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S R Weiss

Publications and source records attributed to S R Weiss.

At least 109 records · Page 6Linked to original sources
PubMed1994

Analysis of the hippocampal GABAA receptor system in kindled rats by autoradiographic and in situ hybridization techniques: contingent tolerance to carbamazepine.

Tolerance to the anticonvulsant effects of carbamazepine (CBZ) in the amygdala kindling paradigm is a contingent process, since it only develops in rats treated with CBZ before the kindling stimulation and not in those animals treated after the stimulation. The present study was designed to investigate the GABAA receptor system in CBZ contingent tolerance. Receptor autoradiography utilizing various radioligands that bind to different components of the GABAA receptor system and in situ hybridization with oligonucleotides that recognize different subunits of the GABAA receptor were performed. Kindling increased binding to benzodiazepine, picrotoxin, and GABA recognition sites selectively in the dentate gyrus of the hippocampus. Kindling also increased levels of mRNA for the alpha 4, beta 1, and beta 3 subunits but did not change alpha 1, alpha 2, or gamma 2 subunit levels. Rats tolerant to CBZ showed decreased [3H]muscimol binding, diazepam-insensitive [3H]Ro 15-4513 binding, and decreased alpha 4 subunit mRNA content compared to non-tolerant rats, whereas [3H]flunitrazepam binding, [35S]TBPS binding, and the levels of beta 1, and beta 3 subunit mRNAs remained elevated. The data suggest an indirect interaction of CBZ with the GABAA receptor system, since CBZ reportedly does not bind to this receptor system.

Affinity Labels↗
PubMed1994

Modulation of hippocampal glucocorticoid and mineralocorticoid receptor mRNA expression by amygdaloid kindling.

In situ hybridization was used to examine the effects of amygdala kindling on the expression of mRNAs for mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in the rat hippocampus. Kindling increased MR mRNA levels in the dentate gyrus of the hippocampus 4 h after the last seizure, and these levels remained elevated 24 h later, but returned to baseline at 4 days. The only other hippocampal region that showed changes was the ipsilateral CA2 subfield where MR mRNA was significantly increased only at the 4-hour time point. Kindling also increased the levels of GR mRNA in the dentate gyrus at 4 h; however, GR mRNA levels significantly decreased below control values at 24 h before returning to normal at 4 days. These data indicate differential transient alterations in hippocampal MR and GR receptor mRNA expression following amygdala-kindled seizures.

Amygdala↗
PubMed1993

Autoradiographic analysis of serotonin receptors and transporter in kindled rat brain.

While serotonin (5-HT) has been shown to be anticonvulsant in several types of experimentally induced seizures, 5-HT receptor binding has not been investigated in the kindling model of epilepsy. The present study examined the effects of amygdala kindling on two 5-HT receptor subtypes and on the 5-HT transporter in rat brain. Kindling induced a persistent bilateral increase in 5-HT1A binding in the dentate gyrus, while 5-HT1B receptors increased only in a delayed fashion. Binding to the 5-HT transporter was transiently decreased in dentate gyrus. In cerebral cortex, binding of the three ligands was unchanged. Alterations in 5-HT receptors and the 5-HT transporter may endogenously modulate kindled seizures. Additionally, autoradiography of adenosine A1 receptors revealed no change for these receptors in any brain region.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Effect of cocaine, lidocaine kindling and carbamazepine on batrachotoxin-induced phosphoinositide hydrolysis in rat brain slices.

Repeated administration of a subconvulsant dose of a local anesthetic will eventually induce seizures, a phenomenon similar to electrical kindling. We have investigated the effect of repeated lidocaine and cocaine administration on the phosphoinositide (PI) hydrolysis induced by batrachotoxin (BTX), a specific Na channel activator. Rats were injected with cocaine or saline daily for 6 days and PI hydrolysis was assayed in sliced frontal cortex. Cocaine treatment had no effect on BTX-induced PI hydrolysis while in vitro cocaine blocked the BTX effect. In a second experiment, rats received daily injections of lidocaine or saline. After a rat developed at least two seizures, it was sacrificed together with a rat receiving lidocaine injections which had never seized and a rat receiving saline injections. Basal, BTX and ibotenic acid (IBO; a glutamate receptor agonist)-stimulated PI hydrolysis did not differ among the three groups in slices of either hippocampus (HC) or piriform cortex (PC) though IBO-stimulated PI hydrolysis was much greater in the HC than in the PC. Neither in vitro nor in vivo carbamazepine altered the effect of cocaine on BTX-induced PI hydrolysis. These results demonstrate that local anesthetic kindling does not alter PI hydrolysis coupled to Na channel or IBO activation.

Animals↗
PubMed1993

Carbamazepine attenuates cocaine-induced increases in dopamine in the nucleus accumbens: an in vivo dialysis study.

Carbamazepine's effects on cocaine-induced increases in dopamine overflow in the nucleus accumbens were studied using in vivo microdialysis in anesthetized rats. Rats were chronically treated with a diet containing carbamazepine or no drug for one week prior to microdialysis procedures. The basal levels of dopamine in the nucleus accumbens did not differ between groups; however, the increases in dopamine following cocaine administration (4 mg/kg i.v.) were significantly reduced by carbamazepine. In addition, basal levels of dihydroxyphenyl acetic acid (DOPAC) were significantly diminished in the carbamazepine group and a trend in the same direction was observed for homovanilic acid (HVA). These results are consistent with reports that carbamazepine might decrease dopamine synthesis. Further studies are required to determine the mechanism of carbamazepine's inhibition of cocaine-induced dopamine overflow and its potential clinical implications.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Identification of peplomer cleavage site mutations arising during persistence of MHV-A59.

Primary mouse glial cell cultures were infected with mouse hepatitis virus strain A59 (MHV-A59) and maintained over an 18 week period. Viruses isolated from these cultures 16-18 weeks postinfection produce small plaques on fibroblasts and cause only minimal levels of cell-to-cell fusion at times when wild type causes nearly complete cell fusion. However, when mutant-infected cultures were examined 24-36 hours postinfection approximately 90% of the cells were in syncytia showing that the fusion defect is not absolute but rather delayed. Addition of trypsin to mutant-infected cultures enhanced cell fusion a small (2- to 5-fold) but significant degree. Sequencing of portions of the spike genes of six fusion-defective mutants revealed that all contained the same single nucleotide mutation resulting in a substitution of aspartic acid for histidine in the spike cleavage signal. Mutant virions contained only the 180 kDa form of spike protein suggesting that this mutation prevented the normal proteolytic cleavage of the 180 kDa protein into the 90 kDa subunits. Examination of revertants of the mutants supports this hypothesis. Replacement of the negatively-charged aspartic acid with either the wild type histidine or a non-polar amino acid was associated with the restoration of spike protein cleavage and cell fusion.

Animals↗
PubMed1993

A newly identified MHV-A59 ORF1a polypeptide p65 is temperature sensitive in two RNA negative mutants.

Polypeptide products of MHV-A59 gene 1 have been identified in infected DBT cells and in the products of in vitro translations of genome RNA. In this paper we report the identification in infected cell lysates of a 65-kDa polypeptide (p65) encoded in ORF 1a. Studies on the kinetics of appearance and processing of p65 show that p65 is detectable after p28 but before the appearance of p290, p240 and p50. No homologue of the p65 polypeptide identified in infected cell lysates was immunoprecipitated from in vitro translations of genomic RNA, providing further evidence that in vitro processing of polypeptides encoded in ORF 1a of gene 1 differs from that which occurs late in infection of DBT cells. Although the function of p65 is unknown, two MHV-A59 ts mutants isolated and characterized by Baric et al. (3,4) do not produce detectable levels of p65 at the non-permissive temperature indicating that p65 may play an important role in the virus life cycle.

Animals↗
PubMed1993

The ns 4 gene of mouse hepatitis virus (MHV), strain A 59 contains two ORFs and thus differs from ns 4 of the JHM and S strains.

The sequence of the MHV-A 59 non-structural gene 4 (ns 4) reveals two open reading frames. The upstream ORF potentially encodes a 19 amino acid (2.2 kDa) polypeptide and the downstream ORF potentially encodes a 106 amino acid (11.7 kDa) polypeptide. This is in contrast to MHV-JHM gene 4 which expresses a 15 kDa protein. Cell free translation of a synthetic mRNA containing both ORFs of MHV-A 59 ns 4 results in the synthesis of a 2.2 kDa polypeptide; the predicted 11.7 kDa product of the MHV-A 59 downstream ORF is not detected during cell free translation nor in infected cells. These results add to the recent data suggesting that expression of some of the ns proteins of MHV is not necessary for efficient growth in tissue culture.

Amino Acid Sequence↗
PubMed1993

Contingent tolerance to carbamazepine is not affected by calcium-channel or NMDA receptor blockers.

We previously demonstrated that tolerance to carbamazepine's anticonvulsant effects occurs only with contingent presentation of the drug relative to the seizure (i.e., drug administration before but not after the seizure). Moreover, this tolerance can be reversed by altering the contingencies of drug administration (e.g., giving the drug after the seizure has occurred) without discontinuation of drug treatment. These findings imply an associative component to tolerance development in this model. Thus, we evaluated the effects on contingent tolerance development of two agents that have been shown to affect rate of tolerance development and acquisition or retention in other learning paradigms. Rats were electrically kindled in the amygdala until they reliably experienced seizures with each stimulation. In three separate studies, MK-801 (0.3 and 0.15 mg/kg), an NMDA receptor antagonist, and nimodipine (20 mg/kg), an L-type calcium channel blocker, were coadministered with carbamazepine prior to each kindling stimulation to evaluate the rate of tolerance development compared to controls. No effect of either drug was seen on the rate of contingent tolerance development to carbamazepine, suggesting that neither NMDA receptors nor L-type calcium channels are critically involved in this type of tolerance. The contingent tolerance paradigm may, however, prove useful in elucidating novel biochemical mechanisms of associative learning that might ultimately be explored in clinical situations where tolerance is a problem.

Animals↗
PubMed1993

Cross-tolerance between carbamazepine and valproate on amygdala-kindled seizures.

Carbamazepine and valproate are two clinically used anticonvulsants which are also effective in the treatment of manic-depressive illness. Although the biochemical profiles of these drugs are markedly different, some mechanisms in common may be implied by their partially overlapping spectrum of therapeutic efficacy in seizure and affective disorders. Further evaluation of common biological targets of these agents was attempted by determining whether cross-tolerance would occur to the anticonvulsant effects of carbamazepine and valproate on amygdala-kindled seizures. It had previously been shown that tolerance to carbamazepine's anticonvulsant effects on amygdala-kindled seizures occurs only with contingent drug administration, i.e., it occurs only when the drug is injected before the kindling stimulation, and not when the drug is given after the seizure. In the current studies, rats that were made tolerant to carbamazepine showed cross-tolerance to valproate. Kindled rats given carbamazepine after each seizure stimulation (i.e., non-tolerant controls) did not show tolerance to valproate's anticonvulsant effects, indicating that the cross-tolerance between carbamazepine and valproate was also contingent. The clinical implications and potential common biochemical target mechanisms of the cross-tolerance between carbamazepine and valproate deserve further investigation.

Amygdala↗
PubMed1993

Differential effects of kindled and electrically induced seizures on a glutamate receptor (GluR1) gene expression.

To address the question of whether the mode of seizure induction contributes to the effects of seizures on glutamate receptor gene expression, we examined rat dorsal hippocampal slides by in situ hybridization after kindling by electrical stimulation of the amygdala, or after electrically induced tonic-clonic seizures. Levels of a glutamate receptor subtype (GluR1) mRNA were analyzed at three periods post kindled seizures and found to be decreased only in brains that were obtained 24 h after the last kindled seizure. This downregulation of GluR1 mRNA was transient and was observed only in animals that had behavioral manifestations after being electrically stimulated. It is probable that maintenance of the kindled state cannot be explained by a long-lasting change in GluR1 gene expression. Repeated electroshock-induced seizures increased GluR1 mRNA levels in the hippocampus. Our results show that mode of induction is an important determinant of the effects of seizures on the levels of expression of a glutamate receptor gene.

Analysis of Variance↗
PubMed1993

Fusion-defective mutants of mouse hepatitis virus A59 contain a mutation in the spike protein cleavage signal.

Infection of primary mouse glial cell cultures with mouse hepatitis virus strain A59 results in a productive, persistent infection, but without any obvious cytopathic effect. Mutant viruses isolated from infected glial cultures 16 to 18 weeks postinfection replicate with kinetics similar to those of wild-type virus but produce small plaques on fibroblasts and cause only minimal levels of cell-to-cell fusion under conditions in which wild type causes nearly complete cell fusion. However, since extensive fusion is present in mutant-infected cells at late times postinfection, the defect is actually a delay in kinetics rather than an absolute block in activity. Addition of trypsin to mutant-infected fibroblast cultures enhanced cell fusion a small (two- to fivefold) but significant degree, indicating that the defect could be due to a lack of cleavage of the viral spike (fusion) protein. Sequencing of portions of the spike genes of six fusion-defective mutants revealed that all contained the same single nucleotide mutation resulting in a substitution of aspartic acid for histidine in the spike cleavage signal. Mutant virions contained only the 180-kDa form of spike protein, suggesting that this mutation prevented the normal proteolytic cleavage of the 180-kDa protein into the 90-kDa subunits. Examination of revertants of the mutants supports this hypothesis. Acquisition of fusion competence correlates with the replacement of the negatively charged aspartic acid with either the wild-type histidine or a nonpolar amino acid and the restoration of spike protein cleavage. These data confirm and extend previous reports concluding cleavage of S is required for efficient cell-cell fusion by mouse hepatitis virus but not for virus-cell fusion (infectivity).

Amino Acid Sequence↗
PubMed1992

Ziskind-Somerfeld Research Award 1992. Endogenous biochemical abnormalities in affective illness: therapeutic versus pathogenic.

Examination of the neurobiology of psychiatric illness in general, and of affective disorders in particular, reveals a variety of associated biochemical abnormalities. These have generally been assumed to be part of the pathological process or secondary to it, and thus deserving of therapeutic efforts aimed at reversal. However, recent clinical and preclinical data suggest that some alterations occurring in the affective disorders may be compensatory and adaptive; that is, part of an endogenous therapeutic mechanism rather than part of the evolving disease process. For example, the symptom of sleep loss in depression seems to fall under this rubric inasmuch as sleep deprivation induces mood improvement in depressed patients. Preclinical data are presented that another primary pathological process--the occurrence of kindled seizures--can evoke endogenous compensatory processes that are either anticonvulsant in their own right, or enable the anticonvulsant effects of a drug such as carbamazepine. It may be that some biochemical abnormalities occurring in affective illness are similarly adaptive. As one example, increased thyrotropin-releasing hormone (TRH) has been reported in the cerebrospinal fluid (CSF) of depressed patients. This elevation of TRH and the resulting neuroendocrine profile may be part of an endogenous counter-regulatory process aimed at mood improvement. Again, preclinical seizure models are supportive in that TRH not only is induced following repeated seizures, but also exerts anticonvulsant effects on these same seizures. In an analogous fashion, TRH elevations in depressed patients may also exert ameliorating effects on depressive symptomatology. This formulation presents directly testable hypotheses that could importantly impact on our understanding of the pathophysiology of affective disorders, and suggests novel therapeutic strategies through the enhancement of endogenous compensatory mechanisms.

Amygdala↗
PubMed1992

Expression of c-fos mRNA in acute and kindled cocaine seizures in rats.

In situ hybridization for c-fos mRNA was performed on brain sections (a) from rats after an acute cocaine-induced seizure or from saline-injected controls and (b) from rats after their first cocaine-kindled seizure, as well as from rats that had not yet developed cocaine-kindled seizures (but were exposed to the same amount of cocaine as those that did exhibit convulsions) and from saline-injected controls. Increased expression of c-fos mRNA was observed in animals demonstrating cocaine-induced seizures acutely or following pharmacological kindling. Rats that experienced acute seizures after cocaine (65 mg/kg) showed pronounced increase in expression of c-fos mRNA in the dentate gyrus of the hippocampus and olfactory bulb. Increases were also observed in several other limbic cortical regions, as well as the striatum and ventromedial hypothalamic nucleus (VMH). In rats that were injected daily with an initially subconvulsive dose of cocaine-HCl (40 mg/kg), the cocaine-kindled seizures induced elevations in c-fos mRNA in the same brain regions as with an acute cocaine-induced seizure with the single exception of the VMH. These findings not only suggest the involvement of limbic, cortical and striatal structures in the cocaine-induced seizure, but also raise the possibility that alterations in the proto-oncogene c-fos and its subsequent impact on gene expression could play a role in the changes in neural excitability associated with cocaine-induced kindling.

Animals↗
PubMed1992

Intracellular processing of the N-terminal ORF 1a proteins of the coronavirus MHV-A59 requires multiple proteolytic events.

Several polypeptide products of MHV-A59 ORF 1a were characterized in MHV-A59 infected DBT cells, using antisera directed against fusion proteins encoded in the first 6.5 kb of ORF1a. These included the previously identified N-terminal ORF 1a product, p28, as well as 290-, 240-, and 50-kDa polypeptides. P28 was always detected as a discrete band without larger precursors, suggesting rapid cleavage of p28 immediately after its synthesis. Once p28 was cleaved there was little degradation of the protein over a 2-hr period. The intracellular cleavage of p28 was not inhibited by the protease inhibitor leupeptin, in contrast to results obtained during in vitro translation of genome RNA (Denison and Perlman, 1986). These data suggest that different protease activities may be responsible for the cleavage of p28 in vitro and in vivo. The 290-kDa protein was an intermediate cleavage product derived from a precursor of greater than 400 kDa. The 290-kDa product was subsequently cleaved into secondary products of 50 and 240 kDa. The intracellular cleavage of the 290-kDa polypeptide was inhibited by leupeptin at concentrations which did not inhibit the early cleavage of p28 or the cleavage of the 290-kDa product from its larger polyprotein precursor. In the presence of zinc chloride, a product of greater than 320 kDa was detected, which appears to incorporate p28 at its amino terminus. This suggests that at least two protease activities may be necessary for processing of ORF1a proteins, one of which cleaves p28 and is sensitive to zinc chloride but resistant to leupeptin, and the other which cleaves the 290-kDa precursor and is sensitive to both inhibitors. Both the 290- and 240-kDa proteins should contain sequences predicted to encode two papain-like protease activities.

Leupeptins↗
PubMed1992

Induction of constitutive heat shock protein 73 mRNA in the dentate gyrus by seizures.

We examined the effects of generalized seizures on heat shock protein (hsp) mRNA induction in the rat brain using in situ hybridization. Seizures induced by electroconvulsive shock, electrical or cocaine kindling caused a selective induction of the constitutive hsp 73 gene in the dentate gyrus. In these seizure paradigms, not thought to induce widespread tissue damage, neither the heat-inducible hsp 72 gene nor a member of the hsp 90 family (hsp 84) were induced. Hsp 73 may play a role in the adaptation and/or in the maintenance of dentate granule cell integrity following seizures.

Amygdala↗
PubMed1992

Alterations in mRNA of enkephalin, dynorphin and thyrotropin releasing hormone during amygdala kindling: an in situ hybridization study.

The present study examined changes in mRNA expression of various neuropeptides at several stages of amygdala kindled seizures. 35S-labelled oligonucleotide probes for mRNA of enkephalin (ENK), dynorphin (DYN) and thyrotropin releasing hormone (TRH) were hybridized to brain sections of rats sacrificed 24 h after a stage 1 or stage 5 seizure, or 2 weeks after a stage 5 seizure. Changes in expression developed as kindling progressed, with long-lasting changes in ENK and transient changes in DYN and TRH. ENK mRNA levels increased in pyriform and entorhinal cortices at stage 1 and 5 and remained elevated in the pyriform two weeks after a stage 5 seizure. In contrast, DYN mRNA was decreased bilaterally in the dentate gyrus 24 h after a stage 5 seizure, but returned to control levels two weeks after a stage 5 seizure. TRH mRNA was dramatically increased 24 h after a stage 1 or stage 5 seizure. After a stage 1 seizure two patterns developed. One showed increases in the pyriform, entorhinal and perirhinal cortices ipsilateral to the stimulation. The other pattern displayed bilateral increases in the dentate gyrus with or without the unilateral increases the limbic cortices. Twenty-four hours after a stage 5 seizure, large bilateral increases were found in these areas, but these returned to baseline levels by two weeks after a stage 5 seizure. The data demonstrate a constellation of alterations in several peptide systems with distinct spatiotemporal patterns, particularly in regions known to be important in kindling and epilepsy, such as the dentate gyrus and pyriform and entorhinal cortices. The relationship of these neuropeptide mRNA changes to those previously found in c-fos mRNA expression during the development of kindling is discussed.

Amygdala↗