Sleep deprivation hastens the antidepressant action of fluoxetine

Among ten bipolar depressed patients admitted to our psychiatric ward, five patients were treated with fluoxetine alone and five subjects were treated with fluoxetine in association with total sleep deprivation (TSD) in order to evaluate the effect of the interaction between the administration of the serotonergic antidepressant compound fluoxetine and repeated cycles of TSD. Patients treated with fluoxetine plus repeated TSD showed a faster amelioration of depressive symptomatology compared with the other group. We discuss our findings hypothesizing an enhancement in dopaminergic and possibly in serotonergic transmission due to repeated TSD adding to the increase in serotonergic transmission due to fluoxetine medication.     

Halothane anesthesia enhances the effect of dopamine uptake inhibition on interstitial levels of striatal dopamine

The anesthetic, isoflurane, has been shown to potentiate the ability of the dopamine (DA)-uptake inhibitor, nomifensine, to increase the brain interstitial dopamine level ([DA]_e). Since the effect of the more commenly used anesthetic, halothane, on this system is unknown, we determined [DA]_e by microdialysis in the striatum of rats, conscious or anesthetized with halothane, in the presence of the more selective DA uptake inhibitor, vanoxerine (GBR 12909), or the DA releaser, d-amphetamine. Basal [DA]_e was not changed by halothane. However, in halothane-anesthetized rats, the vanoxerine (3 mg/kg i.v.)-induced DA response increased severalfold compared to the response in conscious rats. The initial peak response to d-amphetamine (1 mg/kg i.v.) did not change, but the late response (1–3 h after injection) was augmented in anesthetized rats. Halothane is believed to increase firing of DA neurons in the substantia nigra and, hence, to release striatal DA. We hypothesize that [DA]_e, is maintained at a normal level during the increased firing by equally increased activity of the DA transporter. However, when the DA transporter is blocked by vanoxerine, the increased DA release is unimpaired and [DA]_e rises. Correspondence to: A. Fink-Jensen at the above address     

(+)-6,7-Benzomorphan sigma ligands stimulate dopamine synthesis in rat corpus striatum tissue

The benzomorphan δ ligands, (+)-N-allylnormetazocine (NANM) and (+)-pentazocine, but not (+)-cyclazocine, stereospecifically stimulated dopamine synthesis in minces of rat corpus striatum by 15–23% over basal values at 0.1–1.0 μM. The effect of (+)-NANM and (+)-pentazocine was blocked by the reported δ antagonist, BMY-14802 but not by the opiate antagonist naloxone. These results suggest that these (+)-benzomorphans may act as agonists at putative δ peteroreceptorson striatal nerve terminals, or through an indirect mechanism, to modulate dopamine synthesis.     

Neonatal Intermittent Hypoxia Impairs Dopamine Signaling and Executive Functioning

Mesotelencephalic dopamine (DA) pathways are exquisitely vulnerable to ischemic-anoxic insult. These insults are known to produce long-term derangements in DA signaling and have been hypothesized to contribute, at least in part, to pathologic behaviors such as cerebral palsy, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Whether modest intermittent hypoxia, such as that encountered with repetitive apneas in premature infants, contributes to clinically significant impairments in DA signaling, and how these impairments manifest at a systems level, is unknown. To address these voids there is a need to develop animal models emulating features of a common disorder of prematurity, namely, apnea with hypoxia. Behavioral traits exhibited by such models include disturbed sleep-wake architecture, excessive locomotion, and impaired working memory persisting 1 to 2 months post-insult. Western-blot analysis of expression patterns of proteins involved in DA signaling (e.g., DA and vesicular monoamine transporters, tyrosine hydroxylase, and D1 receptors) are consistent with that which might be expected from hyper- or hypodopaminergic functioning in DA-responsive prefrontal cortex and striatal circuits, respectively. These novel observations suggest that intermittent hypoxia occurring during a period of critical brain development disrupts development of those mesotelencephalic pathways modulating the expression of sleep and wakefulness, locomotion, and executive functioning.     

杏仁核和扣带回联合毁损对MAP大鼠脑内多巴胺D2受体的影响

目的探讨联合毁损杏仁核和扣带回对甲基苯丙胺(M AP)大鼠脑内边缘区多巴胺D2受体表达的影响。方法40只SD大鼠随机分为对照组、M AP组、M AP 毁损组和M AP 假毁损组,每组各10只;采用经腹腔注射M AP制备精神分裂症M AP模型,立体定向-射频毁损杏仁核和扣带回,免疫组织化学ABC法观察边缘区D2受体的表达。结果与对照组和M AP 损毁组比较,M AP组及M AP 假毁损组大鼠边缘区D2受体表达有显著性差异(P<0.01);M AP 毁损组大鼠边缘区D2受体阳性细胞率与对照组比较差异无显著性(P>0.05)。结论杏仁核和扣带回的联合毁损可抑制使用M A P诱发的边缘区D2受体表达的亢进。     

Microglia enhance manganese chloride-induced dopaminergic neurodegeneration: Role of free radical generation

Exposure to elevated levels of manganese has been shown to cause neuronal damage in the midbrain and the development of Parkinsonian symptoms. Activation of microglia and release of neurotoxic factors in particular free radicals are known to contribute to neurodegeneration. We have recently reported that manganese chloride (MnCl₂) stimulates microglia to produce reactive oxygen species (ROS). The aim of this study is to determine the role of microglia in the MnCl₂-induced degeneration of dopaminergic (DA) neurons that are particularly vulnerable to oxidative insult. MnCl₂ (10-300 μM; 7 days) was markedly more effective in damaging DA neurons in the rat mesencephalic neuron-glia cultures than the neuron-enriched (microglia-depleted) cultures. In addition, the microglia-enhanced MnCl₂ toxicity was found to be preferential to DA neurons. The microglial enhancement of DA neurotoxicity was further supported by the observation that replenishment of microglia to the neuron-enriched cultures significantly increased the susceptibility of DA neurons to the MnCl₂-induced damage. Analysis of the temporal relationship between microglial activation and DA neurodegeneration revealed that MnCl₂-stimulated microglial activation preceded DA neurodegeneration. Mechanistically, MnCl₂ (10-300 μM) stimulated a concentration- and time-dependent robust production of ROS and moderate production of nitric oxide but no detectable release of tumor necrosis factor-alpha and interleukin-1beta. Application of free radical scavengers including superoxide dismutase/catalase, glutathione, N-acetyl cysteine and an inhibitor of nitric oxide biosynthesis significantly protected DA neurons against the MnCl₂-induced degeneration. These results demonstrate that microglial activation and the production of reactive nitrogen and oxygen free radicals promote the MnCl₂-induced DA neurodegeneration.     

垂体腺瘤中多巴胺D2受体的研究进展

多巴胺（dopamine，DA）是中枢神经系统内最主要的儿茶酚胺类神经递质，在中枢和外周神经系统中都担当了十分重要的作用。DA和其受体的发现引发了神经、临床精神病学的重大突破。正常垂体的前叶和中叶组织中，都存在一定水平的D2受体表达，它们介导了多巴胺对泌乳素（prolactin，PRL）和促黑色素细胞素等激素分泌的负调节作用。D2受体在PRL型垂体腺瘤中存在高表达，在对PRL型垂体腺瘤的治疗中，D2受体激动剂获得了良好的临床效果，目前已成为大多数泌乳素型腺瘤首选的治疗方法。随着分子生物学和放射医学技术的发展，对多巴胺D2受体分子的研究取得了长足的进步。除了PRL型腺瘤外，在相当一部分的非PRL型腺瘤一包括生长激素型和促性腺激素型和无功能性垂体腺瘤等疾病中，都检测到D2受体的表达，D2受体激动剂的治疗效果得到了深入的探讨和分析。D2受体不同亚型的表达水平也得到进一步的检测，其发挥作用的分子机制也受到关注。D2受体不同亚型的表达水平与D2受体激动剂治疗敏感性之间的联系值得进一步关注。虽然在一些具体的研究结果上，在报道中还存在差异和争论，但有理由相信：随着对D2受体和其亚型分子结构的深入了解，以及相关药物开发的不断完善，D2受体激动剂将在垂体腺瘤的治疗——尤其是在非PRL型腺瘤的治疗中。发挥更积极的作用。     

Dopaminergic control of transmission from group II muscle afferents to spinal neurones in the cat and guinea-pig

The effects of dopamine and its agonists on transmission from muscle afferents to spinal neurones were investigated in the cat and guinea-pig spinal cord, by measuring the drug effects on the amplitude of monosynaptic field potentials evoked by electrical stimulation of group I and group II muscle afferents. Local iontophoretic application of dopamine, the dopamine D1/D5 agonist SKF-38393 and the D2/D3/D4 agonist quinpirole all depressed the group II field potentials evoked at the base of the dorsal horn. Group II field potentials in the intermediate zone were depressed by dopamine to a similar degree as the dorsal horn field potentials, whereas the dopamine agonists were without effect upon them. The intermediate zone field potentials evoked by group I muscle afferents were not depressed by any of the drugs. The dopamine-evoked depression of the group II-evoked field potentials in the dorsal horn in the guinea-pig spinal cord was reduced by the simultaneous application of haloperidol. The results demonstrate that dopamine receptors mediate the depression of transmission from group II muscle afferents to interneurones in the dorsal horn, but not to neurones in the intermediate zone of the spinal cord.     

Aromaticl-amino acid decarboxylase immunoreactive cells in the rat striatum: a possible site for the conversion of exogenousl-DOPA to dopamine

The efficacy ofl-dihydroxyphenylalanine (l-DOPA) in ameliorating the symptoms of Parkinson's disease (PD) is attributed to its conversion to dopamine (DA) by the enzyme aromaticl-amino-acid decarboxylase (AADC) in the striatum. Although the site of this conversion in the DA-denervated striatum has yet to be identified, it has been proposed thatl-DOPA could be converted to DA at non-dopaminergic sites containing AADC. In the present study, we used immunocytochemical techniques to examine the localization of AADC and DA in the striatum of rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopaminergic projection. In the DA-denervated striatum, we observed AADC-immunoreactive (-IR) cells with morphological characteristics similar to a class of small aspiny interneuron. Although usually obscured by a dense plexus of AADC-IR fibers, these cells could also occasionally be detected in the intact striatum. Acute administration of L-DOPA to DA-denervated animals elicited contralateral rotational behavior as well as a pronounced c-fos protein immunoreactivity in the striatum ipsilateral to the lesion. Following acute administration ofl-DOPA, but not after acute saline, DA-IR cells were detected in the denervated striatum. These DA-IR cells are similar in morphology and were found in the same location as the AADC-IR cells. These results strongly suggest the existence of a class of AADC-containing striatal cells that can form DA from exogenousl-DOPA in the rat. In the DA deafferented striatum, DA produced by these cells from exogenousl-DOPA could be released to exert physiological effects on DA receptive tissue. It is possible that similar cells could contribute to the efficacy ofl-DOPA in the treatment of Parkinson's disease.     

Characterisation of dopamine receptors in insect (Apis mellifera) brain

In vitro binding experiments using the vertebrate D₁ dopamine receptor ligand [³H]SCH23390 and the vertebrate D₂ dopamine receptor ligand [³H]spiperone were conducted on membrane preparations of honey bee (Apis mellifera) brain. Specific binding of [³H]SCH23390 was saturable and reversible. Analysis of saturation data gave an apparent K_d of 6.3 ± 1.0 nM and B_max of 1.9 ± 0.2 pmol/mg protein for a single class of binding sites. The specificity of high affinity [³H]SCH23390 binding was confirmed in displacement experiments using a range of dopaminergic antagonists and agonists. The rank order of potency for antagonists was: R(+)-SCH23390 > cis-(Z)-flupentixol ≥ chlorpromazine > fluphenazine> S(+)-butaclamol > spiperone. R(±)-SKF38393 and dopamine were the most effective agonists tested. [³H]SCH23390 labels a site in bee brain that is similar, but not identical to the vertebrate D₁ dopamine receptor subtype. [³H]Spiperone also bound with high affinity to bee brain homogenates. Scatchard analysis of [³H]spiperone saturation data revealed a curvilinear plot suggesting binding site heterogeneity. The high affinity site had a apparent K_d of 0.11 ± 0.02 nM and B_max of 9.2 ± 0.5 fmol/mg protein. The calculated values for the low affinity site were a K_d of 19.9 nM and B_max of 862 fmol/mg protein. Kinetic analyses also indicated that [³H]spiperone recognises a heterogeneous population of sites in bee brain. Furthermore, agonist competition studies revealed a phenolaminergic as well as a dopaminergic component to [³H]spiperone binding in bee brain. The rank order of potency of dopaminergic antagonists in competing for [³H]spiperone binding was: spiperone > fluphenazine> S(+)-butaclamol > domperidone> R(+)-SCH23390 > S(−)-sulpiride.