Mohamed Jaber

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.

Effects of enriched environment on animal models of neurodegenerative diseases and psychiatric disorders.

Environmental stimulation throughout development adjusts the neurobehavioral systems involved in learning, memory and defensive responses. Environment-mediated phenotypic plasticity can be considered from two different, yet complementary, viewpoints. On one hand, the possibility that environmental interventions protect against the effects of genetic and/or acquired vulnerabilities, offers unprecedented avenues towards the elaboration and refinement of therapeutic strategies. On the other hand, an accurate understanding of the adaptive mechanisms regulating the interaction between an experimental subject and its environment may substantially benefit the quality of experimental data. Here we review experimental evidence showing that enriched environment can be beneficial in several psychiatric and neurodegenerative disorders implicating the monoamine systems where it can (i) compensate for impairments in animal models of schizophrenia, Huntingtons, and Parkinsons diseases; (ii) increase resistance to the addictive properties of psychostimulant drugs; (iii) level-out the consequences of prenatal stress in animal models of depression. Additionally we discuss why some of the effects of environmental enrichment question the validity of current animal models of mental disorders.

Absence of MPTP-Induced Neuronal Death in Mice Lacking the Dopamine Transporter

MPTP has been shown to induce parkinsonism both in human and in nonhuman primates. The precise mechanism of dopaminergic cell death induced following MPTP treatment is still subject to intense debate. MPP+, which is the oxidation product of MPTP, is actively transported into presynaptic dopaminergic nerve terminals through the plasma membrane dopamine transporter (DAT). In this study, we used mice lacking the DAT by homologous recombination and demonstrated that the MPTP-induced dopaminergic cell loss is dependent on the presence of the DAT. For this we have used tyrosine hydroxylase immunoreactivity (TH-IR) labeling of dopamine cells of the substantia nigra compacta in wild-type, heterozygote, and homozygote mice that were given either saline or MPTP treatments (two ip injections of 30 mg/kg, 10 h apart). Our results show a significant loss of TH-IR in wild type (34.4%), less loss in heterozygotes (22.5%), and no loss in homozygote animals. Thus dopamine cell loss is related to levels of the DAT. These results shed light on the degenerative process of dopamine neurons and suggest that individual differences in developing Parkinsons disease in human may be related to differences of uptake through the DAT of a yet unidentified neurotoxin.

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.

Reversal of cocaine addiction by environmental enrichment

Environmental conditions can dramatically influence the behavioral and neurochemical effects of drugs of abuse. For example, stress increases the reinforcing effects of drugs and plays an important role in determining the vulnerability to develop drug addiction. On the other hand, positive conditions, such as environmental enrichment, can reduce the reinforcing effects of psychostimulants and may provide protection against the development of drug addiction. However, whether environmental enrichment can be used to “treat” drug addiction has not been investigated. In this study, we first exposed mice to drugs and induced addiction-related behaviors and only afterward exposed them to enriched environments. We found that 30 days of environmental enrichment completely eliminates behavioral sensitization and conditioned place preference to cocaine. In addition, housing mice in enriched environments after the development of conditioned place preference prevents cocaine-induced reinstatement of conditioned place preference and reduces activation of the brain circuitry involved in cocaine-induced reinstatement. Altogether, these results demonstrate that environmental enrichment can eliminate already established addiction-related behaviors in mice and suggest that environmental stimulation may be a fundamental factor in facilitating abstinence and preventing relapse to cocaine addiction.

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 β-adrenergic receptor kinase (βARK1) in two types of genetically altered mice. The first group is heterozygous for βARK1 gene ablation, βARK1(+/−), and the second is not only heterozygous for βARK1 gene ablation but is also transgenic for cardiac-specific overexpression of a βARK1 COOH-terminal inhibitor peptide, βARK1(+/−)/βARKct. In contrast to the embryonic lethal phenotype of the homozygous βARK1 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), βARK1(+/−) mice develop normally. Cardiac catheterization was performed in mice and showed a stepwise increase in contractile function in the βARK1(+/−) and βARK1(+/−)/βARKct mice with the greatest level observed in the βARK1(+/−)/βARKct 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 βARK1(+/−) and βARK1(+/−)/βARKct 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 βARK1 activity. This has important implications in disease states such as heart failure (in which βARK1 activity is increased) and suggests that βARK1 should be considered as a therapeutic target in this situation. Even partial inhibition of βARK1 activity enhances β-adrenergic receptor signaling leading to improved functional catecholamine responsiveness.

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 Parkinsons disease implying that blockade of DAT may be beneficial in this condition.

Environmental Enrichment During Early Stages of Life Reduces the Behavioral, Neurochemical, and Molecular Effects of Cocaine

It is known that negative environmental conditions increase vulnerability to drugs, whereas little is known on whether positive environmental conditions such as enriched environments (EE) have protective effects against addiction. We have previously found that EE consisting of bigger cages containing several toys that were changed once per week reduce cocaine-induced increases in locomotor activity. Here, we also show that the rewarding effects of cocaine are blunted in mice reared from weaning to adulthood in EE compared to mice reared in standard environments (SE). In addition, although both EE and SE mice develop behavioral sensitization to cocaine, EE mice show less activation in response to repeated administration of cocaine injections and reduced responses to cocaine challenges. In vivo microdialysis experiments demonstrate that the protective effects of EE do not depend on reduced cocaine-induced increases in the dopamine levels in the ventral or dorsal striatum. On the other hand, they were associated with reduced cocaine-induced expression of the immediate early gene zif-268 in the nucleus accumbens (shell and core) of EE mice. Finally, basal levels of Delta-Fos B, a transcription factor known to be increased by sustained activation of striatal neurons, are higher in the striatum of EE compared to SE mice and repeated administration of cocaine increases Delta-Fos B levels in SE mice but decreases them in EE mice. Altogether our results demonstrate that exposure to complex environments during early stages of life produce dramatic changes in the striatum that result in reduced reactivity to drugs of abuse.

Environmental Enrichment Reduces Cocaine Seeking and Reinstatement Induced by Cues and Stress but Not by Cocaine

Whereas earlier studies have focused on the preventive effects of enriched environments (EE) in drug addiction, in a recent study we suggested that EE can also have ‘curative’ effects. In fact, we found that cocaine addiction-related behaviors can be eliminated by housing cocaine-treated mice in EE during periods of forced abstinence. However, those results were obtained with two simple models of addiction, conditioned place preference (CPP), and behavioral sensitization. In this study, we used intravenous drug self-administration procedures in rats to further investigate the beneficial effects of EE on cocaine addiction in a reinstatement model of relapse. Singly housed rats learned to self-administer cocaine during 10 consecutive daily sessions (0.6 mg/injection, 6 h/day). They were then housed three per cage in either standard environments (SE) or EE and were kept abstinent in the animal facility until testing for extinction and reinstatement. We found that 30 days of EE significantly and consistently reduced cocaine seeking during a 6-h extinction session. In addition, EE significantly reduced cue- and stress-induced reinstatement. Surprisingly, given our earlier results in mice with CPP, EE did not reduce cocaine-induced reinstatement regardless of the level of exposure to cocaine and the duration of the period of abstinence and exposure to EE. Altogether, these results support the hypothesis that EE can reduce cocaine-induced craving and highlight the importance of positive life conditions in facilitating abstinence and preventing relapse to cocaine addiction.

Reestablishment of damaged adult motor pathways by grafted embryonic cortical neurons

Damage to the adult motor cortex leads to severe and frequently irreversible deficits in motor function. Transplantation of embryonic cortical neurons into the damaged adult motor cortex was previously shown to induce partial recovery, but reports on graft efferents have varied from no efferent projections to sparse innervation. Here, we grafted embryonic cortical tissue from transgenic mice overexpressing a green fluorescent protein into the damaged motor cortex of adult mice. Grafted neurons developed efferent projections to appropriate cortical and subcortical host targets, including the thalamus and spinal cord. These projections were not a result of cell fusion between the transplant and the host neurons. Host and transplanted neurons formed synaptic contacts and numerous graft efferents were myelinated. These findings demonstrate that there is substantial anatomical reestablishment of cortical circuitry following embryonic cortex grafting into the adult brain. They suggest that there is an unsuspected potential for neural cell transplantation to promote reconstruction after brain injury.