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S R Snodgrass

Publications and source records attributed to S R Snodgrass.

At least 37 records · Page 2Linked to original sources
PubMed1987

The guinea pig myoclonic model: behavioral supersensitivity to 5-hydroxytryptophan induced by intracisternal 5,7-dihydroxytryptamine.

To study the species difference of guinea pigs and rats in response to 5-hydroxytryptophan (5-HTP), we injected both animals intracisternally with 5,7-dihydroxytryptamine. In rats with 5,7-dihydroxytryptamine lesions, 5-HTP evoked the well described myoclonic-serotonergic syndrome. In the guinea pig, 5,7-dihydroxytryptamine lesions significantly increased the severity of myoclonic response to 5-HTP (150 mg/kg) compared to vehicle controls, resulting in lethal convulsions. Guinea pigs treated with 5,7-dihydroxytryptamine did not develop spontaneous myoclonus, or when treated with 5-HTP, other 'serotonergic behaviors' such as lateral head weaving, hindlimb abduction, and forepaw tapping. Guinea pigs tolerated intracisternal 5,7-dihydroxytryptamine less well than rats, with a higher mortality, although immediate post-injection convulsions were less severe and did not require phenobarbital prophylaxis. Staged lower doses of 5,7-dihydroxytryptamine (100-200 micrograms) were better tolerated than a single high dose of neurotoxin (400 micrograms). The regional profile of 5,7-dihydroxytryptamine lesions in the guinea pig resembled that of the rat, with maximal depletion of 5-HT in spinal cord and selected forebrain structures, and little effect in diencephalon and midbrain. Depletions in the guinea pig were less selective for 5-HT using desipramine pretreatment than in the rat. In naive guinea pigs and rats, regional content of 5-HT was similar. These data suggest that the functional integrity of serotonergic neurons is not requisite for the expression of myoclonus induced by 5-HTP in the guinea pig. 5,7-Dihydroxytryptamine lesions in the guinea pig resulted in behavioral and neurochemical similarities and differences in comparison with the rat.

5,7-Dihydroxytryptamine↗
PubMed1987

Harmala alkaloids and related beta-carbolines: a myoclonic model and antimyoclonic drugs.

The neuropharmacologic profile of intraperitoneally injected harmala alkaloids and related beta-carbolines was evaluated in the rat. All drugs induced central effects (convulsions, catalepsy, or altered startle), but only harmaline and harmine were tremorogenic at low doses. Methoxylation of the carboline 7 position was requisite for this effect. Coadministration of harmaline (but not harmine) and 5-hydroxytryptophan (tryptamine or m-chlorophenyl-piperazine) induced a lethal convulsive myoclonic syndrome which could not be evoked by either drug separately. Compared with the myoclonic-serotonergic syndrome evoked by 5-hydroxytryptophan in rats with 5.7-dihydroxytryptamine lesions, harmaline+5-hydroxytryptophan-treated rats displayed more continuous and greater axial myoclonic jerks and some postural differences. Clorgyline or tranylcypromine but not pargyline could be substituted for harmaline. The harmaline syndrome was blocked by the benzodiazepine agonists, physostigmine and verapamil. The harmaline+5-hydroxytryptophan syndrome was blocked by drugs acting at benzodiazepine receptors (CL 218,872 greater than ethyl-beta-carboline-3-carboxylate, clonazepam, diazepam, Ro 15-1788, pentobarbital), and baclofen. Naloxone, benztropine, quipazine, and apomorphine had partial effects, and calcium channel blockers prevented death but did not prevent convulsions. 5-Hydroxytryptamine antagonists were poor blockers, although cyproheptadine and ketanserin significantly reduced mortality. Phenobarbital was more effective than other anticonvulsants. Lesion studies suggested a role for monoaminergic neurons and the inferior olive in the expression of the harmaline+5-hydroxytryptophan syndrome. These data describe a complex convulsive myoclonic syndrome that is behaviorally related to but pharmacologically distinct from the serotonin syndrome, which may be useful in studying serotonergic-benzodiazepine interactions in the pathophysiology of myoclonus.

5-Hydroxytryptophan↗
PubMed1987

Effects of 5-HT receptor subtype-selective drugs on locomotor activity and motor habituation in the DHT adult rat model.

5-Hydroxytryptophan (5-HTP) induces biphasic time and dose dependent effects on locomotor activity (LMA) and motor habituation in rats with 5,7-dihydroxytryptamine (DHT) lesions. To identify the role of serotonin (5-HT) receptors in these responses, we studied the effects of 5-HT2 receptor antagonists on LMA occurring spontaneously and evoked by 5-HTP or putative selective 5-HT agonists in rats injected intracisternally with DHT or vehicle. Motor habituation was assessed by analysis of computer-tabulated 10 minute "bins" during hour long recording. Neuroleptic 5-HT2 antagonists prevented 5-HTP stimulation of LMA in DHT-lesioned rats in the rank order of potency pirenperone greater than pipamperone greater than ketanserin = cinanserin. The non-neuroleptic ritanserin, however, did not reduce LMA stimulated by the 5-HT1B agonist RU24969 but did reverse transient suppression of LMA induced by high dose 5-HTP and by the putative 5-HT2 agonist DOI. RU24969, like 5-HTP, induced a failure of motor habituation which differed from DOI-evoked alteration. 8-OH-DPAT did not affect motor habituation at the dose tested. These data suggest that the 5-HT1B site mediates 5-HTP-evoked locomotor hyperactivity in the DHT model, that the 5-HT2 site participates in the transient hypoactivity seen with high doses of 5-HTP, and that 5-HT1 and 5-HT2 sites may be functionally linked. Both sites differentially influence motor habituation, which appears to be under complex regulation. Bin analysis is a sensitive index of these habituation effects.

5,7-Dihydroxytryptamine↗
PubMed1987

High-dose clonidine motor syndrome: relationship to serotonin syndrome.

Reciprocal forepaw treading, hindlimb abduction, and Straub tail are some of the abnormal motor behaviors of the classical 'serotonin syndrome,' which results from activation of serotonin (5-HT) receptors. However, we also observed them in the syndrome evoked by the alpha-adrenergic agonist clonidine, at high doses (5-40 mg/kg). Other features of the clonidine syndrome (scored from videotapes) were body and head tremor, forelimb hyperextension, ataxia, vertical jumping, tactile hyperreactivity, and autonomic signs (piloerection, pupillary dilatation, salivation, proptosis). The clonidine syndrome persisted for several hours and was not lethal. Clonidine suppressed locomotor activity (photocell recording) and induced episodes of catalepsy and 5-HT-independent impairment of motor habituation. Single high doses of drugs active at several different neurotransmitter receptors significantly reduced total behavioral score through effects primarily on tremor and autonomic signs, but none prevented the clonidine syndrome. Lesions of monoaminergic neurons [intracisternal 5,7-dihydroxytryptamine (DHT) or 6-hydroxydopamine] or monoamine depletion by intraperitoneal reserpine all failed to prevent this motor syndrome. Co-administration of 5-HTP and clonidine did not exacerbate the clonidine syndrome in naive rats and did not prevent the onset of the serotonergic syndrome in rats with DHT lesions. These data suggest that neither catecholamines nor 5-HT have a major role in the serotonin-like behavioral responses to high doses of clonidine.

Adrenergic alpha-Antagonists↗
PubMed1987

3-Acetylpyridine lesions and four serotonergic behavioral syndromes in the rat.

We studied the effect of 3-acetylpyridine (3-AP) lesions on the serotonergic-myoclonic syndromes evoked by quipazine (QP), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), fenfluramine (FF), and p-chloroamphetamine (PCA) in the adult rat. Eleven behaviors were scored from videotapes by an observer blind to drug status. In unlesioned rats, drugs could be differentiated by forelimb and axial myoclonus, pivoting and backing. All drugs significantly suppressed rearing. 3-AP produced a lasting action-enhanced body tremor which differed from axial myoclonus in its vertical direction and rhythmicity. 3-AP lesions modified the effect of drugs on several behaviors, increasing axial (QP, FF, PCA) and forelimb (5-MeO-DMT, FF, PCA) myoclonus and decreasing locomotor score. Prior lesions with 5,7-dihydroxytryptamine did not prevent the effect of 3-AP or any behaviors of the serotonin syndrome, but had a slight effect on the magnitude of forelimb myoclonus, head weaving, and hunching induced by some drugs. Neither lesion abolished or reduced myoclonus. These data suggest that intact 5-HT terminals are not requisite for the tremorogenic and cytotoxic effect of 3-AP. To the extent that chemical lesions with 3-AP are selective for the inferior olive (IO), the role of the IO in myoclonus in several 5-HT rodent myoclonic models appears to be regulatory rather than stimulatory.

5,7-Dihydroxytryptamine↗
PubMed1987

Lorazepam in childhood status epilepticus and serial seizures: effectiveness and tachyphylaxis.

We report our experience with 300 consecutive parenteral doses of lorazepam (LOR) for status epilepticus (SE) or serial seizures in 77 children and young adults. The median dose for SE in children less than 12 years old was 0.10 mg/kg. LOR stopped the SE in 79% and diminished the intensity of SE in an additional 4%. Prior acute or chronic anticonvulsant use (excepting chronic benzodiazepines) did not alter effectiveness or increase side effects. Duration of freedom from seizures following acute therapy was independent of LOR dosage. In patients requiring sequential doses, LOR becomes progressively less effective. Side effects were few and, when present, always associated with a single or first dose in a series. LOR is a safe and effective acute anticonvulsant agent for in-hospital control of SE in the pediatric age group. Tachyphylaxis of anticonvulsant action occurs when serial doses are used.

Adolescent↗
PubMed1986

Serotonin-lesion myoclonic syndromes. I. Neurochemical profile and S-1 receptor binding.

This paper and the following one describe the effects of L-5-hydroxytryptophan (5-HTP) (after 3 intracisternal injections of 5,7-dihydroxytryptamine (DHT], fenfluramine (FF), p-chloroamphetamine (PCA) and drug combinations on (i) brain regional amine concentration (HPLC with LEC) and serotonin S-1 receptor binding; and (ii) 'serotonergic' behaviors in the same adult rats. Serotonin (5-HT) neurotoxins produced significantly different regional profiles of 5-HT depletion. Multiple DHT injections caused a 90-100% depletion of 5-HT concurrently in neocortex, hippocampus, striatum, septum/accumbens, pons, cerebellum, and cervical cord. Only PCA significantly depleted midbrain. Drug combinations with DHT resembled DHT alone rather than additive depletions, except for PCA + DHT, which produced a hybrid pattern of depletion. The S-1 binding assay, using cold 5-HT to displace [3H]5-HT, was performed with and without ascorbate, EDTA, CaCl2, and pargyline. Without ascorbate, binding was specific, saturable, region-dependent, and non-linear with high (Kd 1-3 nM) and low affinity (10-20 nM) components but no cooperativity (0.8 less than nH less than 1.0). Bmax and Kd did not differ significantly between vehicle- and drug-treated animals in neocortex, hippocampus, striatum, thalamus, hypothalamus, midbrain, pons, medulla, cervical cord, cerebellum, or septum/accumbens two weeks after lesioning, while the assay did detect a 60% reduction in Bmax induced by ascorbic acid (1 mM). The effects of assay conditions exceeded the changes sometimes reported in S-1 receptor Bmax after 5-HT lesions.

5,7-Dihydroxytryptamine↗
PubMed1986

Serotonin-lesion myoclonic syndromes. II. Analysis of individual syndrome elements, locomotor activity and behavioral correlations.

This study evaluated the behavioral elements of three 5-HT-related syndromes (intraperitoneal 5-hydroxytryptophan after intracisternal 5,7-dihydroxytryptamine (DHT), p-chloroamphetamine (PCA), fenfluramine (FF), or combinations of drugs) scored from video-tapes and their relationship to locomotor activity (LMA) photocell recording, regional monoamine concentration and S-1 receptor binding. Rearing was eliminated by drugs which produce the myoclonic syndrome and was the single best indicator of control treatments (saline or 5-HTP in unlesioned rats and saline in DHT-lesioned rats). Global 'abnormality', hunching (rigid arching of back), hindlimb abduction, forepaw myoclonus, stereotyped lateral head movements, backing, and immobility occurred significantly only in drug-treated rats. Multiple forms of myoclonus (appendicular and truncal) and convulsions were dose-dependent drug effects. Both 5-HTP (after DHT) and PCA increased LMA significantly, but hyperactivity induced by PCA could be blocked by giving 5-HTP concomitantly. Substantial 5-HT presynaptic destruction by DHT prevented backing but not other behavioral or locomotor effects of FF and PCA. Drug combinations did not produce additive behavioral effects. Backing, immobility, and locomotor activity best differentiated between drug treatments, and could be used to correctly allocate animals to drug groups. Drug treatments also could be differentiated by reducing the number of behavioral variables into summary variables (principal components) and by discriminant analysis. Only forepaw myoclonus and total behavioral score were correlated with 5-HT concentrations (brainstem), indicating behavioral heterogeneity. Our study suggests that there is a common core 'myoclonic-serotonergic' syndrome (forepaw myoclonus, head weaving, hindlimb abduction, hunching) of stimulation of 5-HT receptors plus additional drug-specific elements (backing, LMA). Although brainstem receptors appear to be an important locus for some of these behaviors, S-1 receptors do not explain the behavioral supersensitivity to 5-HTP in our DHT-lesioned rats.

5,7-Dihydroxytryptamine↗
PubMed1986

Enhanced selective 5-HT depletions in the DHT rat model: denervation supersensitivity and recovery of function.

The effects of enhancing 5-HT depletion with multiple intracisternal injections of 5,7-dihydroxytryptamine (DHT) on spontaneous or L-5-hydroxytryptophan (5-HTP)-induced behaviors (videotaped) and locomotor activity (photocell recording) were studied in the adult rat. After four DHT injections, 5-HT content in septum/accumbens, hippocampus, striatum, neocortex, cerebellum, and cervical spinal cord fell to 0-10% of controls. Multiple injections also significantly improved depletions in brainstem and diencephalon, which were not as extensive. Spontaneous locomotor activity (LMA) was increased in DHT-lesioned rats for 1 week. The associated behavioral abnormalities, hindlimb hyperextension and incomplete rearing were also transient and differed from the motor syndrome evoked by 5-HTP. Multiple DHT injections did not qualitatively modify the 5-HTP syndrome but shifted the dose response curve to the left compared to single injections. Syndrome behaviors shared a similar dose threshold and could be evoked with 30 mg/kg 5-HTP. Two weeks after DHT, the locomotor response to 5-HTP (65 mg/kg) was method dependent or biphasic: decreased in brief recordings when syndrome abnormalities were greatest and increased in hour-long recordings. LMA correlated with rearing in controls and inversely with total behavioral abnormality in DHT-lesioned rats injected with 5-HTP. Multiple regression of LMA with regional 5-HT content was significant for hippocampus, striatum, and septum/accumbens. These data suggest that the development of denervation supersensitivity, the proposed mechanism of the 5-HTP-evoked motor syndrome, may be responsible for the rapid recovery of function in LMA.(ABSTRACT TRUNCATED AT 250 WORDS)

5,7-Dihydroxytryptamine↗
PubMed1986

Antimyoclonic properties of S2 serotonin receptor antagonists in the rat.

The capacity of the putative S2 serotonin receptor antagonists, pirenperone, pipamperone, ketanserin and cinanserin, to block the myoclonic syndrome produced by 30 mg/kg of L-5-hydroxytryptophan (5-HTP) [after lesioning 5-hydroxytryptamine (serotonin, 5-HT)-containing neurons with 5,7-dihydroxytryptamine (DHT)] or 15 mg/kg of fenfluramine (FF) or p-chloroamphetamine (PCA) was tested in adult male Sprague-Dawley rats. S2 antagonists inhibited limb (arrhythmic and asynchronous) and axial (truncal) myoclonus in a dose-dependent manner in the rank order of potency: pirenperone greater than pipamperone greater than ketanserin = cinanserin. Abnormal movements (myoclonus, lateral head weaving) of the myoclonic syndromes were better antagonized than postural abnormalities (hindlimb abduction, hunching of back). Centrally acting drugs, selective for S2 receptors (pirenperone, pipamperone), exhibited greater antimyoclonic properties than the non-selective 5-HT antagonist methysergide, which was as effective as ketanserin and cinanserin. Significant non-specific reduction in myoclonus without the improvement of other behavioral responses followed treatment with sedative/neuroleptic drugs, such as haloperidol (but not the non-neuroleptic dopamine antagonist sulpiride), clonazepam and diazepam. The anticonvulsants valproic acid (100 and 300 mg/kg), adrenocorticotrophic hormone (ACTH; 100 and 300 U/kg), diphenylhydantoin (15 mg/kg), and phenobarbital (20 mg/kg) and drugs which do not act principally at S2 receptors were ineffective in these models. These data support the hypothesis that myoclonus in behavioral models induced by 5-HT is S2 receptor mediated. S2 antagonists could have a role in the treatment of human myoclonus.

5-Hydroxytryptophan↗
PubMed1986

Effects of adult or neonatal treatment with 6-hydroxydopamine or 5,7-dihydroxytryptamine on locomotor activity, monoamine levels, and response to caffeine.

Rats were treated as neonates or adults with desmethylimipramine (DMI) followed by intraventricular 6-hydroxydopamine (6-HDA) or 5,7 dihydroxytryptamine (5,7-DHT). Locomotor activity of treated rats was measured in photocell cages. Neonatal treatment with 5,7-DHT produced hypoactivity during development while neonatal 6-HDA led to hyperactivity. Treatment of adult rats with 5,7-DHT or 6-HDA, while resulting in equivalent monoamine depletions, was without effect on locomotor activity. The dose response function for caffeine was determined in these rats. Depletion of dopamine by either neonatal or adult treatment with 6-HDA decreased caffeine stimulation of locomotor activity. The adenosine receptor agonist l-phenylisopropyladenosine (L-PIA) decreased locomotor activity in all rats in a dose-dependent fashion.

5,7-Dihydroxytryptamine↗
PubMed1986

Motor habituation in the DHT model: bin analysis of daytime and nocturnal locomotor activity.

We evaluated the usefulness of locomotor bin analysis as a measure of motor habituation, and the effects on habituation of serotonergic manipulations. Spontaneous and L-5-hydroxytryptophan (5-HTP)-evoked locomotor activity (LMA) was measured by photocells and computer-tabulated at 10 minute intervals (bins) during the day and at night in 150 adult rats treated intracisternally with 5,7-dihydroxytryptamine (DHT) or vehicle. Bins were analyzed by visual inspection, which differentiated decremental, incremental, continuous, and discontinuous patterns, and by calculating the ratio of the first to last bin of an hour. In controls, bin ratios were high due to rapid decline (decremental bin pattern) of daytime LMA. After DHT lesions, in contrast, ratios were low for one week. This was due to a failure of normal motor habituation, as reflected by an increase in continuous, discontinuous, and incremental bin patterns. 5-HTP evoked similar dose-related bin abnormalities in DHT-treated rats, after spontaneous patterns had returned to normal, and to a lesser extent in controls. However, no consistent drug or lesion effects on nocturnal LMA were seen. In comparison to daytime LMA, nocturnal LMA showed less habituation, and bin patterns were predominantly of the discontinuous type and more varied. These data suggest that bin analysis contributes useful information on motor habituation and drug and lesion effects and is easily incorporated into automated recording of LMA.

5,7-Dihydroxytryptamine↗
PubMed1986

Huntington's disease in Venezuela: neurologic features and functional decline.

We studied 65 Huntington's disease patients and 225 at-risk individuals over the past 4 years. The rate of decline of these untreated patients from Venezuela was similar to that seen in US patients who had received neuroleptic drugs. Chorea, oculomotor dysfunction, and dysdiadochokinesis were early symptoms; parkinsonian features and dystonia came later. Juvenile patients declined nearly twice as fast as adult-onset patients. No distinctive neurologic phenotypes were seen in children of two affected parents.

Adult↗
PubMed1985

Comparative pharmacological effects on visual cortical neurons in monocularly deprived cats.

Monocularly deprived (MD) cats show a loss of responsiveness to visual stimulation of the deprived eye among visual cortical neurons. Several lines of evidence suggest that this effect involves, at least in part, a suppression of deprived eye input, possibly mediated by GABA inhibition. In order to better understand the nature of this suppression we have evaluated the effectiveness of different types of disinhibitory and excitatory agents to reverse the effects of MD. We investigated bicuculline (a GABA antagonist); picrotoxin (a GABA antagonist with a different mechanism of action from bicuculline); strychnine (a glycine antagonist); ammonium ion (a blocker of membrane chloride channels); physostigmine (a cholinesterase inhibitor); and naloxone (an opiate antagonist and also a GABA antagonist). All drugs were given intravenously. Bicuculline restored binocularity to 50% of the visual cortical neurons tested and naloxone to 36%. With both drugs, receptive fields of the normal eye tended to lose specificity. The emergent deprived eye receptive fields were usually similar to those of the normal eye after drug administration. Ammonium ion produced binocular responses in 27% of neurons tested, but receptive fields were grossly abnormal; moreover, ammonium infusion tended to depress neuronal responsiveness. All other drugs tested failed to restore binocularity. These experiments lend further credence to the hypothesis that GABA inhibition contributes to the cortical effects of MD, since only drugs with GABA antagonistic action were effective in restoring neuronal responsiveness to the deprived eye.

Acetates↗
PubMed1985

The picrotoxinin binding site and its relationship to the GABA receptor complex.

The binding characteristics of [3H] alpha-dihydropicrotoxinin to the picrotoxinin binding site were investigated in membrane preparations of adult rat forebrain and living cultures of rat cerebral cortex. The binding of [3H]alpha-dihydropicrotoxinin to rat forebrain was decreased by lysing, treating with Triton X-100, and heating. Coincubation with gamma-aminobutyric acid (GABA), benzodiazepines, or alterations in the Na+ or Cl- composition of the media had no effect on the binding to the rat brain preparation. However, in the living neurons in tissue culture both GABA and diazepam significantly decreased the binding of [3H]alpha-dihydropicrotoxinin. The dose-response relationships for GABA antagonism of [3H]alpha-dihydropicrotoxinin binding and for picrotoxinin antagonism of the GABA enhancement of [3H]flunitrazepam binding in cultured cortical neurons were also investigated. The Hill coefficients for these actions were reciprocal, suggesting that they result from complementary interactions between the binding sites for GABA and picrotoxinin. These data support the association of the picrotoxinin binding site with the postsynaptic GABA receptor complex.

Acetates↗