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S E Hyman

Publications and source records attributed to S E Hyman.

At least 37 records · Page 2Linked to original sources
PubMed1999

Contrasting calcium dependencies of SAPK and ERK activations by glutamate in cultured striatal neurons.

Stress-activated protein kinase (SAPK) and extracellular signal-regulated kinase (ERK), both members of the mitogen-activated protein kinase (MAPK) family, may in some circumstances serve opposing functions with respect to cell survival. However, SAPK and ERK can also be coordinately activated in neurons in response to glutamate stimulation of NMDA receptors. To explore the mechanisms of these MAPK activations, we compared the ionic mechanisms mediating SAPK and ERK activations by glutamate. In primary cultures of striatal neurons, glutamatergic activation of ERK and one of its transcription factor targets, CREB, showed a calcium dependence typical of NMDA receptor-mediated responses. In contrast, extracellular calcium was not required for glutamatergic, NMDA receptor-mediated activation of SAPK and phosphorylation of its substrate, c-Jun. Increasing extracellular calcium enhanced ERK activation but reversed SAPK activation, further distinguishing the calcium dependencies of these two NMDA receptor-mediated effects. Finally, reducing extracellular sodium prevented the glutamatergic activation of SAPK but only partially blocked that of ERK. These contrasting ionic dependencies suggest a mechanism by which NMDA receptor activation may, under distinct conditions, differentially regulate neuronal MAPKs and their divergent functions.

Animals↗
PubMed1999

Cyclic AMP-dependent activation of the proenkephalin gene requires phosphorylation of CREB at serine-133 and a Src-related kinase.

The transcription factor CREB [cyclic AMP response element (CRE)-binding protein] is activated by several kinase pathways on phosphorylation of serine-133. Phosphorylation of CREB at serine-133 is required for the induction of target gene expression. The proenkephalin gene is a target of cyclic AMP-dependent agonists like forskolin, and its expression is driven by the enhancer element CRE-2. It has been shown that CREB binds CRE-2 in extracts from striatum and hypothalamus. However, these studies did not show a functional requirement for CREB serine-133 phosphorylation in CRE-2 function. We demonstrate that CREB binds CRE-2 in primary astrocyte cultures and that transcriptional activation of CRE-2 requires CREB phosphorylation at serine-133. In addition, it has recently been shown that, at least in some contexts, CREB phosphorylation is not sufficient to activate target gene expression and that another intracellular signal seems to be required. Therefore, we also sought to determine if another signaling event, in addition to CREB phosphorylation, might be involved in cyclic AMP-mediated induction of the proenkephalin gene. We have found that the inhibition of src-related nonreceptor tyrosine kinases blocks forskolin-induced proenkephalin gene expression without having any effect on serine-133-phosphorylated CREB levels and that constitutively activated src kinase can activate the proenkephalin promoter.

Animals↗
PubMed1998

DARPP-32: regulator of the efficacy of dopaminergic neurotransmission.

Dopaminergic neurons exert a major modulatory effect on the forebrain. Dopamine and adenosine 3',5'-monophosphate-regulated phosphoprotein (32 kilodaltons) (DARPP-32), which is enriched in all neurons that receive a dopaminergic input, is converted in response to dopamine into a potent protein phosphatase inhibitor. Mice generated to contain a targeted disruption of the DARPP-32 gene showed profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse, and antipsychotic medication. The results show that DARPP-32 plays a central role in regulating the efficacy of dopaminergic neurotransmission.

Amphetamines↗
PubMed1998

A complex program of striatal gene expression induced by dopaminergic stimulation.

Dopamine acting in the striatum is necessary for normal movement and motivation. Drugs that change striatal dopamine neurotransmission can have long-term effects on striatal physiology and behavior; these effects are thought to involve alterations in gene expression. Using the 6-hydroxydopamine lesion model of Parkinson's disease and differential display PCR, we have identified a set of more than 30 genes whose expression rapidly increases in response to stimulation of striatal dopamine D1 receptors. The induced mRNAs include both novel and previously described genes, with diverse time courses of expression. Some genes are expressed at near-maximal levels within 30 min, whereas others show no substantial induction until 2 hr or more after stimulation. Some of the induced genes, such as CREM, CHOP, and MAP kinase phosphatase-1, may be components of a homeostatic response to excessive stimulation. Others may be part of a genetic program involved in cellular and synaptic plasticity. A very similar set of genes is induced in unlesioned animals by administration of the psychostimulant cocaine or the antipsychotic eticlopride, although in distinct striatal cell populations. In contrast to some previously described early genes, most of the novel genes are not induced in cortex by apomorphine, indicating specificity of induction. Thus we have identified novel components of a complex, coordinated genetic program that is induced in striatal cells in response to various dopaminergic manipulations.

Animals↗
PubMed1998

5-HT3 receptor activation is required for induction of striatal c-Fos and phosphorylation of ATF-1 by amphetamine.

Dopamine (DA) has been shown to be required for the induction of striatal gene expression by psychostimulants. However, direct DA agonists or selective inhibitors of DA reuptake are relatively weak inducers of striatal gene expression compared with cocaine or amphetamine. So although necessary, DA alone is not sufficient to mediate the full gene induction response to psychostimulants. In addition to its actions on the DA transporter, amphetamine also enhances serotonin (5-HT) release in the striatum. In this study, we investigated the mechanism by which 5-HT contributes to the regulation of striatal gene expression by amphetamine. We found that selective lesions of serotonergic terminals in the rat forebrain using 5,7-dihydroxytryptamine prevented the full induction of striatal c-Fos by 4 mg/kg amphetamine. Furthermore, amphetamine-induced striatal c-Fos was completely inhibited by administration of the 5-HT3 receptor antagonist, MDL-72222, but not by the 5-HT2A/2C receptor antagonist, ritanserin. Consistent with this finding, the induction of c-Fos by 5-HT in primary cultures of E18 striatal neurons devoid of DA input was blocked by the 5-HT3 receptor antagonists, MDL-72222 and ICS 205-930, but not by 5-HT2A/2C antagonism. Additionally, blockade of 5-HT3 receptors by MDL-72222 inhibited the phosphorylation of activating transcription factor-1 (ATF-1) at Ser63 by amphetamine, but not the phosphorylation of cAMP response element binding protein (CREB) at Ser133. These results suggest that 5-HT3 receptor activation may be required for amphetamine-induced expression of ATF-1-regulated target genes in the striatum, which may include c-Fos.

Activating Transcription Factor 1↗
PubMed1998

Cocaine decreases cortical cerebral blood flow but does not obscure regional activation in functional magnetic resonance imaging in human subjects.

The authors used functional magnetic resonance imaging (fMRI) to determine whether acute intravenous (i.v.) cocaine use would change global cerebral blood flow (CBF) or visual stimulation-induced functional activation. They used flow-sensitive alternating inversion recovery (FAIR) scan sequences to measure CBF and blood oxygen level-dependent (BOLD) sensitive T2* scan sequences during visual stimulation to measure neuronal activation before and after cocaine and saline infusions. Cocaine (0.6 mg/kg i.v. over 30 seconds) increased heart rate and mean blood pressure and decreased end tidal carbon dioxide (CO2). All measures returned to baseline by 2 hours, the interinfusion interval, and were unchanged by saline. Flow-sensitive alternating inversion recovery imaging demonstrated that cortical gray matter CBF was unchanged after saline infusion (-2.4 +/- 6.5%) but decreased (-14.1 +/- 8.5%) after cocaine infusion (n = 8, P < 0.01). No decreases were detected in white matter, nor were changes found comparing BOLD signal intensity in cortical gray matter immediately before cocaine infusion with that measured 10 minutes after infusion. Visual stimulation resulted in comparable BOLD signal increases in visual cortex in all conditions (before and after cocaine and saline infusion). Despite a small (14%) but significant decrease in global cortical gray matter CBF after acute cocaine infusion, specific regional increases in BOLD imaging, mediated by neurons, can be measured reliably.

Adult↗
PubMed1997

Glutamate, but not dopamine, stimulates stress-activated protein kinase and AP-1-mediated transcription in striatal neurons.

Drugs that stimulate dopamine and glutamate receptors have been shown to induce the expression of AP-1 proteins (such as c-Fos and c-Jun) in the striatum and to induce binding of these proteins to AP-1 sites on DNA, leading to the hypothesis that AP-1-mediated transcription contributes to the long-term effects of these drugs. To examine this hypothesis, we compared the regulation of AP-1-mediated transcription to the inductions of AP-1-binding activity and genes encoding AP-1 proteins in primary cultures of striatal neurons. Although glutamate, dopamine, and forskolin (an activator of adenylate cyclase) all induce c-fos mRNA and AP-1 binding, we found, surprisingly, that only glutamate induces transcription of a transfected AP-1-driven fusion gene. To explore the basis for this discrepancy, we investigated the possibility that the phosphorylation of c-Jun may also be required for AP-1-mediated transcription in striatal neurons. Glutamate, but neither dopamine nor forskolin, raises the levels of phosphorylated c-Jun as well as the activity of a Jun kinase (SAPK/JNK) in striatal cultures. Both the glutamatergic induction of AP-1-mediated transcription and activation of SAPK/JNK appear to be mediated, at least in part, via NMDA receptors. In striatal neurons, the phosphorylation of AP-1 proteins produced by glutamate may be required to convert AP-1 protein expression and binding to transcriptional activation.

Activating Transcription Factor 2↗
PubMed1997

Acute effects of cocaine on human brain activity and emotion.

We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, ventral tegmentum, and pons and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pons, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving.

Adult↗
PubMed1996

Influence of cocaine on the JAK-STAT pathway in the mesolimbic dopamine system.

Chronic exposure to cocaine produces characteristic biochemical adaptations within the rat ventral tegmental area (VTA), a brain region rich in dopaminergic neurons implicated in the reinforcing and locomotor-activating properties of cocaine. Some of these changes are mimicked by chronic ciliary neurotrophic factor (CNTF) infusions into the same brain area. We show in this study that chronic cocaine treatment regulates the signal transduction pathway used by CNTF specifically in the VTA. There is an increase in immunoreactivity of Janus kinase (JAK2), a CNTF-regulated protein tyrosine kinase, in the VTA after chronic but not acute cocaine administration. This increase is not seen in the nearby substantia nigra or several other brain regions studied. Furthermore, this increase in JAK2 is not seen after chronic administration of other psychotropic drugs and was not observed for JAK1. The increase in JAK2 levels is associated with an increased responsiveness of the system to acute CNTF infusion into the VTA, as measured by induction in this brain region of signal transducers and activators of transcription (STAT) DNA binding activity and of Fos-like proteins, two known functional endpoints of JAK activation. Double-labeling immunohistochemical studies show that JAK2 immunoreactivity in the VTA is enriched in dopaminergic and nondopaminergic cells, both of which exhibit increased JAK2 immunoreactivity after chronic cocaine treatment. These findings suggest a scheme whereby some of the effects of chronic cocaine on VTA dopaminergic neurons are mediated directly by regulation of the JAK-STAT pathway in these cells, as well as perhaps indirectly by regulation of this pathway in nondopaminergic cells.

Animals↗