Effects of acute and chronic bupropion on locomotor activity and dopaminergic neurons

Acute administration of bupropion (10 or 30 mg/kg) to rats increased locomotor activity in a dose-related manner. The highest dose increased the dopamine (DA) concentration while both doses reduced the concentration of dihydroxyphenylacetic acid (DOPAC) in the striatum. The enhancement of locomotor activity and the decrease of striatal DOPAC concentrations were increased with chronic administration (up to 40 days) of bupropion. The rate of DA synthesis in the striatum was increased by the acute administration of d-amphetamine but was not altered by acute or chronic administration of bupropion.     

Benzodiazepines suppress the light response of retinal dopaminergic neurons in vivo

Sedative dosages of the benzodiazepine, diazepam (76 micro mol/kg, i.p.), reduce the light-evoked increase in retinal dopamine turnover, while intraocular applications of the water-soluble benzodiazepine, flurazepam (0.50 or 1.0 micro mol/eyeball), produce a dose-dependent suppression of light-enhanced dopamine synthesis. These results provide the first evidence that the benzodiazepines alter a physiologically important retinal response in vivo. They also suggest that some the visual effects produced by the benzodiazepines may have an intraretinal locus of action.     

Amphetamine exerts anomalous effects on dopaminergic neurons in neonatal rats in vivo.

The effects of amphetamine, apomorphine and haloperidol on the spontaneous activity of electrophysiologically identified nigral dopaminergic neurons were examined with extracellular recordings in vivo in neonatal rats ranging in age from postnatal day 1 to postnatal day 28, and in adult rats. In postnatal day 1-6 pups amphetamine (5 mg/kg i.p.) produced a paradoxical increase in neuronal firing in 45% and had no effect on 30% of the 20 neurons examined. During the second week half of the neurons recorded were unresponsive to amphetamine. Typical amphetamine-induced inhibition was observed in only 25% of the neurons from postnatal day 1-6 and 50% of those from postnatal day 7-15 rats compared to 81.8% in postnatal day 16-28 pups and 100% in adults. Apomorphine (50-200 micrograms/kg i.p.; 5-20 micrograms/kg i.v.), significantly inhibited the spontaneous activity of dopaminergic neurons, including cells that previously failed to be inhibited by amphetamine, independent of age. The apomorphine-induced inhibition was consistently reversed by administration of haloperidol (0.5-2.0 mg/kg, i.p.; 50-200 micrograms/kg i.v.). The anomalous responses to amphetamine in early neonatal rats may be related to its paradoxical behavioral effects in human children afflicted with attention deficit disorder.     

Selective local action of angiotensin II on dopaminergic neurons in the rat hypothalamus in vivo

Summary Microdialysis was used to investigate whether angiotensin II modulates the basal and K⁺-induced release of endogenous noradrenaline, dopamine and their metabolites 3,4-dihydroxyphenylglycol (DOPEG) and 3,4-dihydroxyphenylacetic acid (DOPAC) from the anterior hypothalamus of the anaesthetized rat. The release of the amines was stimulated twice (ST1 and ST2) with either 50 mmol/l or 100 mmol/l K⁺. The release of each amine induced by K⁺ was reproducible and concentration-dependent. Angiotensin II when present in the perfusion fluid after ST1 at a concentration of 0.1 and 10 mol/l (chosen after in vitro experiments had shown that the recovery of the peptide across the dialysis membrane was only 3.6%), had no significant effect on amine release. However, 10 mol/l angiotensin II induced an immediate, significant increase in basal DOPAC outflow which reached a maximum of 89% in the 100 mmol/l K⁺ and 53% in the 50 mmol/l K⁺ experiments. No such effect was observed with DOPEG outflow. In a separate experimental series, addition of angiotensin II without a preceding K⁺ stimulation period did not significantly affect the outflow of the amines and metabolites.The results suggest that angiotensin II can selectively influence dopamine metabolism in the anterior hypothalamus in vivo but does not act locally to acutely facilitate the release of endogenous catecholamines from this brain area.     

Effects of heterocyclic amines in food on dopamine metabolism in nigro-striatal dopaminergic neurons

We investigated the effects of 14 heterocyclic amines in food on nigro-striatal dopaminergic neurons. Among 14 compounds tested, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) caused substantial decreases in 3,4-dihydroxy-phenylalanine (DOPA) formation in striatal tissue slice system. When Trp-P-1 or Trp-P-2 was unilaterally infused in the rat striatum by an in vivo micro-dialysis technique, both compounds produced a transient increase of dopamine (DA) and continuous decreases in the metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the perfusate. This suggests that the two compounds inhibit monoamine oxidase (MAO) in vivo. Indeed they were found to be very potent inhibitors of MAO in vitro. Systemic administration of Trp-P-1 to C57 Black mice caused a marked decrease of DOPAC content and a significant increase of DA in the striatum, indicating inhibition of MAO in vivo. These results suggest that Trp-P-1 and Trp-P-2 contained in food could alter the metabolism of DA in the brain.     

Effects of dopaminergic stimulants on cyclic nucleotide levels in mouse brain in vivo

Summary Dopaminergic stimulants (amantadine, amphetamine, apomorphine, nomifensine and L-dopa plus benserazide) increased cyclic GMP levels in the medial forebrain and cerebellum of mice. Cyclic AMP levels were not significantly altered under these conditions. Drug-induced stereotyped behaviour correlated in intensity and duration to the changes in cyclic GMP levels in the medial forebrain.Amantadine, apomorphine and nomifensine showed a linear dose response relationship, but differed as to the extent and time course of the increase in cyclic GMP. Amantadine and apomorphine were more effective in elevating cyclic GMP in the medial forebrain than in the cerebellum. Amphetamine produced an exponential dose-related elevation of cyclic GMP in both parts of the brain, being more effective in the cerebellum than in the medial forebrain at high doses, thus indicating a complex mechanism of action. L-Dopa (50 mg/kg) and benserazide (40 mg/kg) alone did neither significantly increase cyclic GMP levels nor induce stereotyped behaviour. However, in animals pretreated with benserazide (15 min prior to L-dopa) L-dopa produced a significant elevation of cyclic GMP and stereotyped behaviour.     

丙戊酸钠对帕金森病小鼠多巴胺能神经元及胶质细胞源性神经营养因子表达的影响

帕金森病(Parkinson's disease ,PD)是一种神经系统退行性疾病,主要表现为中脑黑质致密部多巴胺能神经元的丧失,纹状体多巴胺含量下降[1],至今尚无有效的治疗手段.丙戊酸钠(valproate,VPA) 是临床上作为治疗双相精神障碍的药物,能有效控制患者的躁狂和抑郁症状[2].胶质细胞源性神经营养因子(glial cell line derived neurotrophic factor,GDNF)最初从大鼠胶质瘤细胞系B49条件培养液中分离纯化,对大鼠中脑多巴胺能神经元有特异性营养作用[3].为探讨VPA对小鼠帕金森病中脑黑质多巴胺能神经元及纹状体GDNF表达的影响,本研究拟用C57BL小鼠1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyfidine,MPTP)法建立帕金森病模型,通过中脑黑质致密部(SNc)酪氨酸羟化酶(TH)的免疫组织化学染色及原位杂交方法观察纹状体GDNF表达,有望为PD寻求更有效的治疗手段,并对VPA更广泛的临床应用提供依据.     

Effects of clozapine on the activity of central dopaminergic and noradrenergic neurons.

The effects of clozapine on the spontaneous firing rate of noradrenergic (NE, locus coeruleus), dopaminergic (DA, zona compacta, ventral tegmental area) and non-dopaminergic (zona reticulata) neurons was studied in chloral hydrate anesthetized rats. Clozapine administered intraperitoneally significantly increased the spontaneous activity of NE and DA neurons. After a cumulative dose of 8 mg/kg clozapine, the increase of mean firing rate per min of zona compacta and ventral tegmental area neurons attained almost similar values. Amphetamine reversed the clozapine-induced stimulation of NE and DA neurons. Zona reticulata neurons were depressed by clozapine. Neither amphetamine nor physostigmine were effective in antagonizing the inhibition. Our results suggest that clozapine blocks central NE and DA receptors. Furthermore, they fail to reveal a smaller sensitivity of the striatum as compared to the limbic system to the effects of clozapine.     

尼莫地平对帕金森病大鼠模型多巴胺能神经元的保护作用

目的 观察尼莫地平对6-羟基多巴胺(6-OHDA)诱导的帕金森病(Parkinson disease,PD)大鼠多巴胺能神经元的保护作用.方法 脑立体定位注射6-OHDA建立大鼠PD模型,从行为学、病理、免疫组化方面观察尼莫地平干预后PD大鼠旋转行为、黑质细胞的变化.结果 (1)行为学观察:尼莫地平预先给药组PD大鼠模型成功率低于PD模型组.对照组、尼莫地平组治疗前后行为学无明显变化;左旋多巴组、尼莫地平与左旋多巴联合给药组治疗后旋转行为较给药前明显减慢(P＜0.05).(2)酪氨酸羟化酶(TH)组阳性细胞计数:第二阶段各组间TH阳性细胞计数无统计学差异,各组用药前后TH阳性细胞计数亦无统计学差异.结论 尼莫地平预先干预可降低PD模型成功率,即对PD的预防可能有一定作用;但模型成功后给予尼莫地平未能改善PD大鼠行为学和病理形态学的变化.     

Effects of prolactin on tyrosine hydroxylase activity of central dopaminergic neurons of male rats

Previous work from our laboratory has indicated that ovine prolactin can produce a rapid stimulation (within 1 h) of dopamine release from nigrostriatal and mesolimbic dopaminergic neurons of male rats. In the present experiment we attempted to determine whether this effect of prolactin was a function of an increase in the activation of dopamine synthesis. To examine this possibility we used the drug NSD 1015. This drug is a decarboxylase inhibitor that leads to dopa accumulation and is used as an index of in vivo tyrosine hydroxylase activity. Our results demonstrated that ovine prolactin increased turnover of dopamine but had no effect upon tyrosine hydroxylase activation (up to 4 h) in both dorsal and ventral striatal dopaminergic neurons. In contrast, ovine prolacting had a clear effect (within 4 h) on tyrosine hydroxylase activity in mediobasal hypothalamic dopaminergic neurons. These results suggest that ovine prolactin can differentially alter synthesis/release processes of dopamine from these sites.     

色霉素对多巴胺能神经元的保护作用

目的研究色霉素对MPP+诱导凋亡的多巴胺能神经元的保护作用。方法体外培养的胎鼠腹侧中脑神经元,以MPP+引起多巴胺能神经元凋亡作为帕金森病的细胞模型,Hoechst 33258荧光核染色法检测神经元的凋亡情况,免疫细胞化学方法检测多巴胺能神经元内磷酸化Tau水平。结果10μmol·L-1 MPP+可以升高Tau磷酸化水平,诱导神经元发生典型的凋亡。而色霉素通过抑制Tau磷酸化,减少神经元凋亡,使TH-阳性细胞数目增加。结论色霉素可以通过抑制Tau磷酸化而对MPP+诱导凋亡的多巴胺能神经元发挥保护作用,色霉素可能用于临床防治帕金森病等神经退行性疾病。     

Biochemical effects of minaprine on striatal dopaminergic neurons in rats

The biochemical effects of minaprine, a new psychotropic drug, were investigated on striatal dopaminergic neurons in the rat. Minaprine did not displace [³H]spiperone in-vitro binding from striatal membranes but had clear effects on dopamine (DA) metabolites. Homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were significantly decreased in a dose-dependent manner after intraperitoneal administration of minaprine 30 min before killing. In rats injected with minaprine 15 mg kg⁻¹ i.p. at different intervals, the decrease in striatal HVA and DOPAC was time-dependent and a concomitant rise in 3-methoxytryramine (3-MT) concentrations was observed. The maximum of these effects was reached 30 min after minaprine. When administered 5 min after a monoamineoxidase (MAO) inhibitor (pargyline, 100 mg kg⁻¹ i.p.) and 30 min before killing, minaprine did not affect pargyline-induced changes in HVA, DOPAC and 3-MT levels. This together with other data suggests that minaprine affects DA metabolism by acting, at least partially, at presynaptic level through in-vivo inhibition of MAO activity.     

Effects of chronic treatments with amineptine and despiramine on motor responses involving dopaminergic systems

The acute effects of increasing doses of the antidepressant drugs amineptine (5–40 mg/kg, IP) and desipramine (5–20 mg/kg IP) were studied in mice on three parameters of the activity (the horizontal activity, the vertical activity and the number of small movements without displacement) measured in a computerized Digiscan actimeter. The horizontal and vertical activities were dose dependently and similarly increased by acute amineptine, whereas the number of movements without displacement was increased up to 10 mg/kg with no further significant modification up to 40 mg/kg; in contrast, all three parameters were reduced in an identical manner by desipramine. The changes in the responses to the selective D-1 dopamine (DA) receptor agonist SK&F 38393 (1.87–30 mg/kg, SC), to the selective D-2 DA receptor agonist LY 171555 (0.1–1.6 mg/kg, SC) and to the selective DA uptake inhibitor GBR 12783 (1.25–20 mg/kg, IP) were measured on the three parameters of activity in mice chronically treated with amineptine (20 mg/kg, IP twice daily during 15 days) or by desipramine (10 mg/kg, IP, twice daily during 15 days). The chronic treatments with amineptine or desipramine did not modify the motor stimulant effects GBR 12783 and of SK&F 38393 on the three parameters (excepted for a slight modification of the horizontal activity for 7.5 mg/kg SK&F 38393 in mice chronically treated with amineptine). In contrast, the motor inhibitory effects of the lowest doses of LY 171555 (0.1–0.4 mg/kg) were strongly reduced in mice chronically treated with amineptine or desipramine but only on the horizontal activity with no change on the vertical activity and on the number of small movements without displacement. These data indicate that, as in chronic treatment with typical antidepressant drugs like desipramine, chronic treatment with amineptine alters selectively the sedative effects induced by stimulation of D-2 DA autoreceptors in the mesolimbic dopaminergic area involved in the horizontal (locomotor) activity.     

Inhibitory effects of trace amines on rat midbrain dopaminergic neurons

Trace amines are biological compounds that are still awaiting identification of their role in neuronal function. Using intracellular electrophysiological recordings, we investigated the depressant action of two trace amines (beta-phenylethylamine and tyramine) on the firing activity of dopaminergic neurons of the substantia nigra pars compacta and ventral tegmental area. This inhibition was due to a membrane hyperpolarisation that was blocked by the D2 dopamine receptor antagonist sulpiride and was not potentiated by the dopamine-uptake blocker, cocaine. Inhibition of the dopamine transporter did not mediate the effects of trace amines, because unlike cocaine, trace amines did not potentiate the inhibitory responses to exogenously applied dopamine. The inhibitory actions of beta-phenylethylamine and tyramine were present in reserpine-treated animals but were abolished when the dopamine-synthesis inhibitor carbidopa was applied. Our data suggest that trace amines cause an indirect activation of dopamine autoreceptors, by an increased efflux of newly synthesised dopamine. The inhibition of dopaminergic activity by trace amines may relate to their involvement in neuronal processes linked to drug addiction, schizophrenia, attention deficit hyperactive disorders and Parkinson's disease.     

喜树碱对炎症诱导的多巴胺能神经元损伤的保护作用

目的探讨喜树碱对炎症诱导的多巴胺能神经元(DN)损伤的保护作用及其可能机制。方法建立DN培养体系及混合培养体系,观察不同干预下DN的生存率、酪氨酸羟化酶(TH)mRNA表达及肿瘤坏死因子α(TNF-α)、一氧化氮(NO)、白细胞介素6(IL-6)、胶质源性神经生长因子(GDNF)含量的变化。结果在DN培养体系中,喜树碱10mg/L较对照组明显促进DN凋亡(P<0.05)。在混合培养体系中,与对照组比较,不同浓度喜树碱均增加TH阳性细胞数和THmRNA的表达(P<0.05),降低NO、TNF-α及IL-6的含量(P<0.05),但只有喜树碱10mg/L能促进DN的凋亡(P<0.05)。结论适量的喜树碱能抑制星形胶质细胞分泌炎性介质,保护神经元。