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Biomedical subjects

N Hiroi

Publications and source records attributed to N Hiroi.

At least 19 recordsLinked to original sources
PubMed1998

Regulation of cocaine reward by CREB.

Cocaine regulates the transcription factor CREB (adenosine 3', 5'-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction. Overexpression of CREB in this region decreases the rewarding effects of cocaine and makes low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increases the rewarding effects of cocaine. Altered transcription of dynorphin likely contributes to these effects: Its expression is increased by overexpression of CREB and decreased by overexpression of mutant CREB. Moreover, blockade of kappa opioid receptors (on which dynorphin acts) antagonizes the negative effect of CREB on cocaine reward. These results identify an intracellular cascade-culminating in gene expression-through which exposure to cocaine modifies subsequent responsiveness to the drug.

Animals↗
PubMed1998

Essential role of the fosB gene in molecular, cellular, and behavioral actions of chronic electroconvulsive seizures.

The role of Fos-like transcription factors in neuronal and behavioral plasticity has remained elusive. Here we demonstrate that a Fos family member protein plays physiological roles in the neuronal, electrophysiological, and behavioral plasticity associated with repeated seizures. Repeated electroconvulsive seizures (ECS) induced isoforms of DeltaFosB in frontal cortex, an effect that was associated with increased levels of the NMDA receptor 1 (NMDAR1) glutamate receptor subunit. Induction of DeltaFosB and the upregulation of NMDAR1 occurred within the same neurons in superficial layers of neocortex. Activator protein-1 (AP-1) complexes composed of DeltaFosB were bound to a consensus AP-1 site in the 5'-promoter region of the NMDAR1 gene. The upregulation of NMDAR1 was absent in mice with a targeted disruption of the fosB gene. In addition, repeated ECS treatment caused progressively shorter motor seizures (tolerance) in both rats and wild-type mice, as well as reduced NMDA-induced inward currents in pyramidal neurons from superficial layers of the neocortex of wild-type mice. These behavioral and electrophysiological effects were also significantly attenuated in fosB mutant mice. These findings identify fosB gene products as transcription factors critical for molecular, electrophysiological, and behavioral adaptations to motor seizures.

Adaptation, Psychological↗
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

Preferential localization of self-stimulation sites in striosomes/patches in the rat striatum.

Histological sections of the mammalian striatum reveal a "matrix" that is histochemically distinguishable from patches, or "striosomes". The latter are cross sections of a compartment that consists primarily of tube-shaped structures radiating through the matrix. As a test of the hypothesis that the function of the striosome/patch compartment includes the mediation of behaviors related to reward, the present study examined electrical self-stimulation of the caudoputamen in rats with electrodes in either of the two compartments. Rats acquired and maintained bar-pressing responses that were contingent on stimulation through electrodes making contact with striosomes/patches more reliably than animals with electrodes terminating exclusively in the matrix. The results provide in vivo evidence that the striosome/patch compartment is functionally differentiated from the matrix compartment: Stimulation centered in or around the striosome/patch compartment but not in the matrix led to rapid acquisition of a new behavior.

Animals↗
PubMed1998

Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor.

There is increasing evidence that genetic factors can influence individual differences in vulnerability to drugs of abuse. Serotonin (5-hydroxytryptamine, 5-HT), acting through many receptors can modulate the activity of neural reward pathways and thus the effects of various drugs of abuse. Here we examine the effects of cocaine in mice lacking one of the serotonin-receptor subtypes, the 5-HT1B receptor. We show that mice lacking 5-HT1B display increased locomotor responses to cocaine and that they are more motivated to self-administer cocaine. We propose that even drug-naive 5-HT1B-knockout mice are in a behavioural and biochemical state that resembles that of wild-type mice sensitized to cocaine by repeated exposure to the drug. This altered state might be responsible for their increased vulnerability to cocaine.

Animals↗
PubMed1998

Human ACTH hypersensitivity syndrome associated with abnormalities of the ACTH receptor gene.

OBJECTIVE: Activating mutations of the ACTH receptor have not been previously described. We investigated a 69-year-old woman with normal blood cortisol but undetectable blood ACTH concentrations. The aim of this study was to evaluate her hypothalamo-pituitary-adrenal axis by measuring circadian variation in blood ACTH and cortisol, and by performing CRH and ACTH stimulation and dexamethasone suppression tests. We also examined biological activity of her circulating blood ACTH using bovine adrenocortical cell suspensions and ACTH receptor gene structure by Northern blotting analysis. RESULTS: Random plasma cortisol concentrations ranged from 182 to 328 nmol/l, while ACTH concentrations were always undetectable. After an intravenous bolus injection of human CRH 100 micrograms, plasma ACTH rose slightly, while plasma cortisol increased appropriately. ACTH stimulation tests revealed that a small amount of ACTH (5 ng/kg b.w.) had the maximal cortisol stimulatory activity, and even smaller amounts of ACTH (0.5 and 0.05 ng/kg b.w.) produced significant increases in cortisol levels. ACTH bioassay of the patient's plasma demonstrated weak biological activity in the HPLC fractions which corresponded to the band of synthetic human ACTH 1-39. The ACTH receptor coding region was amplified by polymerase chain reaction using the leucocyte genomic DNA. There were two base mutations; cysteine 21-->arginine and serine 247-->glycine in the sequences coding for the first extramembranous N-terminal domain and the third extramembranous loop of the ACTH receptor. CONCLUSIONS: This patient with normal blood cortisol but undetectable ACTH levels showed increased adrenocortical sensitivity to ACTH and two point mutations in the ACTH receptor gene. This study, therefore, reports a previously undescribed syndrome--ACTH hypersensitivity syndrome--and provides insights into the molecular mechanism of ACTH receptor action.

Adrenal Cortex Function Tests↗
PubMed1997

FosB mutant mice: loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects.

Chronic exposure to cocaine leads to prominent, long-lasting changes in behavior that characterize a state of addiction. The striatum, including the nucleus accumbens and caudoputamen, is an important substrate for these actions. We previously have shown that long-lasting Fos-related proteins of 35-37 kDa are induced in the striatum by chronic cocaine administration. In the present study, the identity and functional role of these Fos-related proteins were examined using fosB mutant mice. The striatum of these mice completely lacked basal levels of the 35- to 37-kDa Fos-related proteins as well as their induction by chronic cocaine administration. This deficiency was associated with enhanced behavioral responses to cocaine: fosB mutant mice showed exaggerated locomotor activation in response to initial cocaine exposures as well as robust conditioned place preference to a lower dose of cocaine, compared with wild-type littermates. These results establish the long-lasting Fos-related proteins as products of the fosB gene (specifically DeltaFosB isoforms) and suggest that transcriptional regulation by fosB gene products plays a critical role in cocaine-induced behavioral responses. This finding demonstrates that a Fos family member protein plays a functional role in behavioral responses to drugs of abuse and implicates fosB gene products as important determinants of cocaine abuse.

Animals↗
PubMed1997

[ACTH receptor].

Explore the source record for details and available documents.

Adrenocorticotropic Hormone↗
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↗
PubMed1996

Atypical and typical neuroleptic treatments induce distinct programs of transcription factor expression in the striatum.

Atypical and typical neuroleptics, when administered chronically, can bring about profound but contrasting changes in schizophrenic symptoms and motor activation and dramatically modulate brain neurochemistry. To explore the transcriptional events that might be involved in this neurochemical regulation, we used immunohistochemistry and immunoblotting to examine the expression patterns of two bZip transcription factors, c-Fos and FosB, in the striatum of rats treated acutely and chronically with neuroleptic drugs of different classes. Typical and atypical neuroleptic drugs produced contrasting regulatory effects on a FosB-like protein of ca. 36-39 kDa, the molecular weight of truncated FosB (delta FosB). Chronic treatments with two typical neuroleptics, haloperidol and metoclopramide, but not with the atypical neuroleptic clozapine, led to markedly enhanced FosB-like immunoreactivity in the caudoputamen. Further, c-Fos-like protein in the striatum, considered a marker for the induction of antipsychotic actions by neuroleptic treatments, was downregulated by chronic treatment with the two potent antipsychotic drugs tested, but not by chronic treatment with metoclopramide, which has low antipsychotic efficacy but induces extrapyramidal side effects. These results suggest that chronic treatments with neuroleptics having different effects on cognitive and motor behavior induce different long-term changes in transcription factor expression in the striatum. Nevertheless, we found that neuroleptics of both classes regulated transcription factor expression in overlapping populations of striatal neurons expressing enkephalin or DARPP-32. Contrasting patterns of transcriptional regulation in these neurons may thus contribute to the distinct neurochemical and behavioral effects that characterize neuroleptics of different classes.

Analysis of Variance↗
PubMed1996

Regulation of ERK (extracellular signal regulated kinase), part of the neurotrophin signal transduction cascade, in the rat mesolimbic dopamine system by chronic exposure to morphine or cocaine.

Local infusion of brain-derived neurotrophic factor (BDNF) into the ventral tegmental area (VTA) can prevent and reverse the ability of chronic morphine or cocaine exposure to induce tyrosine hydroxylase (TH) in this brain region. The present study examined a possible role for extracellular signal regulated kinases (ERKs), the major effector for BDNF and related neurotrophins, in morphine and cocaine action in the VTA. Chronic, but not acute, administration of morphine or cocaine increased ERK catalytic activity specifically in the VTA. This increase in ERK activity reflected an increase in the state of phosphorylation of ERK, with no change in levels of total ERK immunoreactivity. Chronic infusions of BDNF into the VTA reduced total ERK immunoreactivity with no change in ERK activity, and also blocked the morphine-induced increase in ERK activity. These results suggest that chronic BDNF elicits a compensatory increase in the phosphorylation of the remaining ERK molecules and thereby prevents any additional increase in response to drug exposure. Such a role for ERK in morphine action was demnostrated directly by chronically infusing antisense oligonucleotides to ERK1 into the VTA. This treatment selectively reduced levels of ERK1 immunoreactivity in a sequence-specific manner without detectable toxicity. Intra-VTA infusion of ERK1 antisense oligonucleotides mimicked the effects of chronic BDNF infusions on ERK immunoreactivity, ERK activity, and TH immunoreactivity in the VTA under both control and morphine-treated conditions. The chronic morphine-induced increases in ERK activity and TH expression in the VTA also were blocked by local infusion of NMDA glutamate receptor antagonists, suggesting a role for glutamate in mediating these drug effects. Together, these findings support a scheme whereby chronic, systemic administration of morphine or cocaine leads to a sustained increase in ERK phosphorylation state and activity in the VTA, which, in turn, contributes to drug-induced increases in TH, and perhaps other drug-induced adaptations, elicited selectively in this brain region.

Animals↗
PubMed1995

Compartmental organization of calretinin in the rat striatum.

The present study examined the compartmental distribution of a calcium-binding protein, calretinin, in the rat striatum. Calretinin-immunoreactive cells were homogeneously scattered throughout the striatum, but calretinin-immunoreactive fibers were clustered as patches in the medial, central and ventral caudoputamen and in the lateral nucleus accumbens. These patches corresponded to striosomes, identified by immunostaining for calbindin-D28 K in adjacent sections. In the medial nucleus accumbens, calretinin-immunoreactive fibers showed diffuse distribution with occasional islands of calretinin-poor zones. These islands contained tightly packed, Nissl-stained cells, which have been previously shown to correspond to mu-opiate receptor-rich patches. Calretinin-positive fibers fill striosomes/patches in the caudoputamen and in the lateral nucleus accumbens and avoid them in the medial nucleus accumbens.

Animals↗
PubMed1995

Exacerbation of rheumatoid arthritis after removal of adrenal adenoma in Cushing's syndrome.

A 46-year-old woman with rheumatoid arthritis had been on non-steroidal antiinflammatory agents for eighteen years until she developed cushingoid features and hypertension resistant to antihypertensive drugs. She had high plasma cortisol and 24 h urinary 17-hydroxycorticosteroids (17HCS) which were not suppressed by 8 mg dexamethasone per day for two days. The circadian rhythm of plasma cortisol was absent and plasma ACTH concentrations were suppressed before and after intravenous administration of CRH. Abdominal computed tomography demonstrated a tumor (3.0 x 3.0 x 2.3 cm) in the right adrenal gland and a 131I-6 beta-19-nor-methylcholesterol scan revealed marked uptake on the same side. The patient underwent a right adrenalectomy and the diagnosis of a cortisol secreting benign adenoma was histologically confirmed. Blood pressure declined and cushingoid features regressed, but three months after the operation and while the patient was on replacement, she complained of pain on motion, marked tenderness and swelling of fingers, wrists, elbows, knees and foot joints, and had very high rheumatoid factors. Treatment with immunosuppressive drugs and oral and intraarticular administration of glucocorticoids were necessary to relieve the clinical symptoms of rheumatoid arthritis. In summary, we report a patient with rheumatoid arthritis and Cushing's syndrome due to an adrenal adenoma, in whom rheumatoid arthritis was exacerbated after curing the Cushing's syndrome. This suggests that it is imperative to follow the development and/or course of autoimmune diseases after the treatment of Cushing's syndrome.

17-Hydroxycorticosteroids↗
PubMed1995

Differences in down-regulation of glucocorticoid receptor mRNA by cortisol, prednisolone and dexamethasone in HeLa cells.

Glucocorticoids regulate the levels of their cognate receptors in a number of target tissues and in many different cell lines. We have compared the effect of three glucocorticoids, cortisol and its synthetic derivatives, prednisolone an dexamethasone, on the levels of glucocorticoid receptor (GR) mRNA in HeLa cells. Clinically, the synthetic derivatives are more active in hormonal action and have a longer half-life than cortisol. In the present study, the amounts of GR mRNA in HeLa cells were examined by Northern blot hybridization after treatment with cortisol, prednisolone or dexamethasone. These glucocorticoids decreased GR mRNA levels differently. After 24 h treatment with 1 x 10(-5) M cortisol, GR mRNA levels were only marginally suppressed (90% of the control), while prednisolone and dexamethasone suppressed GR mRNA levels to 67 and 57%, respectively. These differences may relate to the biological activities of these glucocorticoids. In time course studies, GR mRNA levels of the cells treated with cortisol and prednisolone decreased to the minimum levels within 4 h and then recovered gradually, while those treated with dexamethasone reached the minimum level at 8 h and remained suppressed for more than 24 h. These differences may relate to the biological half-lives of these glucocorticoids.

Anti-Inflammatory Agents↗
PubMed1995

Regulation of delta FosB and FosB-like proteins by electroconvulsive seizure and cocaine treatments.

Previous work has shown that c-Fos and several Fos-like proteins or Fras (Fos-related antigens) are induced acutely in brain in response to a wide variety of stimuli. In contrast, several stimuli induce apparently distinct Fos-like proteins, termed chronic Fras, after chronic administration. We show that delta FosB, a truncated splice variant of FosB, responds like the other acute Fras: it is induced rapidly and transiently in cerebral cortex after acute electroconvulsive seizure (ECS) and in striatum after acute cocaine but does not accumulate after chronic ECS or cocaine treatment. Although the chronic Fras are immunochemically related to delta FosB, they can be distinguished from delta FosB based on their temporal properties in that they are induced after chronic ECS and cocaine treatments only. Moreover, the chronic Fras and delta FosB can be distinguished by their migration patterns on one- and two-dimensional gel electrophoresis. The chronic Fras, therefore, appear to be novel FosB-related proteins. We also provide evidence that the chronic Fras heterodimerize primarily with Jun-D and Jun-B, as opposed to c-Jun. The possibility that AP-1 complexes containing the chronic Fras function as negative regulators of AP-1 mediated transcription is discussed.

Amino Acid Sequence↗