventromedial hypothalamic nucleus (VMH) of ovariectomized sexually inexperienced rats primed 40 hr earlier with 4 μg of estradiol benzoate (EB). This dose of EB induced only weak lordosis behavior in 25% of the subjects (Ss). Strychnine at the 3 and 9 μg dosages, but not at 27 μg, induced intense lordosis behavior, but no proceptivity, in most estrogen-primed Ss (69% in 3 μg, 94% in 9 μg). Ovariectomized adrenalectomized EB-primed Ss also displayed significant lordosis behavior (59%) following infusion of 9 μg of strychnine into the VMH. Strychnine (9 μg) failed to stimulate lordosis in ovariectomized Ss that were not estrogen-primed. Administration of 5 μg EB followed 40 hr later by 2 mg of progesterone (P) elicited intense lordosis behavior in most Ss. Bilateral injections into the VMH of glycine (100 μg), β-alanine (100 μg) or taurine (50 μg) to rats that were already displaying estrous behavior (80 LQ) in response to the sequential administration of EB and P failed to depress lordosis when tested between 5 min and 60 min postinjection. Similarly, glycine (20 or 100 μg) injected into the VMH of estrogen-primed, ovariectomized rats within 15 minutes of a 2 mg SC injection of P failed to interfere with the subsequent response to this steroid when tested 2 and 4 hr after P. The results suggest that strychnine injected into the VMH facilitates lordosis behavior in estrogen-primed rats by removing a tonic inhibitory effect exerted by glycinergic neurons on VMH neurons. Failure of glycine or glycine agonists, when injected into the VMH, to inhibit lordosis induced by EB and P may be due to either their rapid removal from the synaptic region or to the inability of the local restricted injections of amino acids to inhibit all the VMH neurons activated by the systemic administration of the steroids.

Uses and limitations of strychnine as a probe in neurotransmission

Uses and limitations of strychnine as a probe in neurotransmission

Cortically induced masticatory rhythm in masseter motoneurons after blocking inhibition by strychnine and tetanus toxin

In the first series of experiments, we studied whether or not strychnine (STR)-resistant inhibition of masseter motoneurons (MASS·MNs) was involved in their rhythmical inhibition that occurs during masticatory activity, induced by repetitive stimulation of the cortical masticatory area (CMA) in the cat. After systemic STR injection, repetitive CMA stimulation induced rhythmically alternating activity in the masseteric and anterior digastric nerves with a shorter cycle time than before STR-administration. The short-latency IPSPs in the MASS·MNs evoked by single shocks applied to the CMA were abolished. In contrast, repetitive CMA stimulation still induced a rhythmical alternation of EPSPs and IPSPs in the MASS·MNs, although the IPSPs were significantly reduced in amplitude. In the second series, we attempted to abolish the STR-resistant component of the rhythmical IPSP with tetanus toxin (TT). This was injected into one superficial masseter muscle of the guinea pig. In the majority of animals repetitive CMA stimulation induced a tonic EMG superimposed by rhythmical bursts in the TT-intoxicated masseter muscle. Repetitive CMA stimulation induced a rhythmical sequence of EPSPs and superimposed spikes in the MASS·MNs innervating the TT-intoxicated masseter muscle in paralyzed guinea pigs. It was concluded that: (1) the cortically-evoked short-latency inhibition of MASS·MNs is STR-sensitive, as is part of the rhythmical inhibition during CMA-induced mastication; and (2) rhythmical inhibition is not essential for the central generation of the rhythmical activity in the MASS·MNs.

Cortically induced masticatory rhythm in masseter motoneurons after blocking inhibition by strychnine and tetanus toxin.

In the first series of experiments, we studied whether or not strychnine (STR)-resistant inhibition of masseter motoneurons (MASS . MNS) was involved in their rhythmical inhibition that occurs during masticatory activity, induced by repetitive stimulation of the cortical masticatory area (CMA) in the cat. After systemic STR injection, repetitive CMA stimulation induced rhythmically alternating activity in the masseteric and anterior digastric nerves with a shorter cycle time than before STR-administration. The short-latency IPSPS in the MASS . MNS evoked by single shocks applied to the CMA were abolished. In contrast, repetitive CMA stimulation still induced a rhythmical alternation of EPSPS and IPSPS in the MASS . MNS, although the IPSPS were significantly reduced in amplitude. In the second series, we attempted to abolish the STR-resistant component of the rhythmical IPSP with tetanus toxin (TT). This was injected into one superficial masseter muscle of the guinea pig. In the majority of animals, repetitive CMA stimulation induced a tonic EMG superimposed by rhythmical bursts in the TT-intoxicated masseter muscle. Repetitive CMA stimulation induced a rhythmical sequence of EPSPS and superimposed spikes in the MASS . MNS innervating the TT-intoxicated masseter muscle in paralyzed guinea pigs. It was concluded that: (1) the cortically-evoked short-latency inhibition of MASS . MNS is STR-sensitive, as is part of the rhythmical inhibition during CMA-induced mastication; and (2) rhythmical inhibition is not essential for the central generation of the rhythmical activity in the MASS . MNS.

Pharmacologic, nonhormonal treatment of impotence: Evaluation of associated factors

A group of impotent patients previously treated with Strychiomel was evaluated. Strychiomel is a compound of three drugs, yohimbine, thioridazine (Mellaril), and strychnine sulfate, each of which has a specific effect. The results suggest that the compound drug may be beneficial in the majority of patients (66.7%) when impotence occurs without hormonal or severe vascular or psychologic problems. Other factors such as age or presence of other simultaneous diseases do not appear to be significant when treatment with this multiaction drug (Strychiomel) is utilized.

Differential effects of gamma-hexachlorocyclohexane (lindane) on pharmacologically-induced seizures

Gamma-hexachlorocyclohexane (gamma-HCH), the active ingredient of the insecticide lindane, has been shown to decrease seizure threshold to pentylenetrazol (PTZ) 3 h after exposure to gamma-HCH and conversely increase threshold to PTZ-induced seizures 24 h after exposure to gamma-HCH (Vohland et al. 1981). In this study, the severity of response to other seizure-inducing agents was tested in mice 1 and 24 h after intraperitoneal administration of 80 mg/kg gamma-HCH. One hour after the administration of gamma-HCH, the activity of seizure-inducing agents was increased, regardless of their mechanism, while 24 h after gamma-HCH a differential response was observed. Seizure activity due to PTZ and picrotoxin (PTX) was significantly decreased; however, seizure activity due to 3-mercaptopropionic acid (MPA), bicuculline (BCC), methyl 6,7-dimethoxy-4-ethyl-B-carboline-3-carboxylate (DMCM), or strychnine (STR) was not different from control. In vitro, gamma-HCH, pentylenetetrazol and picrotoxin were shown to inhibit 3H-TBOB binding in mouse whole brain, with IC50 values of 4.6, 404 and 9.4 microM, respectively. MPA, BCC, DMCM, and STR showed no inhibition of 3H-TBOB (t-butyl bicyclo-orthobenzoate) binding at concentrations of 100 micron. The pharmacological challenge data suggest that tolerance may occur to seizure activity induced by PTZ and PTX 24 h after gamma-HCH, since the response to only these two seizure-inducing agents is decreased. The in vitro data suggest that the site responsible for the decrease in seizure activity 24 h after gamma-HCH may be the GABA-A receptor-linked chloride channel.

Effect of peptidyl-dipeptidase inhibitors in experimental convulsions in mice.

The anticonvulsant effect of compounds that inhibit peptidyl-dipeptidase (PDP) on bicuculline (BIC)- and strychnine (STRYC)-induced seizures was assessed after intracerebroventricular (ICV) or intraperitoneal (IP) administration in Swiss albino mice. STRYC-induced seizures were delayed by ICV injections and high IP doses of captopril, but not by ICV or IP injections of enalapril or by lower doses of captopril (0.1 mg/kg and 1 mg/kg IP). BIC-induced seizures were not suppressed by ICV or IP injections of either compound; on the contrary, captopril and enalapril exhibited proconvulsant effects when given IP or ICV by shortening the time of onset of tonic seizures and death. Results indicate that the anticonvulsant effect of captopril against STRYC-induced seizures is not mediated by central gamma-aminobutyric acid (GABA) receptors or by the inhibition of PDP.