Post-decapitation Convulsions Research Articles

Antagonism of 5-methoxy-N,N-dimethyltryptamine-induced changes in postdecapitation convulsions in rats by repeated treatment with drugs enhancing 5-hydroxytryptamine neurotransmission.

Repeated administration of drugs that increase tryptaminergic neurotransmission antagonized the increase in latency to onset and the duration of postdecapitation convulsions (PDCs) induced by an acute 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) injection; Zimelidine (2 X 5 mg kg-1), fluoxetine (2 X 5 mg kg-1), amiflamine (2 X 2.5 mg kg-1) and alpha-ethyltryptamine (2 X 2.5 mg kg-1) administered orally over 10 days caused a substantial blockade of the increase in latency to onset and duration of PDCs following 5-MeODMT, whereas alaproclate (2 X 5 mg kg-1), clorgyline (1 X 1 mg kg-1) and pargyline (2 X 2.5 mg kg-1) caused a lesser blockade. Repeated 5-MeODMT (3 X 2 mg kg-1) administration blocked the acute effects of 5-MeODMT (2 and 4 mg kg-1) upon PDCs completely. These findings indicate down-regulation of the 5-hydroxytryptamine receptors which mediate the action of 5-MeODMT on the PDCs and offer a simple model system for studying 5-HT receptor sensitivity changes at the spinal level.

Effects of clonidine and alpha-adrenoceptor antagonists on motor activity in DSP4-treated mice II: interactions with apomorphine.

Adult mice were administered either the noradrenaline (NA) neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or distilled water (control), 10-12 days before motor activity testing, and 6 h before testing all the mice were administered reserpine (10 mg/kg), the monoamine-depleting agent. The interactive effects of (I) clonidine, the alpha(2)-adrenoceptor agonist, with the dopamine (DA) agonist, apomorphine, and the alpha(2)-antagonist, yohimbine, and (II) with either yohimbine or the alpha(1)-antagonist, prazosin, upon motor behaviour in activity test chambers were studied in reserpinized DSP4-treated and control mice. It was shown that apomorphine (3 mg/kg) increased locomotor and total activity in both reserpinized DSP4-treated and control mice but the effect was attenuated in the DSP4 mice. Co-administration of clonidine (3 mg/kg) with apomorphine potentiated the effects of apomorphine on motor activity and this effect was enhanced markedly by DSP4 pretreatment. Yohimbine (10 mg/kg) antagonized the motor activity-stimulating effects of apomorphine in both DSP4-treated and control mice. Co-administration of clonidine with apomorphine, following yohimbine, restored motor activity levels to those obtained in the absence of yohimbine and this effect upon locomotor activity was enhanced by DSP4 pretreatment. The effects of clonidine on motor activity were enhanced by NA-denervation. Prazzosin (3 mg/kg) enhanced the locomotor activity of both reserpinized DSP4-treated and control mice after the initial 30-min period but was not affected by DSP4 treatment. Analysis of post-decapitation convulsions (PDCs) indicated loss of the reflex by DSP4 pretreatment. Reserpine pretreatment abolished the initial, exploratory phase (30 min) of motor activity. These results demonstrate interactions between NA and DA systems that may bear eventual relevance to neurologic disorders such as parkinsonism.

Restoration of norepinephrine and reversal of phenotypes in mice lacking dopamine beta-hydroxylase.

Mice with a targeted disruption of the dopamine beta-hydroxylase (DBH) gene are unable to synthesize norepinephrine (NE) and epinephrine. These mice have elevated levels of dopamine in most tissues, although the levels are only a fraction of those normally found for NE. It is noteworthy that NE can be restored to normal levels in many tissues after a single injection of the synthetic amino acid precursor of NE, L-threo-3,4-dihydroxyphenylserine (DOPS). In other tissues, NE can be restored to normal levels after multiple injections of DOPS, whereas in the midbrain and cerebellum, restoration of NE is limited to 25-30% of normal. NE levels typically peak approximately 5 h after DOPS administration and are undetectable by 48 h. Epinephrine levels are more difficult to restore. The elevated levels of dopamine fall modestly after injection of DOPS. S(-)-Carbidopa, which does not cross the blood-brain barrier, inhibits aromatic L-amino acid decarboxylase and effectively prevents restoration of NE by DOPS in the periphery, while allowing restoration in the CNS. Ptosis and reductions in male fertility, hind-limb extension, postdecapitation convulsions, and uncoupling protein expression in dopamine beta-hydroxylase-deficient mice are all reversed by DOPS injection.

O-118 - Involvement of α1A-adrenoceptors in post-decapitation convulsions in rats.

O-118 - Involvement of α1A-adrenoceptors in post-decapitation convulsions in rats.

Changes in the duration of postdecapitation convulsions mediated by adrenergic and serotonergic receptors in the rat

Changes in the duration of postdecapitation convulsions mediated by adrenergic and serotonergic receptors in the rat

Suppression of clinical weakness in experimental autoimmune encephalomyelitis associated with weight changes, and post-decapitation convulsions after intracisternal-ventricular administration of 6-hydroxydopamine

Selective depletion of central nervous system norepinephrine (NE) by the neurotoxin 6-hydroxydopamine (6-OHDA) in rats subsequently inoculated with myelin basic protein (MBP) and complete Freund's adjuvant (CFA) produced experimental autoimmune encephalomyelitis (EAE) without the usual expected degree of weakness. The preservation of strength occurred in spite of continued weight loss. Post-decapitation myoclonic convulsive kick latency and kick number, which are known to depend on spinal cord NE, agreed well with the degree of weakness through the clinical disease course. The only difference between EAE groups was that the stronger 6-OHDA pretreated EAE animals did not have an elevated pons-medulla NE compared to saline intracisternal-ventricular (i.c.v.) pretreated controls. We conclude that 6-OHDA can influence the clinical course of weakness by interfering with central noradrenergic activity independent of other features associated with disease in EAE. This effect of 6-OHDA may be exerted through alteration of the blood-spinal cord barrier function and/or central nervous system blood flow.

Effects of isofloxythepin enantiomers on prolactin secretion and postdecapitation convulsions in rats

Racemic isofloxythepin and its enantiomers (0.05–1.0 mg/kg) administered subcutaneously increased serum prolactin levels in a dose-dependent manner in rats. The potencies of the drugs were equal for this variable. They (0.05–1.0 mg/kg, SC) also decreased dose-dependently the incidence and duration of postdecapitation convulsions, the convulsions being abolished at 1.0 mg/kg in all groups. Although (−)-enantiomer had slightly stronger effects than those of raceme and (+)-enantiomer, there were no great differences in their inhibitory effects on postdecapitation convulsions. The results indicate that isofloxythepin enantiomers in addition to raceme increase serum prolactin levels and inhibit postdecapitation convulsions and that they seem to have similar potency in blocking of dopamine receptors and α 1-adrenoceptors.

Benzodiazepines increase tonic component of postdecapitation convulsions in mice

The effects of benzodiazepines (BDZs) and GABA system on tonic and clonic component of postdecapitation convulsion (PDC) were studied in mice. Mice decapitated at the occipito-cervical junction, exerted biphasic convulsions, i.e., initially tonic and subsequently clonic convulsions. BDZs such as diazepam or clonazepam increased tonic and clonic components of PDC. These effects were not antagonized by Ro 15-1788, a benzodiazepine receptor antagonist. The increased tonic component was antagonized by the GABA receptor antagonists, bicuculline and picrotoxin, whereas the clonic component was augmented by them. Aminooxyacetic acid, which increases the endogenous GABA content by inhibiting the GABA-transaminase, increased the tonic component significantly; this increase was antagonized by both bicuculline and picrotoxin. Muscinol, a GABA agonist, however did not affect the tonic components but rather augmented the clonic component. Bicuculline and picrotoxin did not antagonize this effect of muscimol. These results indicate that endogenous GABA may play a crucial role in mediating the tonic component of PDC and the facilitation of this component by BDZs may also be due to the activation of GABA in the spinal cord. Furthermore, the mechanisms of the tonic component may be different from that of the clonic component.

Inhibition of post-decapitation convulsions in the rat by dibenzothiepin neuroleptics via [formula omitted] blockade

The mechanisms involved in inhibitory effects of isofloxythepin, a newly synthesized dibenzothiepin neuroleptic, on post-decapitation convulsions were studied in rats. Isofloxythepin (0.05–2.0 mg/kg s.c.) inhibited post-decapitation convulsions in a dose-dependent manner as shown by the decrease in the incidence and the shortening of the duration of convulsions. The convulsions were also inhibited by oxyprothepin, zotepine or chlorpromazine but not by haloperidol. Prazosin and bunazosin, both α 1- adrenoceptor adrenhoceptor, suppressed the post-decapitation convulsions but a non-selective α-adrenoceptor antagonist, tolazoline, was without effect. The convulsions were inhibited dose dependently by clonidine, an α 2- adrenoceptor agonist, but were prolonged in duration by yohimbine, an α 2- adrenoceptor antagonist. Yohimbine antagonized the inhibitory effects of isofloxythepin, prazosin and clonidine. The noradrenaline-induced contraction of rat vas deferens was inhibited by isofloxythepin, prazosin or chlorpromazine. Isofloxythepin bound to α 1- receptors as did chlorpromazine in the rat brain cortex. The results imply that post-decapitation convulsions seem to be inhibited by a block of postsynaptic α 1- adrenoceptors , enhanced by a block of presynaptic α 2- adrenoceptors and reduced by isofloxythepinvia the blocking of postsynaptic α 1- adrenoceptors . The convulsions thus could serve as a good model for studying the actions of drugs on the central nervous system α-adrenoceptors.

Modulation of postdecapitation convulsions in rats by α-adrenergic and 5-hydroxytryptamine 1A agents

Postdecapitation convulsions were analyzed in rats after the administration of a variety of adrenergic and serotonergic agents. Drugs were selected on the basis of their relative affinities for 5-hydroxytryptamine 1A, α 2-adrenergic and/or α 1-adrenergic receptors. The 5-hydroxytryptamine 1A-selective agonists, 8-hydroxy- N, N-dipropyl-2-aminotetralin and buspirone, significantly increased the duration of the convulsions. The α 2-adrenergic antagonists, yohimbine and corynanthine, had no affect on either the latency or duration of the convulsions. By contrast, each of the three α 1-adrenergic agents increased the latency and decreased their duration. However, the order of potency was WB 4101 > ipsapirone > prazosin and this rank order did not correlate with drug potencies for the α 1-adrenergic receptor as determined by radioligand binding studies. The high potency of both ipsapirone and WB 4101 in inhibiting the postdecapitation convulsions may relate to the combined effects of the drugs at both α 1-adrenergic and 5-hydroxytryptamine 1A receptors.

5-Hydroxytryptamine antagonists and the 5-methoxy-N,N-dimethyltryptamine-induced changes of postdecapitation convulsions.

The ability of various compounds to antagonise the 5-MeODMT induced prolongations of latency and duration of postdecapitation convulsions (PDCs) were compared. The 5-hydroxytryptamine (5-HT) receptor antagonists, mianserin, methergoline, cinanserin and methysergide antagonised the 5-MeODMT (0.5 to 4.0 mg/kg) induced prolongations of latency to onset of convulsions substantially and to a lesser extent the prolongation of duration. The efficacy of the 5-HT antagonists for blocking 5-MeODMT changes of PDCs was roughly of the order mianserin greater than cinanserin greater than methysergide greater than methergoline. Pirenperone, the 5-HT2 antagonist, and pimozide, the dopamine receptor antagonist did not antagonise the 5-MeODMT induced changes. Mianserin, methergoline, cinanserin and methysergide, by themselves, prolonged the duration of PDCs but did not affect latency. Pirenperone (0.25 mg/kg) prolonged both the latency and duration of the PDCs while pimozide (0.5-2.0 mg/kg) had no effect upon PDCs. This evidence suggests that 5-MeODMT induced changes of PDCs are mediated via 5-HT1 receptors and thus a reliable model to combine with other measures of spinal function is suggested.

Effects of new neuroleptics, isofloxythepin and zotepine, on post-decapitation convulsions and prolactin secretion in rats

Oral administration of isofloxythepin (0.5–8.0 mg/kg) inhibited decapitation convulsions in a dose-dependent manner as shown by decreasing the incidence and shortening the convulsion's duration, the effects continuing until 24 hr after administration. Zotepine (8, 16 mg/kg, SC) also decreased the duration but not the incidence of the convulsion. However, the other neuroleptics such as haloperidol, spiperone, perphenazine, trifluoperazine, pimozide and sulpiride failed to affect decapitation convulsions. Reserpine (8 mg/kg, SC) inhibited decapitation convulsions, accompanied by decreasing levels of norepinephrine, dopamine and serotonin in the spinal cord. Isofloxythepin at doses of 4 and 8 mg/kg, PO which completely abolished decapitation convulsions, failed to change norepinephrine and dopamine levels but increased serotonin levels in the spinal cord. Isofloxythepin (0.5–8.0 mg/kg) increased serum prolactin levels in a dose-dependent manner and zotepine (16 mg/kg), haloperidol (1 mg/kg) and reserpine (8 mg/kg) also elevated the levels. The results imply that both isofloxythepin and zotepine, but not the other neuroleptics, inhibit convulsions without decreasing spinal levels of norepinephrine which appears to be the amine most directly involved in the occurence of decapitation convulsions, although these neuroleptics enhance prolactin secretion by blocking dopamine receptors in the pituitary.

The hindlimb extension reflex is not a reliable marker of post-decapitation convulsions or spinal noradrenaline depletion in rats

The degree of hindlimb extension reflex (ER), post-decapitation reflex (PDR) and noradrenaline (NA) depletion was measured under various treatment regimens involving the neurotoxins DSP4 and 6-OHDA. Neither neonatal 6-OHDA treatment, direct application of 6-OHDA to the locus coeruleus nor DSP4 treatment produced a blockade of ER that could be associated with the loss of PDR and the spinal NA depletion, whereas intrathecal 6-OHDA treatment caused a strong loss of both ER and PDR related to severe spinal NA depletion. No correlation was obtained between the ER and PDR in a large number of DSP4-treated rats.

Effects of acute administration of 5-methoxy-N,N-dimethyltryptamine upon the latency and duration of post-decapitation convulsions.

The effect of acute administration of rats with the 5-hydroxytryptamine (5-HT) agonist drug 5-methoxy-N,N-dimethyltryptamine on the convulsions released by decapitation was examined. The postsynaptic agonist, 5-methoxy-N,N-dimethyltryptamine, prolonged the latency and duration from the 0.5 mg/kg dose upwards. Methergoline, 2.0 mg/kg intraperitoneally injected immediately prior to 5-methoxy-N,N-dimethyltryptamine, caused some considerable blockade of the effects of the 5-HT agonist on post-decapitation convulsions (PDG's). Long-term p-chloroamphetamine (2x10 mg/kg) and p-chlorophenylalanine (1 x 300 mg/kg) did not antagonise the 5-methoxy-N-N-dimethyltryptamine induced changes of PDC's but, by themselves, prolonged PDC duration. The utility of the 5-methoxy-N,N-dimethyltryptamine-PDC method for studying 5-HT receptor mechanisms may be worth considering.

Effect of phenoxybenzamine on the GABA system and on convulsive activity.

The effect of phenoxybenzamine on the concentration of GABA and the aminooxyacetic acid (AOAA) induced accumulation of GABA in four brain regions was compared with its effect on the occurrence and latency of picrotoxin-induced convulsions. Also the effect of phenoxybenzamine on post-decapitation convulsions was followed. Whereas 0.1 mg/kg of phenoxybenzamine decreased the levels and the AOAA-induced accumulation of GABA in the substantia nigra and cerebellar cortex, 1.0 mg/kg produced an increased GABA accumulation in the substantia nigra. Both doses of the drug decreased the AOAA-induced accumulation of GABA in the cingulate cortex. Administration of phenoxybenzamine decreased the latency and increased or decreased the occurrence of picrotoxin-induced convulsions depending on the intensity of picrotoxin effect. Phenoxybenzamine also prolonged the latency and shortened the duration of post-decapitation convulsions in rats. The results suggest that two different mechanisms mediate the effects of phenoxybenzamine on the latency and occurrence of picrotoxin-induced convulsions.

Postdecapitation convulsions in the rat measured with an animex motility meter: Relation to central α-adrenoceptors

Postdecapitation convulsions (PDC) were quantified by recording the number of movements of the trunk of decapitated rats with an Animex motility meter. PDC were inhibited by α 1-adrenoceptor blocking agents, phenoxybenzamine and prazosin, but unaffected by α 2-adrenoceptor antagonists, yohimbine and piperoxan, or a β-adrenoceptor blocker, propranolol. Chronic administration of antidepressant drugs: amitriptyline, imipramine and zimelidine augmented the PDC. Preliminary experiments with [ 3H]prazosin binding suggest that the increased PDC response is related to an increase in α 1-adrenoceptor binding, most likely owing to an increase in receptor density.

Alterations in drug induced catalepsy and post-decapitation convulsions following brain and spinal cord depletion of norepinephrine by the neurotoxin DSP-4

The effects of central norepinephrine depletion produced by DSP-4 on drug-induced catalepsy and post-decapitation convulsions were examined in the rat. Haloperidol-induced catalepsy was potentiated in DSP-4 treated rats, while arecoline-induced catalepsy was attenuated. Furthermore, post-decapitation convulsions were eliminated in DSP-4 treated animals. DSP-4 may prove to be a useful tool with which to investigate the behavioral consequences of damage to the locus coeruleus noradrenergic system.

Selective depletion of spinal noradrenaline inhibits post-decapitation convulsions in rats.

Local administration of 6-hydroxydopamine in the subarachnoidal space of the spinal cord in rats resulted in a selective long-lasting depletion of spinal noradrenaline, but not of dopamine, and prevented the occurrence of post-decapitation convulsions.

Physiological function of descending noradrenaline projections to the spinal cord: Role in post-decapitation convulsions

Destruction of the descending noradrenergic innervation to the spinal cord, but not that to the cerebellum or the forebrain, by the use of intracerebral injection of 6-hydroxydopamine completely prevented the occurrence of the usual decapitation convulsion. Depletion of brain noradrenaline by synthesis inhibition with DDC, FLA 57 or FLA 63 g reduced the duration of the post-decapitation convulsion. Blockade of α-noradrenergic receptors by phentolamine or phenoxybenzamine, but not of β-receptors by propranolol, also reduced the duration of the convulsion. The presynaptic α-agonist, clonidine, at either 1 mg/kg or 0.05 mg/kg also reduced the magnitude of the convulsion but either blockade of dopamine receptors with pimozide or destruction of the ascending dopamine systems by 6-hydroxydopamine was without effect. It is concluded that dopamine systems are not involved in post-decapitation convulsions and that the noradrenergic involvement is by the descending spinal projections acting on a post-synaptic α-receptor in the spinal cord, but also modulated by presynaptic α-receptors possibly on the locus coeruleus perikarya.

Selective depletion of spinal noradrenaline abolishes post-decapitation convulsions

Previous data have suggested that spinal noradrenaline (NA) might be important in the normal expression of post-decapitation convulsions. This hypothesis was tested by selective depletion of spinal NA through stereotaxic infusions of 6-hydroxydopamine into the medulla in adult rats. This treatment was found to substantially reduce spinal NA and to abolish the post-decapitation convulsions. The results are discussed in terms of the mechanism underlying the involvement of NA in this reflex.