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M Jaber

Publications and source records attributed to M Jaber.

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

Differential regulation of tyrosine hydroxylase in the basal ganglia of mice lacking the dopamine transporter.

Mice lacking the dopamine transporter (DAT) display biochemical and behavioural dopaminergic hyperactivity despite dramatic alteration in dopamine homeostasis. In order to determine the anatomical and functional integrity of the dopaminergic system, we examined the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis as well as DOPA decarboxylase and vesicular monoamine transporter. TH-positive neurons in the substantia nigra were only slightly decreased (-27.6 +/- 4.5%), which can not account for the dramatic decreases in the levels of TH and dopamine that we previously observed in the striatum. TH mRNA levels were decreased by 25% in the ventral midbrain with no modification in the ratio of TH mRNA levels per cell. However, TH protein levels were decreased by 90% in the striatum and 35% in the ventral midbrain. In the striatum, many dopaminergic projections had no detectable TH, while few projections maintained regular labelling as demonstrated using electron microscopy. DOPA decarboxylase levels were not modified and vesicular transporter levels were decreased by only 28.7% which suggests that the loss of TH labelling in the striatum is not due to loss of TH projections. Interestingly, we also observed sporadic TH-positive cell bodies using immunohistochemistry and in situ hybridization in the striatum of homozygote mice, and to some extent that of wild-type animals, which raises interesting possibilities as to their potential contribution to the dopamine hyperactivity and volume transmission previously reported in these animals. In conjunction with our previous findings, these results highlight the complex regulatory mechanisms controlling TH expression at the level of mRNA, protein, activity and distribution. The paradoxical hyperdopaminergia in the DAT KO mice despite a marked decrease in TH and dopamine levels suggests a parallel to Parkinson's disease implying that blockade of DAT may be beneficial in this condition.

Animals↗
PubMed1998

Control of myocardial contractile function by the level of beta-adrenergic receptor kinase 1 in gene-targeted mice.

We studied the effect of alterations in the level of myocardial beta-adrenergic receptor kinase betaARK1) in two types of genetically altered mice. The first group is heterozygous for betaARK1 gene ablation, betaARK1(+/-), and the second is not only heterozygous for betaARK1 gene ablation but is also transgenic for cardiac-specific overexpression of a betaARK1 COOH-terminal inhibitor peptide, betaARK1(+/-)betaARKct. In contrast to the embryonic lethal phenotype of the homozygous betaARK1 knockout (Jaber, M., Koch, W. J., Rockman, H. A., Smith, B., Bond, R. A., Sulik, K., Ross, J., Jr., Lefkowitz, R. J., Caron, M. G., and Giros, B. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 12974-12979), betaARK1(+/-) mice develop normally. Cardiac catheterization was performed in mice and showed a stepwise increase in contractile function in the betaARK1(+/-) and betaARK1(+/-)betaARKct mice with the greatest level observed in the betaARK1(+/-)betaARKct animals. Contractile parameters were measured in adult myocytes isolated from both groups of gene-targeted animals. A significantly greater increase in percent cell shortening and rate of cell shortening following isoproterenol stimulation was observed in the betaARK1(+/-) and betaARK1(+/-)betaARKct myocytes compared with wild-type cells, indicating a progressive increase in intrinsic contractility. These data demonstrate that contractile function can be modulated by the level of betaARK1 activity. This has important implications in disease states such as heart failure (in which betaARK1 activity is increased) and suggests that betaARK1 should be considered as a therapeutic target in this situation. Even partial inhibition of betaARK1 activity enhances beta-adrenergic receptor signaling leading to improved functional catecholamine responsiveness.

Adrenergic beta-Agonists↗
PubMed1998

Profound neuronal plasticity in response to inactivation of the dopamine transporter.

The dopamine transporter (DAT) plays an important role in calibrating the duration and intensity of dopamine neurotransmission in the central nervous system. We have used a strain of mice in which the gene for the DAT has been genetically deleted to identify the DAT's homeostatic role. We find that removal of the DAT dramatically prolongs the lifetime (300 times) of extracellular dopamine. Within the time frame of neurotransmission, no other processes besides diffusion can compensate for the lack of the DAT, and the absence of the DAT produces extensive adaptive changes to control dopamine neurotransmission. Despite the absence of a clearance mechanism, dopamine extracellular levels were only 5 times greater than control animals due to a 95% reduction in content and a 75% reduction in release. Paradoxically, dopamine synthesis rates are doubled despite a decrease of 90% in the levels of tyrosine hydroxylase and degradation is markedly enhanced. Thus, the DAT not only controls the duration of extracellular dopamine signals but also plays a critical role in regulating presynaptic dopamine homeostasis. It is interesting to consider that the switch to a dopamine-deficient, but functionally hyperactive, mode of neurotransmission observed in mice lacking the DAT may represent an extreme example of neuronal plasticity resulting from long-term psychostimulant abuse.

Animals↗
PubMed1998

Dopamine receptors: from structure to function.

The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1 and D5) couple to the G protein Gs and activate adenylyl cyclase. The other receptor subtypes belong to the D2-like subfamily (D2, D3, and D4) and are prototypic of G protein-coupled receptors that inhibit adenylyl cyclase and activate K+ channels. The genes for the D1 and D5 receptors are intronless, but pseudogenes of the D5 exist. The D2 and D3 receptors vary in certain tissues and species as a result of alternative splicing, and the human D4 receptor gene exhibits extensive polymorphic variation. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine secretion. In the periphery, dopamine receptors are present more prominently in kidney, vasculature, and pituitary, where they affect mainly sodium homeostasis, vascular tone, and hormone secretion. Numerous genetic linkage analysis studies have failed so far to reveal unequivocal evidence for the involvement of one of these receptors in the etiology of various central nervous system disorders. However, targeted deletion of several of these dopamine receptor genes in mice should provide valuable information about their physiological functions.

Animals↗
PubMed1998

[Behavioral, cellular and molecular consequences of the dopamine transporter gene inactivation].

Mice lacking the the plasma membrane dopamine transporter (DAT), following gene inactivation or knock out, show an increase in their spontaneous locomotor activity that is of the same magnitude than in normal mice treated with amphetamine or cocaine, known to increase levels of dopamine in the basal ganglia. Many adaptive responses have occurred in these animals than could not compensate for the hyper activity of the dopamine system. Surprisingly, while intracellular dopamine levels were of only 5%, extracellular dopamine levels were increased by 300%. We investigated the regulation of tyrosine hydroxylase (TH), the rate limiting enzyme of dopamine synthesis, and found that this enzyme is regulated at the levels of mRNA, protein, trafficking as well as in its regional, cellular and subcellular organization. Our results establish not only the central importance of the transporter as the key element controlling dopamine levels in the brain, but also its role in the behavioral and biochemical action of amphetamine, cocaine and morphine. In addition, these mice have provided key elements leading to possible clinical and social implications for illnesses such as Parkinson disease, attention deficit disorder and drug addiction.

Animals↗
PubMed1997

The dopamine transporter: a crucial component regulating dopamine transmission.

The dopamine system is implicated in the control of locomotion, cognition, and endocrine function. The relative contribution of the various dopamine-related components is not well established mainly because drugs that target the dopaminergic system often lack selectivity. The in vivo gene inactivation procedure, or knockout, enables the creation of new strains of mice lacking a specific gene. This technique has been applied recently to inactivate the expression of the plasma membrane dopamine transporter. Here we summarize the main findings obtained with these transgenic mice carrying this "genetic defect," leading to a better understanding of the relative contribution of the dopamine transporter regarding locomotor activity, regulation of the expression of peptides under the control of dopaminergic activity, and responses to various drugs targeting the dopamine system. Our results establish not only the central importance of the transporter as the key element controlling dopamine levels in the brain, but also its role as an obligatory target for the behavioral and biochemical action of amphetamine and cocaine. In addition, the genetically altered mice offer a unique model to test the specificity and selectivity of dopamine transporter-acting drugs and may provide important new concepts related to the clinical and social implications of conditions such as Parkinson's disease, schizophrenia, and drug addiction.

Amphetamines↗
PubMed1997

Cocaine and amphetamine elicit differential effects in rats with a unilateral injection of dopamine transporter antisense oligodeoxynucleotides.

We have developed an antisense oligodeoxynucleotide to the dopamine transporter and used it to discriminate the behavioral properties of amphetamine and cocaine. In SK-N-MC cells permanently transfected with the dopamine transporter complementary DNA, treatment with 5 mM antisense oligodeoxynucleotide reduced dopamine uptake by 25% when compared to sense control. Unilateral intranigral administration of dopamine transporter antisense (50 microM) twice daily in freely moving rats for 2.5 days was sufficient to reduce dopamine transporter messenger RNA by 70% as measured by in situ hybridization, but not protein levels as measured by [3H]mazindol binding. However, intranigral treatment via implanted osmotic minipump over a period of seven days produced reductions in both dopamine transporter messenger RNA and protein levels (32%) at a dose of 500 pmol/day. These results indicate a longer half-life for the dopamine transporter than expected. Potassium chloride depolarization of ipsilateral striatal slices showed a greater than 200% increase in dopamine overflow on the antisense-treated side compared to the control side. Since imbalance of dopamine tone is known to induce rotational activity, we tested this behavioral paradigm in rats treated with various oligodeoxynucleotides at different doses and time-points. We have found that antisense-treated animals did not rotate spontaneously under any experimental conditions. Using various psychostimulants that target the dopamine transporter and increase dopamine levels, we found that the antisense-treated animals consistently rotated contralaterally in response to amphetamine (2 mg/kg), but not to cocaine (10 mg/kg) or nomifensine (10 mg/kg). These results bring in vivo evidence for a different mode of action of amphetamine and cocaine on the dopamine transporter and lend direct support to the view that amphetamine acts as a dopamine releaser, whereas cocaine acts by blocking dopamine transport.

Amphetamine↗
PubMed1997

Anterior pituitary hypoplasia and dwarfism in mice lacking the dopamine transporter.

Deletion of the dopamine transporter (DAT) results in increased dopaminergic tone, anterior pituitary hypoplasia, dwarfism, and an inability to lactate. DAT elimination alters the spatial distribution and dramatically reduces the numbers of lactotrophs and somatotrophs in the pituitary. Despite having normal circulating levels of growth hormone and prolactin in blood, hypoplastic glands from DAT-/- mice fail to respond to secretagog stimulation. The effects of DAT deletion on pituitary function result from elevated DA levels that down-regulate the lactotroph D2 DA receptors and depress hypothalamic growth hormone-releasing hormone content. These results reveal an unexpected and important role or DA in the control of developmental events in the pituitary gland and assign a critical role for hypothalamic DA reuptake in regulating these events.

Animals↗
PubMed1997

[Dopamine control of neuroendocrine functions. New findings based on the study of transgenic animals].

The dopamine system is implicated in the control of locomotion, cognition and endocrine function. The relative contribution of the various dopamine related components is not well established mainly because drugs that target the dopaminergic system often lack selectivity. The gene inactivation procedure in vivo, or knock out, permits the creation of new strains of mice specifically lacking a designated gene. Unlike pharmacological approaches this molecular procedure offers a unique specificity for the target gene. This technique has been applied recently to inactivate the expression of tyrosine hydroxylase, dopamine, monoamine oxidase, three of the five dopamine receptors, the monoamines vesicular transporter and the plasma membrane dopamine transporter. Here we summarize the main findings obtained with these transgenic animals carrying these "genetic defects" leading to a better understanding of the relative contribution of each of the corresponding gene product regarding locomotor activity, regulation of the expression of peptides under the dopamine control, responses to various drugs targeting the dopamine system and control of pituitary function. A special emphasis is made on the consequences of the knock out of the dopamine transporter where our results establish not only the central importance of the transporter as the key element controlling DA levels in the brain and pituitary, but also its role as an obligatory target for the behavioral and biochemical action of amphetamine and cocaine. Besides the better comprehension of the dopamine transmission, these strains of mice offer unique models to test the specificity and selectivity of dopamine acting drugs and have often provided key elements leading to possible clinical and social implications for illnesses such as Parkinson disease, dwarfism and drug addiction.

Amphetamines↗
PubMed1996

Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function.

The beta-adrenergic receptor kinase 1 (beta ARK1) is a member of the G protein-coupled receptor kinase (GRK) family that mediates the agonist-dependent phosphorylation and desensitization of G protein-coupled receptors. We have cloned and disrupted the beta ARK1 gene in mice by homologous recombination. No homozygote beta ARK1-/- embryos survive beyond gestational day 15.5. Prior to gestational day 15.5, beta ARK1-/- embryos display pronounced hypoplasia of the ventricular myocardium essentially identical to the "thin myocardium syndrome" observed upon gene inactivation of several transcription factors (RXR alpha, N-myc, TEF-1, WT-1). Lethality in beta ARK1-/- embryos is likely due to heart failure as they exhibit a > 70% decrease in cardiac ejection fraction determined by direct in utero intravital microscopy. These results along with the virtual absence of endogenous GRK activity in beta ARK1-/- embryos demonstrate that beta ARK1 appears to be the predominant GRK in early embryogenesis and that it plays a fundamental role in cardiac development.

Animals↗
PubMed1996

Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter.

Disruption of the mouse dopamine transporter gene results in spontaneous hyperlocomotion despite major adaptive changes, such as decreases in neurotransmitter and receptor levels. In homozygote mice, dopamine persists at least 100 times longer in the extracellular space, explaining the biochemical basis of the hyperdopaminergic phenotype and demonstrating the critical role of the transporter in regulating neurotransmission. The dopamine transporter is an obligatory target of cocaine and amphetamine, as these psychostimulants have no effect on locomotor activity or dopamine release and uptake in mice lacking the transporter.

Amphetamine↗
PubMed1996

Dopamine receptors and brain function.

In the central nervous system (CNS), dopamine is involved in the control of locomotion, cognition, affect and neuroendocrine secretion. These actions of dopamine are mediated by five different receptor subtypes, which are members of the large G-protein coupled receptor superfamily. The dopamine receptor subtypes are divided into two major subclasses: the D1-like and D2-like receptors, which typically couple to Gs and Gj mediated transduction systems. In the CNS, the various receptor subtypes display specific anatomical distributions, with D1-like receptors being mainly post-synaptic and D2-like receptors being both pre- and post-synaptic. D1 and D2 dopamine receptors, the most abundant subtypes in the CNS, appear to be expressed largely in distinct neurons. Substance P and dynorphin, which are expressed in D1 receptor-containing neurons, as well as pre-proenkephalin in D2 receptor-containing neurons, have been used as monitors of dopaminergic activity in the CNS. Expression of immediate early genes, in particular fos, has also been found to correlate with dopaminergic transmission. Dopamine released from the hypothalamus controls the synthesis and secretion of prolactin from the anterior pituitary via D2 dopamine receptors. As yet none of the dopamine receptor subtypes have been associated with the etiology of psychotic disorders, such as schizophrenia. However, the recent characterization of D3 and D4 receptors which are, interestingly, expressed in areas of the CNS mediating cognition and affect or showing increased affinity for certain neuroleptics, have renewed the interest and hope of finding effective neuroleptics devoid of side effects. Finally, the recent production of genetically-derived animals lacking several of these receptor genes should help elucidate which specific physiological paradigms the receptors mediate.

Animals↗
PubMed1996

Cloning, characterization, and chromosomal localization of rec1.3, a member of the G-protein-coupled receptor family highly expressed in brain.

During a project to identify G-protein-coupled receptors (GPCR) expressed within taste buds, we have isolated a novel receptor-like sequence. The full length sequence of this receptor (rec1.3) has been obtained in both cow and mouse. Rec1.3 bears little sequence similarity to any GPCR whose ligand is known: the closest identity (33%) is to the orphan receptor edg-1. In cow, rec1.3 is expressed most prominently in the brain, with moderate expression in testis and tongue; in the mouse the expression is more widespread. No specific binding for a range of ligands was detected when the mouse coding sequence was expressed in eukaryotic cells. In situ hybridization showed that rec1.3 is widely expressed throughout the mouse brain and is highly expressed in localized regions of the hindbrain, midbrain and hypothalamus. The rec1.3 gene was localized to the centromeric region of chromosome 4 in mouse, a region associated with neonatal seizures.

Amino Acid Sequence↗
PubMed1996

Presence of katG gene in resistant Mycobacterium tuberculosis.

It has been reported recently that isoniazid resistant strains of Mycobacterium tuberculosis have lost the katG gene which encodes the catalase-peroxidase enzyme. A 35 mer oligonucleotide probe specific for the katG gene of M tuberculosis, 3' end-labelled with digoxigenin, was constructed and hybridised with DNA extracted from 26 clinical isolates of M tuberculosis under high stringency conditions. Twenty two of these isolates were resistant to 0.2 microgram/ml isoniazid and 20 to 1.0 microgram/ml isoniazid. Semiquantitative detection of catalase did not show any discrimination between isoniazid sensitive and resistant strains. The katG gene was present in all clinical strains of M tuberculosis. Therefore, complete deletion of the katG gene does not seem to be the mechanism of isoniazid resistance in M tuberculosis strains isolated from patients in India.

Antitubercular Agents↗
PubMed1995

Effect of reserpine treatment on enkephalin mRNA level in the rat striatum: an in situ hybridization study.

We investigated the molecular mechanisms responsible for the preproenkephalin A mRNA increase following catecholamine depletion by reserpine using quantitative in situ hybridization at the cellular level. Macroscopic analysis showed that short term reserpine treatment increases the preproenkephalin A mRNA level in the rat striatum to +40.2 +/- 9%. Microautoradiography analysis demonstrated different increases in the preproenkephalin A mRNA level in different parts of the striatum: +124 +/- 22% in the dorso-median striatum, +131 +/- 19% in the dorso-lateral striatum, +119 +/- 8% in the ventro-lateral striatum and +75 +/- 6% in the ventro-median striatum. We found no difference in the number of cells expressing PPA mRNA in reserpine treated rats suggesting that these increases are only due to an increase in the number of mRNA expressed by cell.

Animals↗
PubMed1995

Acute and chronic amphetamine treatments differently regulate neuropeptide messenger RNA levels and Fos immunoreactivity in rat striatal neurons.

Repeated administration of amphetamine results in the well known phenomenon of reverse tolerance or sensitization. However, little is known about cellular and molecular mechanisms underlying acute versus chronic response to amphetamine. In this paper, we investigated the effects of acute (1.5 or 5 mg/kg) and chronic (5 mg/kg/day for 14 days) amphetamine treatment on locomotor activity, stereotypy, Fos immunoreactivity and messenger RNA levels of molecules implicated in dopamine transmission in the rat striatum and substantia nigra. In agreement with other studies, acute amphetamine induced a dose dependent increase in locomotor activity and stereotypy. Also, a comparison between the behavior observed after the first injection and the last injection of amphetamine in chronically treated rats showed sensitization as demonstrated by a higher rating of stereotypy. We have found that acute and chronic amphetamine treatments differently modulate the activity of several output neurons. A double labeling procedure with Fos immunohistochemistry coupled with in situ hybridization demonstrated that acute amphetamine treatment induces Fos immunoreactivity predominantly in striatal neurons expressing substance P messenger RNA (77.07 +/- 1.42%). Only 32.6 +/- 2.07% of Fos immunoreactive neurons expressed preproenkephalin A messenger RNA. In chronic amphetamine treated rats, 56.21 +/- 1.32% of the Fos immunoreactive neurons expressed substance P messenger RNA while 52.12 +/- 1.84% expressed preproenkephalin A messenger RNA. Statistical analysis revealed that this difference is mainly due to a decrease in the density of substance P immunoreactive neurons in chronically treated rats in comparison to acute. Amphetamine treatments induced Fos immunoreactivity in the substantia nigra in non-dopamine neurons. As measured by quantitative in situ hybridization, acute amphetamine induced an increase in substance P, preproenkephalin A and dynorphin messenger RNA levels (+23 +/- 0.05%, +45 +/- 0.07% and +24 +/- 0.05%, respectively). No difference in these increases was observed in relation with the dose injected (1.5 or 5 mg/kg). Chronic amphetamine treatment enhanced only substance P and dynorphin messenger RNA levels (+23 +/- 0.04% and +42 +/- 0.04%, respectively). Neither acute nor chronic amphetamine treatment had any effects on D1 or D2 dopamine receptor messenger RNA levels. Our main conclusions are: (1) in acutely treated rats Fos is essentially expressed by substance P neurons; (2) in chronically treated rats, Fos immunoreactivity is expressed by the two efferent striatal populations (i.e. preproenkephalin A and substance P neurons) and the number of Fos immunoreactive neurons is reduced as compared with acute; (3) neuropeptide messenger RNA levels, but not dopamine receptor messenger RNAs, are affected in the response to acute or chronic treatment with amphetamine.

Amphetamine↗
PubMed1995

A simple method of DNA extraction from Mycobacterium tuberculosis.

The application of molecular biology methods has contributed significant insight into the epidemiology of infections caused by Mycobacterium tuberculosis. However, most of the techniques remain out of reach of laboratories in the tropics. We describe here a simple method for extraction of DNA from the pathogen, a first step in the application of molecular biology tools.

Bacteriological Techniques↗