Biomedical subjects

Youssef Sari

Publications and source records attributed to Youssef Sari.

12 recordsLinked to original sources

PubMed2006

Brain deficits associated with fetal alcohol exposure may be protected, in part, by peptides derived from activity-dependent neurotrophic factor and activity-dependent neuroprotective protein.

This review discusses the effects of prenatal alcohol exposure on the developing brain and the potential use of derived peptides from activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP) in neuroprotection against the insults of alcohol. Alcohol is known to impede the growth of the central nervous system and to induce neurodegeneration through cellular apoptosis. Sari et al. have shown that prenatal alcohol exposure reduced the fetal brain weight, the size of the brain regions and the number of serotonin (5-HT) neurons. Prenatal alcohol exposure compromises neural tube midline development. Sari et al. further suggested that the timing of alcohol exposure during pregnancy is critical to the induction of deficits in 5-HT neurons, as well as other types of neurons and consequently results in deficits in neural tube development. ADNF and ADNP are glial-derived proteins discovered to be induced by vasoactive intestinal peptide (VIP). These proteins are expressed during embryonic development. Functional assays and genetic manipulations have identified these proteins as highly important for neural tube closure and brain formation/development. The peptide derivatives of ADNF, ADNF-14 (VLGGGSALLRSIPA), ADNF-9 (or SALLRSIPA = SAL) and of ADNP, NAPVSIPQ = NAP have shown neuroprotective effects and have been proven to prevent brain damage associated with prenatal alcohol exposure in animals. Here, we discuss the many aspects of alcohol-associated growth restriction in the developing brain and the potential inhibition of this severe phenotype through the use of neuroprotective peptides.

Animals↗

PubMed2006

Glutamate and dopamine synaptic terminals in extended amygdala after 14-week chronic alcohol drinking in inbred alcohol-preferring rats.

Alcohol has been shown to affect glutamate (GLU) and dopamine (DA) release and their correlated receptors in the key reward center--extended amygdala--which includes the shell of nucleus accumbens (sNAc) and central nucleus of amygdala (cAmg). It is unclear to date whether there is an alteration in the number of presynaptic GLU/DA nerve terminals. In this study, we investigated the number of GLU and DA terminals in the extended amygdala of alcohol-preferring (P) rats that chronically drank ethanol. P rats have a propensity to drink ethanol to intoxication and develop an alcohol dependency. The P rats were divided into (1) Water group given ad libitum chow and water for 14 weeks; (2) Continuous alcohol group (C-Alc) given ad libitum chow and choice of 15 or 30% (v/v) ethanol or water for 14 weeks; and (3) Repeated deprivation (RD-Alc) group given the same choice of ethanol or water for 6 weeks, followed by a twice repeated cycle of 2 weeks without ethanol followed by 2 weeks with ethanol. Two subpopulations of GLU terminals were labeled by immunostaining for the vesicular GLU transporter 1 (vGLUT1) and vesicular GLU transporter 2 (vGLUT2). DA terminals were labeled by immunostaining for tyrosine hydroxylase (TH). The GLU and DA immunostained (im) varicosities were quantified and analyzed using stereological methods. We found that chronic alcohol did not alter the number of TH-im terminals in the extended amygdala in either the C-Alc or RD-Alc drinking paradigms. Thus, the increases in extracellular levels of DA previously reported following chronic alcohol are likely due to a change in the efficiency of DA release rather than a change in the number of DA terminals. The number of vGLUT1-im terminals was also unchanged in the extended amygdala; however, the number of vGLUT2-im terminals, which represent the greater population of GLU terminals, was increased in the sNAc of the RD-Alc group compared to the Water group. Chronic alcohol is known to affect GLU release, and our findings indicate that repeated alcohol deprivation may preferentially increase GLU terminals in the sNAc bearing the vGLUT2, which are primarily afferents from the thalamus. Our results further indicate that repeated deprivation of alcohol can change the ratio of GLU to DA innervation in the sNAc, a key region of the reward circuitry.

Alcohol Drinking↗

PubMed2006

Effects of chronic alcohol and repeated deprivations on dopamine D1 and D2 receptor levels in the extended amygdala of inbred alcohol-preferring rats.

BACKGROUND: Dopaminergic (DA) activity in the extended amygdala (EA) has been known to play a pivotal role in mediating drug and alcohol addiction. Alterations of DA activity within the EA after chronic exposure to alcohol or substances of abuse are considered a major mechanism for the development of alcoholism and addiction. To date, it is not clear how different patterns of chronic alcohol drinking affect DA receptor levels. Therefore, the current studies investigated the effects of chronic ethanol consumption, with or without deprivations, on D1 and D2 receptor densities within the EA. METHODS: Inbred alcohol-preferring (iP) rats were divided into 3 groups with the following treatments: (1) water for 14 weeks; (2) continuous alcohol (C-Alc) for 14 weeks [24-hour concurrent access to 15 and 30% (v/v) ethanol]; or (3) repeatedly deprived of alcohol (RD-Alc) (24-hour concurrent access to 15 and 30% ethanol for 6 weeks, followed by 2 cycles of 2 weeks of deprivation of and 2 weeks of reexposure to ethanol access). At the end of 14 weeks, the rats were killed for autoradiographic labeling of D1 and D2 receptors. RESULTS: Compared with the water control group, both the C-Alc and the RD-Alc groups displayed increases in D1 receptor binding density in the anterior region of the Acb core, whereas the RD-Alc group displayed additional increases in D1 receptor binding density in anterior regions of the lateral and intercalated nuclei of the amygdala. Additionally, both C-Alc and RD-Alc rats displayed increases in D2 receptor binding density in anterior regions of the Acb shell and core, whereas RD-Alc rats displayed additional increases in D2 receptor binding density in the dorsal striatum. CONCLUSION: The results of this study indicate that 14-week extended alcohol drinking with continuous chronic or repeated deprivations increase binding sites of D1 and D2 receptors in specific regions of the EA with greater sensitivity in the anterior regions. The repeated deprivation has greater effect on altering D1 and D2 receptor binding sites in the Acb, dorsal striatum, and subamygdala regions. The current result indicates that the two drinking paradigms may have common as well as differential mechanisms on alteration of dopamine receptor-binding sites in specific regions of the EA.

Alcoholism↗

PubMed2006

Structural and functional modifications in glutamateric synapses following prolonged ethanol exposure.

This article summarizes the proceedings of a symposium presented at the 2005 annual meeting of the Research Society on Alcoholism in Santa Barbara, California, USA. The organizer and chair was L. Judson Chandler. The presentations were (1) Chronic Ethanol Exposure, N-Methyl-D-Aspartate (NMDA) Receptor Dynamics, and Withdrawal Hyperexcitability, by Adam Hendricson, Regina Maldve, and Richard Morrisett; (2) Ethanol-Induced Synaptic Targeting of NMDA Receptors Is Associated With Enhanced Postsynaptic Density-95 Clustering and Spine Size, by Judson Chandler and Ezekiel Carpenter-Hyland; (3) Presynaptic and Postsynaptic Alterations in the Nucleus Accumbens Following Chronic Alcohol Exposure, by Feng Zhou, Youssef Sari, and Richard Bell; and (4) An Active Role for Accumbens Homer2 Expression in Alcohol-Induced Neural Plasticity, by Karen Szumlinski.

Alcohol Withdrawal Delirium↗

PubMed2005

Fetal alcohol exposure reduces serotonin innervation and compromises development of the forebrain along the serotonergic pathway.

BACKGROUND: We reported previously that a moderate level of fetal alcohol treatment reduces the birth, maturation, and migration of serotonin (5-HT) neurons at embryonic days 11 to 15 (E11-E15). Because 5-HT is known as a differentiation signal for forebrain development, we investigated whether alcohol affects 5-HT innervation to the developing brain and how the target brain areas grow as they receive 5-HT innervation between E15 and E18. METHODS: Pregnant dams were divided into three groups and treated from E7 to E15 or E18 with one of the following conditions: (1) liquid diet that contained 25% ethanol-derived calories (ALC), (2) isocaloric liquid diet pair-fed (PF), or (3) chow fed (Chow). The 5-HT immunostained (5-HT-IM) fibers and size of brain areas were examined as an index of growth along the ascending 5-HT pathway. RESULT: We found that 5-HT-IM fibers innervate the brain regions specifically under active differentiation and that there were three sets of correlated dysmorphology in the ALC group as compared with those of the PF and Chow groups. The three sets are as follows: (1) fewer 5-HT-IM fibers in the medial forebrain bundle and along the projecting pathway through the hypothalamus, septal nucleus, frontal and parietal cortices, and subiculum/hippocampus; (2) underdevelopment of the brain regions along 5-HT fiber projections; and (3) underdevelopment of somatosensory thalamocortical projections, which are known to transiently express 5-HT transporters and to be regulated by 5-HT. No such differences were found between the PF and Chow groups. CONCLUSION: We found that fewer 5-HT fibers grew in the embryos that were exposed to alcohol. As forebrain regions differentiated along the 5-HT projection, we found two reductions: (1) the growth of brain regions along 5-HT projection and (2) the growth of the thalamocortical sensory projection regulated by 5-HT. The reduced 5-HT innervation is in agreement with our previous observation of fewer 5-HT neurons. The subsequent retardation of forebrain growth and sensory thalamocortical fibers along the pathway of reduced 5-HT projection is consistent with the role of 5-HT as a signal for forebrain differentiation.

Alcohol Drinking↗

PubMed2004

Selective serotonin reuptake inhibitor disrupts organization of thalamocortical somatosensory barrels during development.

To further investigate the role of the transiently expressed serotonin (5-HT) transporter (5-HTT) in the development of thalamic fibers projecting to cortical barrels and the potential developmental changes in neuronal circuitry caused by a selective serotonin reuptake inhibitor (SSRI), paroxetine (5 mg/kg, twice daily, s.c.) or saline was administered to rat pups from postnatal day 0 (P0) to P8. Pups were perfused on P8 for 5-HT immunostaining (-im) to confirm the 5-HT uptake blockade, and 5-HTT-im and phospholipase C-beta1 (PLC-beta1)-im to label the thalamic afferents to barrels and barrel cells respectively. Paroxetine treatment completely blocked 5-HT uptake into the thalamocortical fibers as indicated by the negative 5-HT-im in cortical barrel areas. Organization of thalamic afferents to barrels, indicated by 5-HTT-im or PLC-beta1, was altered in paroxetine-treated pups in the following manners: (1) segregation of thalamocortical fibers was partially disrupted and thalamocortical fibers corresponding to anterior snouts and row A mystacial vibrissae were fused; (2) sizes of the unfused thalamocortical fiber patches related to the long caudal vibrissae in rows B, C, D and E were significantly decreased without changes in the brain weights and cortical areas representing these vibrissae; and (3) thalamocortical fibers corresponding to C4 and D4 vibrissae tended to be closer to each other along the arc while the relative positions of thalamocortical fibers related to the rest of the vibrissae were normal. Our study demonstrated that 5-HTT plays an important role in the refinement, but not the formation, of barrel-like clusters of thalamocortical fibers and that the development of neural circuitry in rodent somatosensory cortex was affected by exposure to a SSRI during thalamocortical synaptic formation.

Age Factors↗

PubMed2004

Serotonin1B receptors: from protein to physiological function and behavior.

The serotonin (5-HT)1B receptor is expressed in the central nervous system (CNS) of rodents and its homologous 5-HT1D beta receptor is expressed in human. These receptors are distributed in both serotonergic and non-serotonergic neurons, where they act as auto- or heteroreceptors, respectively. Studies from ours and other laboratories have shown that 5-HT1B receptors are densely expressed in the ventral pallidum, globus pallidus, substantia nigra and dorsal subiculum and moderately expressed in the cerebral cortex, the molecular layer of the hippocampus, the entopeduncular nucleus, the superficial gray layer of the superior colliculus, the caudate putamen and the deep nuclei of the cerebellum. At the ultrastructural level, 5-HT1B receptors were found distributed in axons and axon terminals and these receptors are located on the plasma membrane of unmyelinated axon terminals and in the cytoplasm close to the plasmalemma. The terminal localization of the 5-HT1B receptors in CNS suggests that there is a signal responsible for the protein transport toward the nerve terminals. Studies from ours and other groups using lesion, radioligand binding sites, viral transfection and anterograde methods have shown that 5-HT1B receptors are located at the nerve terminals of different pathways. The 5-HT1B receptors act as terminal receptors and are involved in regulation of the release of various neurotransmitters, including 5-HT itself. The regulation of gamma-aminobutyric acid release by 5-HT1B receptors has been found in projections: from caudate putamen to the globus pallidus or substantia nigra, from nucleus accumbens to the ventral tegmentum area, and from purkinje neurons to the deep nuclei of the cerebellum. The control of glutamate release by 5-HT1B receptors has been found in projections from hippocampus to the dorsal subiculum and of N-acetyl-aspartyl-glutamate release from retinal ganglion cells to the superficial gray layer of the superior colliculus. The control of 5-HT release by 5-HT1B receptors was shown in projections arising from the raphe nuclei to fore- and midbrain regions. Multiple evidences suggest that 5-HT1B receptors are implicated in several physiological functions, behavior and psychiatric diseases including migraine, locomotor activity, drug abuse reinforcement, migraine, aggressive behavior, depression and anxiety states.

Animals↗

PubMed2004

Prenatal alcohol exposure causes long-term serotonin neuron deficit in mice.

BACKGROUND: Previous work from this laboratory showed that prenatal alcohol exposure at approximately 100 mg/dl from embryonic day (E)7 to early midgestation reduced the number and retarded the migration of serotonin (5-HT) neurons in the raphe nuclei in C57BL/6 mice. In this study, we report that the deficit of 5-HT neurons found in midgestation persisted on E18 and into young adulthood. METHODS: Pregnant dams were treated from E7 to E18 in three groups--(1) the alcohol group, fed with liquid diet with 25% ethanol-derived calories; (2) the isocaloric pair-fed group; and (3) the chow group for analysis of concentrations of active caspase-3--to study apoptosis at E18 in the brainstem and the number of 5-HT neurons at E18 and postnatal day 45. The concentrations of active caspase-3 were determined by using a colorimetric assay, and the 5-HT neurons were determined by immunocytochemistry. RESULTS: Prenatal alcohol exposure increased the concentration of active caspase-3 in the brainstem and caused reductions in brain weight by 20% and in the total number of 5-HT-immunostaining neurons in the dorsal and median raphe nuclei by 20% at E18 as compared with those of the pair-fed and chow controls. Continuous observation from prenatal to postnatal stages showed that the reduction of 5-HT-immunostaining neurons in the dorsal and median raphe nuclei persisted in the young adult stage. CONCLUSIONS: Upon prenatal alcohol exposure, an increased concentration of active caspase-3 and a decreased number of 5-HT-immunostaining neurons in the brainstem were observed at E18. The decreased number of 5-HT neurons persisted to the young adult stage of postnatal day 45. This suggests that ethanol has a long-lasting effect on 5-HT deficit. A fetal alcohol exposure-rendered lasting deficit of 5-HT and other transmitter systems may underlie the neuropsychiatric deficits in fetal alcohol spectrum disorder.

Animals↗

PubMed2004

A neuroprotective peptide antagonizes fetal alcohol exposure-compromised brain growth.

We evaluated a 9-amino-acid peptide, SALLRSIPA (SAL), an agonist of activity-dependent neurotrophic factor (ADNF), for its protective properties against fetal alcohol-related brain growth retardation, using an established liquid diet model of alcohol-related neurodevelopmental disorder (ARND) in C57BL/6 mice. Alcohol exposure during neurulation reduced body weight, head size, and specifically brain weight and volume. Major gross brain deficits include underdevelopment of brain areas, cortical thinning, ventricle enlargement, and restricted midline neural tissue growth leading to openings at the roof/floor plate. SALLRSIPA (SAL) treatment increased fetal body weight and restored brain weight, brain volume, and regional brain size. Furthermore, SAL restored cortical thickness, reduced the size and frequency of neural tube openings, and attenuated ventricular enlargement. The ability of SAL to antagonize alcohol-retarded brain growth and development of forebrain and midline neural tube at midgestation suggests its potential use as an antagonist against fetal alcohol- rendered microencephaly early in development.

Animals↗

PubMed2003

Moderate alcohol exposure compromises neural tube midline development in prenatal brain.

We previously reported that fetal alcohol treatment compromised the development of the midline raphe and the serotonin neurons contained in it. In this study, we report that the timely development of midline neural tissue during neural tube formation is sensitive to alcohol exposure. Pregnant dams were treated from embryonic day 7 (E7, prior to neurulation) or E8.5 (at neurulation) with the following diets: (a) alcohol (ALC), given as either a 20% or 25% ethanol-derived calorie (EDC) liquid diet, or (b) isocaloric liquid diet pair-fed (PF), or (c) standard rat chow (Chow). Fetal brains from each group were examined on E13, E15, or E18. Neural tube development was compromised as a result of alcohol exposure in the following ways: (1) approximately 60% of embryos at E13 and 20% at E15 showed perforation of the floor plate in the diencephalic vesicle, (2) although completely closed at E13, 70-80% of embryos failed to complete the formation of neural tissue at the roof as the alcohol exposure continued to E15, and (3) 60-80% of embryos show delayed 'occlusion' of the ventral canal by newly formed nestin-positive neuroepithelial cells and S100beta-positive glia in the brainstem of E15. The compromised (incomplete) neural tube midline (cNTM) occurred near the ventricles at E13 and E15, but was later completed at E18. In all cases, the cNTM was accompanied by an enlarged ventricle, and dose-dependent brain weight reduction. The midline of the neural tube at the roof and floor plates is known to mediate timely trophic induction for neural differentiation. Prenatal midline deficits also have the potential to affect the development of midline neurons such as raphe, septal nuclei, and the timely crossing of commissural fibers. The results of the liquid diet alcohol exposure paradigm suggest it is more a model for Alcohol-Related Neurodevelopmental Disorder (ARND) featuring neuropsychiatric disorders than for full-blown fetal alcohol syndrome (FAS) with noticeable facial dysmorphogenesis and gross brain retardation.

Animals↗

PubMed2003

Serotonin and its transporter on proliferation of fetal heart cells.

Besides neuronal transmission, serotonin (5-HT) also acts as a trophic signal during the development of the central nervous and neural crest systems. In this study, we report that in addition to trophic effect, 5-HT increases the proliferation of fetal heart cells. We showed for the first time that the cultured heart cells, express serotonin transporter (5-HTT), which confirmed the previously observed accumulation of 5-HT in developing heart. The influence of 5-HT on developing heart cells is studied throughout the dosage. We found that 5-HT concentration at physiological level, 4 microM, permits an optimal proliferation of heart cells as indicated by the number of 5-bromo-deoxyuridine immunoreactive (BrdU-im) cells and myosin heavy chain immunoreactive cells (MF20-im); fluctuation towards either concentrations reduce the proliferation. We hypothesized that 5-HTT plays a role in the heart development. Our study indicated that the blockade of 5-HT uptake by paroxetine decreased the number of BrdU-im cells and MF20-im cells. These data indicate a role of 5-HT and 5-HTT on heart development. Abnormal 5-HT level or misuse of 5-HT uptake blocker may alter the heart development.

Analysis of Variance↗

PubMed2002

Deviations in brain early serotonergic development as a result of fetal alcohol exposure.

Serotonin (5-HT) has specific roles not only as a transmitter but also as a signal for differentiation. We recently found that alcohol drinking during pregnancy resulted in incomplete-neural-tube-fusion which hindered the development of midline cells such as 5-HT neurons in mice. We now report that, at the birth of 5-HT neurons (E11), the 5-HT immunoreative (5-HT-im) neurons are often found missing medial projecting fibers towards ventricle in the Alcohol treated group (ALC) as compared with pair-fed (PF) and Chow-fed groups (Chow) in mice. At E13, there are fewer 5-HT-im neurons in either dorsal or median raphe of ALC as compared with PF or Chow; furthermore, neurite outgrowth and migration of the 5-HT neurons are also compromised with alcohol exposure. We, thus, demonstrated that fetal alcohol exposure compromised 5-HT development as early as at the 5-HT neuron birth. Since 5-HT is a signal for development of many forebrain neurons, the deviation of 5-HT in early life may have consequences on brain development that extend beyond those seen in the 5-HT system.

Journal Article↗