Background: A dysfunctional mesocorticolimbic dopamine system has been reported in alcohol dependence and major depressive disorder. Probing mesocorticolimbic dopamine function in severe depression using dextroamphetamine revealed an altered behavioural response and a disrupted mesocorticolimbic circuitry in behavioural and functional magnetic resonance imaging (fMRI) studies. The purpose of this study was to use a similar approach in alcohol dependence. Behavioural Study: to assess dextroamphetamine subjective effects in alcohol-dependent and depressed alcohol-dependent participants. FMRI Study: to assess how the mesocorticolimbic circuitry would respond to a dextroamphetamine challenge in alcohol-dependent participants exposed to alcohol cues. Methods: In both studies, a single oral 30 mg dose of dextroamphetamine was the pharmacological intervention. Behavioural Study: randomized, double-blind, placebo-controlled, between-subject study. Eighteen alcohol-dependent and 22 depressed alcohol-dependent participants were compared using validated self-report drug effect tools (e.g. Addiction Research Center Inventory). FMRI Study: single-blind, between-subject study. FMRI blood oxygen level–dependent (BOLD) activation was measured in 14 alcohol-dependent and 9 healthy control participants during an alcohol-cue exposure task pre- and post-drug. Results: Behavioural Study: DRUG (F1,40=18.6; p<0.001) and GROUP (F1,40=16.6; p<0.001) main effects but no GROUPxDRUG interaction effects (F1,40=0.02; p=0.88) were detected, even when only severely depressed alcohol-dependent individuals were included (F1,30=0.04; p=0.84). FMRI Study: Alcohol-dependent participants exhibited greater ventral striatal activation compared to controls pre-drug and post-drug effect (F1,40=20.1; z=3.8; p<0.001; k>10; (x=10;y=-2;z=-14)). A GROUPxDRUG interaction effect was detected in the medial orbitofrontal cortex (mOFC) (F1,40=21.5; z=4.0; p<0.001; k>10; (x=-12;y=28;z=-20). The alcohol-dependent group exhibited a negligible mOFC response across both pre- and post-drug scanning sessions. In contrast, controls exhibited attenuation of mOFC response post-drug. Conclusion: The lack of significant GROUPxDRUG interaction effects in the Behavioural Study may suggest different neurobiological mechanisms underlying alcohol dependence and depression mesocorticolimbic dysfunction. Alcohol dependence appeared to mitigate the impact of depression severity on participants’ behavioural responses to dextroamphetamine. The FMRI Study data suggest there may be ventral striatal and mOFC disruption in alcohol-dependent participants. We suggest the mOFC may be involved in the reported loss of prefrontal modulation of dopamine cell activity in alcohol dependence. This supports a key role for the mOFC in mesocorticolimbic dysfunction in alcohol dependence.

Background: A dysfunctional mesocorticolimbic dopamine system has been reported in alcohol dependence and major depressive disorder. Probing mesocorticolimbic dopamine function in severe depression using dextroamphetamine revealed an altered behavioural response and a disrupted mesocorticolimbic circuitry in behavioural and functional magnetic resonance imaging (fMRI) studies. The purpose of this study was to use a similar approach in alcohol dependence. Behavioural Study: to assess dextroamphetamine subjective effects in alcohol-dependent and depressed alcohol-dependent participants. FMRI Study: to assess how the mesocorticolimbic circuitry would respond to a dextroamphetamine challenge in alcohol-dependent participants exposed to alcohol cues. Methods: In both studies, a single oral 30 mg dose of dextroamphetamine was the pharmacological intervention. Behavioural Study: randomized, double-blind, placebo-controlled, between-subject study. Eighteen alcohol-dependent and 22 depressed alcohol-dependent participants were compared using validated self-report drug effect tools (e.g. Addiction Research Center Inventory). FMRI Study: single-blind, between-subject study. FMRI blood oxygen level–dependent (BOLD) activation was measured in 14 alcohol-dependent and 9 healthy control participants during an alcohol-cue exposure task pre- and post-drug. Results: Behavioural Study: DRUG (F1,40=18.6; p<0.001) and GROUP (F1,40=16.6; p<0.001) main effects but no GROUPxDRUG interaction effects (F1,40=0.02; p=0.88) were detected, even when only severely depressed alcohol-dependent individuals were included (F1,30=0.04; p=0.84). FMRI Study: Alcohol-dependent participants exhibited greater ventral striatal activation compared to controls pre-drug and post-drug effect (F1,40=20.1; z=3.8; p<0.001; k>10; (x=10;y=-2;z=-14)). A GROUPxDRUG interaction effect was detected in the medial orbitofrontal cortex (mOFC) (F1,40=21.5; z=4.0; p<0.001; k>10; (x=-12;y=28;z=-20). The alcohol-dependent group exhibited a negligible mOFC response across both pre- and post-drug scanning sessions. In contrast, controls exhibited attenuation of mOFC response post-drug. Conclusion: The lack of significant GROUPxDRUG interaction effects in the Behavioural Study may suggest different neurobiological mechanisms underlying alcohol dependence and depression mesocorticolimbic dysfunction. Alcohol dependence appeared to mitigate the impact of depression severity on participants’ behavioural responses to dextroamphetamine. The FMRI Study data suggest there may be ventral striatal and mOFC disruption in alcohol-dependent participants. We suggest the mOFC may be involved in the reported loss of prefrontal modulation of dopamine cell activity in alcohol dependence. This supports a key role for the mOFC in mesocorticolimbic dysfunction in alcohol dependence.

While selective serotonin (5-HT) reuptake inhibitors (SSRIs) are utilized as the first-line strategy in treating depression, new approaches are still desired. Using in vivo electrophysiological techniques, the effects of co-administration of bupropion with the SSRI escitalopram on the firing rate of dorsal raphe 5-HT and locus coeruleus norepinephrine (NE) neurons were investigated. Escitalopram significantly decreased the firing of 5-HT and NE neurons at day 2. The 5-HT firing rate, unlike that of NE, recovered after the 14-day escitalopram regimen. Bupropion did not increase 5-HT firing but decreased that of NE after 2 days. Following 14-day bupropion, 5-HT firing was markedly enhanced, and NE firing was back to baseline. Co-administration of escitalopram and bupropion doubled 5-HT firing after 2 and 14 days, whereas NE neurons were inhibited after 2, but partially recovered after 14 days. Although sustained bupropion administration did not alter the sensitivity of 5-HT1A receptors in hippocampus, the tonic activation of postsynaptic 5-HT1A receptors was enhanced in 14-day bupropion-treated rats to a greater extent than in the 2-day and control rats. The function of terminal 5-HT1B autoreceptors was not changed. The inhibitory action of α2-adrenergic receptors on 5-HT terminals was, however, diminished. The function of terminal α2-adrenergic autoreceptors was also attenuated in rats given bupropion for 14 days. Administration of the antidepressant trazodone suppressed the 5-HT firing at day 2, which recovered to baseline following 14 days. Prolonged trazodone-administration enhanced the tonic activation of postsynaptic 5-HT1A receptors in hippocampus, and decreased the function of terminal 5-HT1B autoreceptors. Finally, a novel psychotropic agent asenapine showed potent antagonistic activity at 5-HT2A, D2, and α2-adrenoceptors. Asenapine, however, acted as a partial agonist at 5-HT1A receptors in dorsal raphe and hippocampus. Overall, the therapeutic effects of various antidepressants may be, at least in part, due to the enhancement of 5-HT and/or NE neurotransmission.

This study examines the use of unmodified magnetite nanoparticles (Fe3O4 NPs) for selective extraction and enrichment of the catecholamines dopamine (DA), noradrenaline (NE), and adrenaline (E), prior to analysis using capillary electrophoresis with UV detection. Coordination between Fe3+ on-the-surface Fe3O4 NPs and the catechol moiety of catecholamines enables Fe3O4 NPs to capture catecholamines from an aqueous solution. We obtained maximum loading of catecholamines on the NP surface by adjusting the pH of the solution to 7.0. In addition, catecholamine loading on the Fe3O4 NPs increased in conjunction with NP concentrations. Ligand exchange found H3PO4 to be efficient in the removal of adsorbed catecholamines on the NP surface. Adding 1.2% poly(diallyldimethylammonium chloride) to the background electrolyte caused efficient separation of the liberated catecholamines with baseline resolution within 20 min. Under optimal extraction and separation conditions, the limit of detections at a signal-to-noise ratio of 3 for E, NE, and DA were 9 nM, 8 nM, and 10 nM, respectively. Significantly, we successfully used the combination of a phenylboronate-containing spin column and the proposed method to determine the concentrations of NE and DA in urine and the content of NE in Portulaca oleracea L. leaves.

Microglia have the potential to produce specific neurotrophic molecules in response to injury and brain diseases. Activated microglia are seen after brain injury or in neurological disease, such as Parkinson¡¦s disease (PD). PD is a progressive neurodegenerative disorder. Although its cause remains unknown, it is believed that enhanced oxidative stress is a major component in the pathogenesis of nigral cell death in PD. Previous results have shown that DA induces apoptosis of dopaminergic neurons in a time- and concentration- dependent manner. In addition, a number of studies have shown that Zn2+ may enter the cell to reach toxic concentrations and that Zn2+ concentration is higher in the striatum of the postmortem brains of PD patients than that of the control brains. We have previously shown that Zn2+ synergistically enhanced the dopamine- and H2O2- induced PC12 cell death. To study the role of microglia in the cell death, I have examined the effect of conditioned medium from a human microglia cell line on the PC12 cell death induced by dopamine and Zn2+. The result shows that conditioned medium inhibits the PC12 cell death and the phosphorylation of JNK induced by dopamine and Zn2+ is diminished by the conditioned medium. It appears that the factor(s) that are responsible for the protection is heat-stable because the conditioned medium heated in 70¢Jfor 30 minutes still has the ability to protect the cell death. Cell death induced by A23187 and C2-ceramide, but not by staurosporine can be protected by the conditioned medium. Results from this study suggest that the microglia secrete some factors which can protect neuron.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成7年12月20日 北川喜己氏の博士論文として提出された

Thèse de doctorat : SCIENCES MEDICALES : Metz : 1999. / 1999METZ037S. 99 ref.

Thèse doctorat : Neurosciences : Strasbourg 1 : 2006. / Titre provenant de l'écran-titre. Bibliogr. 31 p.

Reproduction de : Thèse de doctorat : Physiologie, biologie cellulaire et moléculaire : Poitiers : 2008. / Contient des textes en anglais, extraits de diverses publications et revues, 2008. Titre provenant de l'écran-titre. Bibliogr.

Thesis (Ph. D.)--University of Texas at Austin, 2003. / Supervisor: Christine L. Duvauchelle. Vita. Includes bibliographical references. Available also from UMI Company.