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S R Weiss

Publications and source records attributed to S R Weiss.

At least 127 records · Page 7Linked to original sources
PubMed1992

Mouse hepatitis virus A59 increases steady-state levels of MHC mRNAs in primary glial cell cultures and in the murine central nervous system.

Infection of mixed glial cell cultures with mouse hepatitis virus (MHV)-A59 results in an approximately six-fold increase in the level of major histocompatibility complex (MHC) class I mRNA. In situ hybridization of glial cell cultures infected with MHV-A59 again showed enhanced MHC mRNA expression, both in infected and uninfected cells. These results extend our earlier finding that MHC surface antigens are enhanced on astrocytes and oligodendrocytes after MHV-A59 infection and suggest that this enhancement is a result of an increase in the steady-state level of MHC mRNA. We further demonstrate that increases in MHC mRNA occur in the murine central nervous system (CNS) following infection in vivo. Northern blot analysis of RNA from the brains of infected animals showed transient expression of both MHC class I and class II mRNA over the first 14 days of infection. Expression coincided with viral replication and clearance. In situ hybridization of brain sections from infected animals showed that class I and class II expression was widespread throughout all portions of the brain and in uninfected as well as infected cells. Viral RNA, in contrast, was observed in small foci of cells and mostly within the limbic system. Thus enhancement of MHC mRNA was not restricted either to areas of infection or inflammation. The spatial relationship between viral and MHC expression supports our hypothesis that a soluble mediator is involved in the mechanism of the increase in MHC levels. The fact that MHC induction occurs in vivo as well as in vitro suggests MHC may be important in the mechanism of MHV-induced disease.

Animals↗
PubMed1992

Mechanisms of action of anticonvulsants in affective disorders: comparisons with lithium.

Until recently it appeared that lithium carbonate possessed a unique spectrum of clinical action in the acute and prophylactic treatment of manic and depressive episodes. It is now increasingly apparent that the anticonvulsants carbamazepine and valproate also share components of this spectrum of efficacy in the affective disorders but, in addition, are clinically effective in some lithium nonresponders. This clinical convergence can now drive a reexamination of the potential mechanisms of action of these compounds in the affective disorders. In spite of intensive study over several decades, the mechanism of action of lithium has remained elusive. A basic conundrum in the consideration of the actions of lithium has also been to explain how a simple ion could have such complex effects on multiple neurotransmitter systems and, in particular, have bimodal actions in the treatment of both manic and depressive phases of the illness. We suggest that a fundamental reconceptualization of both mania and depression as overactivated neural systems (either excitatory or inhibitory) could facilitate this conceptualization. Given the recent evidence linking lithium's effects to uncoupling receptor-mediated activity at the level of G-proteins or attenuating it at the level of second messenger systems mediated by adenylate cyclase or phosphoinositide turnover, these mechanisms become ideal candidates for considering how the drug could dampen overactivated systems potentially relevant to either depression or mania. The lag in onset of maximum therapeutic action of lithium, carbamazepine, and valproate further suggests that biologic effects associated with chronic compared with acute administration are the prime candidates for psychotropic effects. Comparison of the acute and chronic effects of carbamazepine with those of valproate is also offered to focus on the most likely receptor, second-messenger, and ion channel mechanisms involved in their anticonvulsant and psychotropic actions. It is hoped that better understanding of the comparative actions of lithium, carbamazepine, and valproate will allow better targeting of individual drugs for individual patients as well as, ultimately, the development of new and more selective treatments for the recurrent affective disorders.

Anticonvulsants↗
PubMed1991

Expression of c-fos mRNA in rat brain after intracerebroventricular administration of corticotropin-releasing hormone.

Expression of the proto-oncogene c-fos is known to increase in rat brain following various types of seizures. Measuring c-fos mRNA or protein levels was shown to be a good cellular marker for neurons activated during central nervous system (CNS) excitation. In this study, we used in situ hybridization analysis of c-fos mRNA to determine brain regions activated by a peptide that has been closely linked to stress responsivity and kindling-like seizure activity. Corticotropin-releasing hormone (CRH) was injected into the left lateral ventricle of rats and produced the late onset of seizures between 1.5-5 h after its administration. Rats were sacrificed at various time points after the administration of CRH or sterile water, and c-fos mRNA levels were determined. In the preseizure state, CRH increased c-fos unilaterally in several cerebral cortical structures (most prominently in the dorsal endopiriform nucleus and in the piriform and insular cortices). CRH-induced seizures increased c-fos bilaterally in the same cortical regions, and in addition, in the hippocampus and olfactory bulb. The data are congruous with the hypothesis that intracerebroventricularly (i.c.v.) administered CRH elicits a rapid kindling-like response.

Animals↗
PubMed1991

Contingent tolerance to carbamazepine: a peripheral-type benzodiazepine mechanism.

Rats were tested for anticonvulsant responsivity to agents active at central and peripheral-type benzodiazepine receptors before and after they were made tolerant to the anticonvulsant effects of carbamazepine on amygdala-kindled seizures. Tolerance to carbamazepine in this paradigm is a contingent process; it occurs when the drug is administered prior to, but not following the kindled seizure. In animals tolerant to carbamazepine, cross-tolerance was observed to the anticonvulsant effects of PK11195, which is active at peripheral-type benzodiazepine receptors, but not to diazepam, which affects central-type benzodiazepine receptors. In animals treated with carbamazepine after the kindled seizure (not tolerant), no alteration in the anticonvulsant effect of PK11195 was observed. These data extend previous biochemical and pharmacological findings suggesting the importance of peripheral-type benzodiazepine receptor mechanisms in the anticonvulsant effects of carbamazepine and suggest a role for this site in the process of contingent tolerance development.

Amygdala↗
PubMed1991

Contingent tolerance to carbamazepine is associated with lowering of amygdala-kindled seizure thresholds.

Amygdala-kindled seizure thresholds were studied in animals which were or were not tolerant to the anticonvulsant effects of carbamazepine. The seizure threshold was defined as the lowest current that elicited a major motor seizure (stage 3 or greater). Amygdala-kindled rats received carbamazepine, once daily, either before each electrical stimulation (carba-before) or after each stimulation (carba-after). The rats given carbamazepine before, but not after, each once-daily kindling stimulation became tolerant to its anticonvulsant effects. Following this manipulation, seizure thresholds were redetermined in both groups of animals while medication-free. The carba-before (i.e., tolerant) animals showed a decreased seizure threshold, while the carba-after (i.e., nontolerant) animals showed no change. Tolerance to carbamazepine was reversed by giving the rats kindled seizures for a period of 7 days without drug; nontolerant animals received the same stimulation and seizures. When seizure thresholds were reevaluated, the carba-before animals (now not tolerant) had returned to their pretolerance values, while the carba-after group again showed no change. This effect of carbamazepine tolerance and its reversal being associated with respective decreases and increases in basal seizure threshold was replicated two more times. In each case the change in the generalized seizure threshold mirrored the change in responsivity of the animals to carbamazepine. These findings, consistent with the formulations of Siegel regarding conditioned compensatory response mechanisms mediating contingent drug tolerance, may have important clinical and theoretical implications.

Amygdala↗
PubMed1991

Regional expression of c-fos mRNA in rat brain during the evolution of amygdala kindled seizures.

The biochemical alterations eliciting the growth and spread of afterdischarge and accompanying the evolution of behavioral seizure stages in electrical kindling are not known. In situ hybridization for c-fos mRNA was used to map potential brain structures recruited during the evolution of major seizures from electrical kindling of the amygdala in rats. Two different patterns of c-fos induction were observed in the earliest stages of kindling (stages 1 and 2). A unilateral cortical distribution included the insular, temporal, perirhinal and parietal cortices and the amygdala. No changes in the hippocampus were noted in this group. The second distribution pattern was limited to the hippocampus (either unilateral or bilateral) and amygdala (unilateral) with no changes in the cortical areas. The afterdischarge durations were significantly (2 fold) longer in the 'hippocampal' group as compared to the 'cortical' group. In the later stages of kindling (stages 4 and 5) the distribution of c-fos mRNA was uniformly bilateral and involved a combination of the hippocampal and cortical distributions observed in the earlier stages and including the amygdala bilaterally as well. The induction of c-fos mRNA appears to provide a map of two different routes in the sequential pathways involved in the evolution of kindled seizures; it may also ultimately prove to be an important component of the kindling process itself. Additionally, c-fos mRNA was elevated bilaterally in the inferior colliculus of animals exhibiting running fits with their seizures. The inferior colliculus was previously shown by others to be involved in running fits accompanying convulsions.

Amygdala↗
PubMed1991

Identification of polypeptides encoded in open reading frame 1b of the putative polymerase gene of the murine coronavirus mouse hepatitis virus A59.

The polypeptides encoded in open reading frame (ORF) 1b of the mouse hepatitis virus A59 putative polymerase gene of RNA 1 were identified in the products of in vitro translation of genome RNA. Two antisera directed against fusion proteins containing sequences encoded in portions of the 3'-terminal 2.0 kb of ORF 1b were used to immunoprecipitate p90, p74, p53, p44, and p32 polypeptides. These polypeptides were clearly different in electrophoretic mobility, antiserum reactivity, and partial protease digestion pattern from viral structural proteins and from polypeptides encoded in the 5' end of ORF 1a, previously identified by in vitro translation. The largest of these polypeptides had partial protease digestion patterns similar to those of polypeptides generated by in vitro translation of a synthetic mRNA derived from the 3' end of ORF 1b. The polypeptides encoded in ORF 1b accumulated more slowly during in vitro translation than polypeptides encoded in ORF 1a. This is consistent with the hypothesis that translation of gene A initiates at the 5' end of ORF 1a and that translation of ORF 1b occurs following a frameshift at the ORF 1a-ORF 1b junction. The use of in vitro translation of genome RNA and immunoprecipitation with antisera directed against various regions of the polypeptides encoded in gene A should make it possible to study synthesis and processing of the putative coronavirus polymerase.

Amino Acid Sequence↗
PubMed1990

The primary structure and expression of the second open reading frame of the polymerase gene of the coronavirus MHV-A59; a highly conserved polymerase is expressed by an efficient ribosomal frameshifting mechanism.

Sequence analysis of a substantial part of the polymerase gene of the murine coronavirus MHV-A59 revealed the 3' end of an open reading frame (ORF1a) overlapping with a large ORF (ORF1b; 2733 amino acids) which covers the 3' half of the polymerase gene. The expression of ORF1b occurs by a ribosomal frameshifting mechanism since the ORF1a/ORF1b overlapping nucleotide sequence is capable of inducing ribosomal frameshifting in vitro as well as in vivo. A stem-loop structure and a pseudoknot are predicted in the nucleotide sequence involved in ribosomal frameshifting. Comparison of the predicted amino acid sequence of MHV ORF1b with the amino acid sequence deduced from the corresponding gene of the avian coronavirus IBV demonstrated that in contrast to the other viral genes this ORF is extremely conserved. Detailed analysis of the predicted amino acid sequence revealed sequence elements which are conserved in many DNA and RNA polymerases.

Amino Acid Sequence↗
PubMed1990

Detection of mouse hepatitis virus nonstructural proteins using antisera directed against bacterial viral fusion proteins.

Mouse hepatitis virus, strain A59 cDNAs were inserted into the procaryotic fusion vector pGE374. RecA/viral/LacZ tripartite fusion proteins were synthesized from these plasmids and purified from E. coli. Antisera were raised in rabbits against these fusion proteins. Viral nonstructural proteins were detected in infected murine fibroblasts and glial cells. The anti-gene B, ORF1 sera detect a 30K cytoplasmic protein while the anti-gene E, ORF2 sera detect a 9.6K protein. Sera raised against proteins encoded in cDNAs from 5' portions of gene A immunoprecipitate the 200-250K polypeptides synthesized in vitro from genome RNA. Antisera raised against proteins encoded in both 5' and 3' portions of gene A immunoprecipitate membrane associated polypeptides of 150K and greater than 600K from MHV infected cells.

Animals↗
PubMed1990

Mouse hepatitis virus ORF 2a is expressed in the cytosol of infected mouse fibroblasts.

A 266-bp fragment of cDNA from within gene B, ORF 2a, of MHV-A59 was used to construct a vector encoding a bacterial/viral fusion protein. Antiserum raised against this fusion protein specifically immunoprecipitates a 30K protein from infected 17Cl-1 mouse fibroblasts. The protein is localized primarily in the cytosol and not in the membranes. This is consistent with its predicted sequence and potential role as an RNA binding protein.

Animals↗
PubMed1990

Conditioning as a critical determinant of sensitization induced by psychomotor stimulants.

It is apparent that stimuli associated with psychomotor stimulants as well as opiates acquire the ability to elicit motor behaviors that probably reflect the acquisition and operation of incentive motivational processes. Such conditioning also appears to be a critical determinant of behavioral sensitization seen with repetitive administration of these agents. The conditioning of motor excitation to stimuli associated with psychomotor stimulants follows the principles of classical conditioning and is relatively long lasting. Dopaminergic mechanisms appear to be involved in the acquisition of such conditioned behaviors, since neuroleptics are effective blockers of the process. Dopaminergic blockade probably disrupts conditioning through several different mechanisms including attenuation of the conditioned and unconditioned excitatory properties of the CS and blockade of the US. DA blockade prevents stimuli associated with psychomotor stimulants from acquiring and subsequently generating positive affective motivational states that are reflected by increases in motoric output. While dopamine appears to be necessary for the formation of conditioned motor excitation, it is not critically involved in the expression of the conditioned effects. This seems to suggest that DA may serve only to modulate the formation of motivationally significant associations but is not involved in the expression of conditioned drug effects that may be mediated through DA-independent pathways. The amygdala and nucleus accumbens are two structures in the CNS involved in the acquisition of conditioned motor excitation. Interestingly, both of these brain regions are the recipients of mesolimbic DA input. Dopamine probably plays different roles in each region during the conditioning process. In the amygdala, mesolimbic DA may serve to modulate processes that attach emotional significance to environmental stimuli; further, DA may play a role in determining which stimuli gain access to structures afferent to the amygdala, including the nucleus accumbens. Dopamine in the nucleus accumbens, on the other hand, serves to determine which limbic inputs gain access to the motor pathways. In this way, DA in the nucleus accumbens may translate the motivational determinants of behavior that are mediated by limbic structures into biologically relevant actions. Understanding the mechanisms that determine the conditioning of drug effects to associated stimuli also has possible relevance for elucidating processes underlying addictive behaviors. For example, it has been proposed (Stewart et al. 1984) that the acquisition of incentive motivational properties by stimuli associated with drugs determines the craving in addicts.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Determinants of coronavirus MHV pathogenesis are localized to 3' portions of the genome as determined by ribonucleic acid-ribonucleic acid recombination.

Recombinant viruses derived from coronaviruses mouse hepatitis virus strains JHM and A59, were used to map biologic properties of the virus to viral genes. The 3' portion (about 25%) of the viral genome, including the genes coding for all of the structural proteins, controls biologic properties such as organ tropism of the virus, pattern of the virus-induced central nervous system pathology in mice, plaque morphology, and virus yield in tissue culture.

Animals↗
PubMed1990

Carbamazepine retards the development of cocaine-kindled seizures but not sensitization to cocaine-induced hyperactivity.

The effects of chronic carbamazepine on cocaine-kindled seizures and behavioral sensitization were examined in this study. Rats were fed a diet containing carbamazepine or no drug and then repeatedly administered cocaine (40 and 50 mg/kg intraperitoneally [IP] [117.6 and 147.0 mumol/kg, respectively]). Carbamazepine markedly decreased the development of cocaine-kindled seizures and their associated lethality, but did not affect the development of sensitization of behavioral stereotypies. Carbamazepine consistently decreased the peak stereotypy ratings at the 40 mg/kg but not 50 mg/kg dose. In a 2-day sensitization paradigm chronic carbamazepine did not affect acute cocaine-induced hyperactivity (day 1; 40 mg/kg), nor did it affect sensitization to a low dose challenge of cocaine (day 2; 10 mg/kg [29.4 mumol/kg]). Sensitization of stereotypy and locomotor activity are thought to be related to the psychomotor stimulant properties of cocaine, while seizures may be associated with cocaine's local anesthetic effects. Our data suggest that carbamazepine is inhibiting mechanisms associated with local anesthetic kindling and only minimally affecting the psychomotor stimulant effects of cocaine.

Animals↗
PubMed1989

A general method for the induction and screening of antisera for cDNA-encoded polypeptides: antibodies specific for a coronavirus putative polymerase-encoding gene.

A prokaryotic vector, pGE374, containing the recA and lacZ genes, out-of-frame, was used for the expression of cDNA derived from the putative polymerase-encoding gene of the coronavirus mouse hepatitis virus strain A59 (MHV-A59). The pGE374/viral recombinant vector generates a tripartite bacterial/viral protein composed of a segment of the RecA protein at the N terminus, the coronaviral sequences in the middle, and an enzymatically active beta-galactosidase at the C terminus. Rabbits immunized with such recombinant proteins generated antibodies to the MHV-A59 portion of the tripartite protein. Because the MHV-A59 polymerase proteins have been difficult to identify during infection, we used a novel method to demonstrate the viral specificity of the antiserum. The viral cDNA was excised from the expression vector, and transferred to a pGem vector, downstream from and in-frame with a portion of the cat gene. This construct contained a bacteriophage RNA polymerase promoter that enabled the cell-free synthesis of a fusion protein that was used to verify that antibodies were generated to the expressed viral DNA. This strategy was shown to successfully result in the specific generation of antibodies to the encoded information of the viral cDNA. Furthermore, this method has general applicability in the generation and characterization of antibodies directed against proteins encoded in cDNAs.

Animals↗