The neurotoxic actions of 1-methyl-4-phenylpyridine (MPP+) are not prevented by deprenyl treatment

1-Methyl-4-phenylpyridine (MPP+) injected into the cerebral ventricles (ICV) of mouse caused depletions of striatal dopamine (DA)(-42%), 3,4-dihydroxyphenylacetic acid (DOPAC) (-34%) and homovanillic acid (HVA) (-16%) content without significant reductions in levels of noradrenaline (NA), serotonin (5-HT) or 5-hydroxyindoleacetic acid (5-HIAA). When deprenyl was administered before MPP+, striatal DA and its metabolites were further depleted, and striatal NA and 5-HT levels also were reduced. Further, whilst ICV MPP+ alone failed to influence the biochemistry of the limbic areas (nucleus accumbens plus tuberculum olfactorium), in the presence of deprenyl MPP+ caused 20-40% reductions in levels of limbic NA, DA, DOPAC, HVA, 5-HT and 5-HIAA. Therefore, deprenyl treatment does not prevent the neurotoxic actions of MPP+; indeed, a more extensive neurotoxicity for MPP+ is revealed in the presence of this monoamine oxidase inhibitor.     

Iptakalim alleviated the increase of extracellular dopamine and glutamate induced by 1-methyl-4-phenylpyridinium ion in rat striatum

The present study examined the effect of iptakalim (Ipt), a novel ATP-sensitive potassium (K(ATP)) channel opener (KCO), on 1-methyl-4-phenylpyridinium ion (MPP(+))-induced dopamine (DA) and glutamate efflux in extracellular fluid of rat striatum, using microdialysis technique. Rats were implanted guide cannula in the striatum and artificial cerebrospinal fluid was infused through a microdialysis probe to detect the level of DA and glutamate in the striatum. MPP(+) significantly enhanced the extracellular levels of DA and its metabolites, DOPAC and HVA, as well as glutamate. Application of Ipt (1, 10, 100 microM) concentration-dependently suppressed DA and its metabolites efflux induced by MPP(+). Concomitantly, Ipt reduced the increase of extracellular glutamate induced by MPP(+). These results suggest that Ipt can regulate DA and glutamate efflux induced by MPP(+) in rat striatum.     

In vivo release of dopamine and its metabolites following a direct infusion of L-dopa into the caudate nucleus of awake, freely behaving rats using a push-pull cannula

In vivo release of dopamine (DA) and its metabolites were determined following a direct infusion of 3,4-dihydroxyphenylalanine (L-DOPA) through a push-pull cannula in the caudate nucleus of unanesthetized, freely behaving rats. L-DOPA infusions increased the release of DA and dihydroxyphenylacetic acid (DOPAC) beginning with 10(-5) M L-DOPA, while homovanillic acid (HVA) was released consistently only following 10(-3) M L-DOPA. Maximal release of DA preceded that of DOPAC which preceded that of HVA. No salient changes in 5-hydroxyindoleacetic acid or behavior were observed following any L-DOPA dose.     

Phencyclidine increases extracellular dopamine metabolites in rat medial frontal cortex as measured by in vivo dialysis

An acute intraperitoneal injection of phencyclidine (PCP) caused a tetrodotoxin-reversible increase in extracellular release of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dialysates from the medial frontal cortex of the rat. Moreover, there was an increase in the tissue content of DOPAC and HVA with acceleration of dopamine (DA), but not noradrenaline, utilization in the cortical area after systemic administration of PCP. These results suggest that PCP facilitates DA metabolism in the medial frontal cortex by increasing impulse flow in the DA neurons projecting to the prefrontal region.     

Morphine-stimulated metabolism of striatal and limbic dopamine is dissimilarly sensitized in rats upon withdrawal from chronic morphine treatment

The effects of acute morphine on the release of dopamine (DA) in the striatum and limbic forebrain of rats upon 48 h withdrawal from 20-day morphine treatment were studied using 3-methoxytyramine (3-MT) in tissue as an index of DA release. Homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were also measured. The chronic morphine treatment did not alter the concentrations of DA metabolites. Acute morphine (10 mg/kg) elevated all three DA metabolites in both brain areas. Morphine withdrawal potentiated the elevation of striatal and limbic 3-MT as well as that of striatal but not limbic HVA. These findings show that both striatal and limbic DA mechanisms are sensitized to morphine upon withdrawal but that sensitization of DA metabolism in these two brain areas occurs differently.     

Dopamine release in the nucleus accumbens of freely moving rats determined by on-line dialysis: effects of apomorphine and the neuroleptic-like peptide desenkephalin-gamma-endorphin

This study examined the effects of apomorphine, sulpiride, desenkephalin-gamma-endorphin (DE gamma E) and a combination of DE gamma E with apomorphine on the release of dopamine (DA) and its main metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens of freely moving rats. A fully automated on-line brain dialysis system was used. A small dose of s.c. administered apomorphine induced a decrease in the output of DA and DOPAC. Sulpiride, infused into the nucleus accumbens, induced a 2-fold increase in the output of DA, DOPAC and HVA. DE gamma E hardly modified either the basal release of DA, DOPAC and HVA or the apomorphine-induced attenuation of the release of DA and DOPAC. These results indicate a dissociation between the behavioural effects of DE gamma E and its effect on the release of DA in vivo.     

龟板对帕金森病大鼠行为和脑内多巴胺水平的影响

目的　探讨益肾中药龟板对帕金森病大鼠的治疗作用。方法　 6 羟基多巴胺脑内定位注射制备帕金森病模型 ,随机将 4 0只SD大鼠分为实验组和对照组 ,观察动物单侧旋转行为以及多巴胺及其代谢产物 3、4 二羟苯乙酸和高草酸含量的变化。结果　造模 8周后实验组帕金森病大鼠旋转圈数 6 97± 1 6 7比对照组 9 4 5± 1 75明显减少 (P <0 0 5 ) ;其纹状体内多巴胺 (DA)及其代谢产物 3、4二羟苯乙酸 (DOPAC)、高香草酸 (HVA)含量显著提高 ,分别为 3 12± 0 4 8,0 2 7± 0 0 6和 0 35±0 0 6 ,而对照组仅为 0 4 9± 0 0 4 ,0 0 7± 0 0 3和 0 2 7± 0 0 3(P <0 0 5 )。结论　益肾中药龟板对大鼠帕金森病具有潜在的临床应用价值。     

Age-related changes in dopaminergic and serotonergic indices in the rat forebrain

Age-related changes in the content of dopamine (DA), homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in anterior cerebral cortex, hippocampus and striatum of the rat have been investigated using HPLC with electrochemical detection. A significant decrease in HVA was observed in the striatum and hippocampus of the aged (27 months) animals, as compared to the controls (2.4 to 2.6 months). A significant decrease in DA levels was also observed in the hippocampus but not in the striatum. In contrast, the level of DA in the cerebral cortex was markedly increased in the aged animals. A concomitant increase in 3-MT level was observed. Finally the level of 5-HIAA was significantly increased in striatum and hippocampus.     

Kir6.2 knockout alters neurotransmitter release in mouse striatum: an in vivo microdialysis study

ATP-sensitive potassium (K-ATP) channels have been demonstrated to play important roles in the brain. In the present study, Kir6.2 knockout (Kir6.2-/-) mice were used to examine the contribution of Kir6.2-containing K-ATP channels to the regulation of neurotransmitter release via in vivo microdialysis studies. The results showed that the extracellular levels of monoamine and amino acid neurotransmitters in Kir6.2-/- mouse striatum were similar to those in Kir6.2+/+ mice under basal conditions. After high K+ (100mM) perfusion, the extracellular levels of DA and amino acids were increased in both genotypes. These increases, however, were significantly lower in Kir6.2-/- mice than those in Kir6.2+/+ mice. Extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC), a major metabolite of DA, were increased in Kir6.2-/- mice but decreased in Kir6.2+/+ mice in response to high K+ stimulus. The releases of 4-hydroxy-3-methoxy-phenylacetic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were attenuated to a similar extent in both mouse genotypes. Taken together, this study provides direct in vivo evidence that Kir6.2-containing K-ATP channels play regulatory roles in neurotransmitter release in the striatum.     

The non-competitive NMDA-receptor antagonist MK-801 prevents the massive release of glutamate and aspartate from rat striatum induced by 1-methyl-4-phenylpyridinium (MPP+)

The concentrations of dopamine (DA) and of the excitatory amino acids (EAAs) glutamate (Glu) and aspartate (Asp) were measured in dialysates from the striatum of awake rats in order to study the link between the release of DA and of EAAs induced by the infusion of 1-methyl-4-phenylpyridinium ion (MPP+). DA and EAAs were detected simultaneously by HPLC-EC. The infusion of MPP+ at the concentration of 1 mM elevated DA levels in the perfusates, but did not affect EAA release. However, MPP+ at 10 mM maximally stimulated Glu and Asp release to 230- and 68-fold of baseline, respectively. In this condition, pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (5 mg/kg, i.p.) prevented the MPP(+)-induced EAA release. In contrast, MK-801 had no effect on DA release induced either by 1 or 10 mM MPP+. These results suggest that MPP(+)-induced DA and EAA release are independently regulated processes. In addition, the finding that MK-801 inhibits MPP(+)-induced EAA release suggests that EAAs may act on NMDA receptors to stimulate their own release through a positive-feedback mechanism.     

The effect of acute and repeated ethanol administration on monoamines and their metabolites in brain regions of rats

Concentrations of norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in eleven brain regions of rats following acute and repeated ethanol administration: (a) an intraperitoneal (i.p.) injection of 1, 2, 3 or 4g ethanol/kg body weight and (b) i.p. injection of 1 or 2g ethanol/kg body weight for seven consecutive days. After acute administration, the concentrations of monoamines and their metabolites appeared to be altered in all brain regions examined except substantia nigra and dorsal amygdala, with maximal variation 2 or 3h after 3g ethanol administration. After repeated administration, the alterations following injections of 2.0g/kg were more marked than the injections of 1.0g/kg. Generally, the levels of NE, DA and 5-HT were decreased while the levels of HVA, DOPAC and 5-HIAA were increased with a few exception. The most prominent findings were seen in the striatum, nucleus accumbens and locus coeruleus. These data indicate that concentrations of monoamines and their metabolites can be determined simultaneously in discrete brain regions and that monoaminergic systems in the brain respond region-specifically to ethanol treatment.     

Effects of chronic intraputamenal infusion of glial cell line-derived neurotrophic factor (GDNF) in aged Rhesus monkeys

In this study, 17-23 year old Rhesus monkeys were used as an early model of Parkinson's disease (PD). Four animals received chronic infusions of GDNF and four received vehicle infusions into the right putamen via programmable pumps for 8 weeks. Weekly videotaping was performed to record general motor performance and a monkey movement analysis panel (mMAP) was used to quantify fine and coarse upper limb motor performance. The GDNF-treated animals showed significant improvements in their overall motor performance in the last 3 weeks of the study compared to controls. Fine motor time of the upper limbs improved significantly in both the GDNF-treated and control animals. After 8 weeks of drug administration, the animals were euthanized and tissue punches were taken from the basal ganglia for measures of dopamine (DA) and DA metabolite levels. In the right putamen, GDNF infusion produced a 217% increase in homovanillic acid (HVA) levels. In addition, DA levels increased by 50% in the right caudate nucleus and there were 122 and 76% increases in 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the right and left caudate nucleus, respectively. HVA levels were also seen to be increased by 212% in the right caudate nucleus. Finally, changes were seen in the right globus pallidus, with 390 and 171% increases in DA and HVA levels, respectively. These data support the hypothesis that GDNF may be beneficial for the treatment of damaged or degenerating DA neurons in aged monkeys and possibly in aged humans.     

The long-term effects of neurotoxic doses of methamphetamine on the extracellular concentration of dopamine measured with microdialysis in striatum.

The extracellular concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the striatum were measured by in vivo microdialysis in freely moving rats one week after the animals were treated with neurotoxic doses of methamphetamine. Methamphetamine produced a marked depletion of striatal DA measured in postmortem tissue, and in the extracellular concentrations of DOPAC, HVA and 5-HIAA. In contrast, the resting extracellular concentration of DA in striatum was the same as in saline-pretreated controls. Furthermore, methamphetamine-pretreated rats were able to increase their concentration of extracellular DA to the same extent as controls in response to a (+)-amphetamine challenge. It is suggested that this adaptive response is probably responsible, at least in part, for the absence of obvious behavioral deficits in animals exposed to neurotoxic doses of methamphetamine.     

Phenylalanine administration influences dopamine release in the rat's corpus striatum

We used intracerebral dialysis to monitor extracellular levels of dopamine and its major metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum. Levels of these compounds were determined after intraperitoneal administration of phenylalanine (200, 500 and 1000 mg/kg). A dose of 200 mg/kg phenylalanine increased basal dopamine release by 59%, peaking at 75 min. There was no change in basal dopamine release after the 500 mg dose, whereas the 1000 mg/kg dose significantly reduced (26%) dopamine release. No significant changes were observed in the concentrations of DOPAC and HVA with any of the treatments, indicating that changes in brain phenylalanine and tyrosine levels may selectively affect production of the dopamine molecules that are preferentially released into synapses.     

Alcohol-preferring rats: genetic sensitivity to alcohol-induced stimulation of dopamine metabolism

The effect of ethanol on brain dopamine (DA) metabolism in the caudate nucleus (CN), olfactory tubercle (OT) and medial prefrontal cortex (MPFC) was compared in two selectively bred rat lines, one ethanol preferring and the other ethanol nonpreferring. Male rats from the 16th and 17th generations of both lines that never experienced ethanol beforehand were used. No differences in the basal concentrations of DA and its metabolites, DOPAC and HVA, in the above brain regions were found between the two lines. The oral administration of 2 g/kg of ethanol to ethanolnonpreferring rats increased DOPAC and HVA and reduced DA levels in the CN and OT but was ineffective in the MPFC. On the other hand, ethanol administration to ethanol-preferring rats decreased DA content and increased DOPAC and HVA levels, not only in the CN and OT, but also in the MPFC. Moreover, the changes induced by ethanol on DA metabolism in the latter group were significantly greater than in ethanol nonpreferring rats. These results indicate that ethanol preferring rats have a genetic high sensitivity to the ethanol effect on DA metabolism, and suggest that such a trait might play a role in ethanol preference.     

Agonist action of the agonist/antagonist analgesic butorphanol on dopamine metabolism in the nucleus accumbens of the rat

The action of butorphanol, an opiate agonist/antagonist, was studied on dopamine (DA) metabolism in several mesocortical and mesolimbic areas and compared with its effects on the nigrostriatal DA pathway. While butorphanol had a bell-shaped dose-response relationship for elevation of DA metabolites in the striatum, it had no action on DA metabolites in the entorhinal, prefrontal, pyriform and cingulate cortices and in the olfactory tubercle. In all of these areas morphine stimulated dopamine metabolism (except for the entorhinal cortex). In contrast, in the nucleus accumbens, butorphanol increased the levels of dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) with no increase in DA steady state levels. This effect was reversible by both opiate antagonists, naloxone and WIN 44441-3 and appears to be mu-opioid receptor-mediated.     

In vivo basal and amphetamine-induced striatal dopamine and metabolite levels are similar in the spontaneously hypertensive, Wistar-Kyoto and Sprague-Dawley male rats

Nigrostriatal alterations are proposed to partially underlie the hypertension and hyperactivity exhibited by the spontaneously hypertensive rat (SHR). Here, in vivo microdialysis was used to measure baseline and d-amphetamine (AMPH)-stimulated striatal dopamine (DA) and metabolite levels in adult male SHR, Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats. At approximately 19 weeks of age, baseline levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were measured after which time, each rat was injected intraperitoneally with 2 mg/kg AMPH and samples were collected for the subsequent 200 min. There were no significant strain differences in baseline levels of DA, HVA, and 5-HIAA. The baseline level of DOPAC was decreased in the WKY relative to the SD. AMPH treatment altered DA, DOPAC, HVA, and 5-HIAA to a similar extent in all strains; thus, there were no significant strain differences, nor did the area under the curve (AUC) for DA levels differ between strains. AUC for DOPAC was significantly smaller for the WKY relative to the SD strain, likely due to the lower baseline level. At the single dose of amphetamine used here, the results indicate that in vivo DA levels in the SHR are similar to the WKY and SD strains.     

Differential effects of acute and chronic nicotine treatment on MPTP-(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced degeneration of nigrostriatal dopamine neurons in the black mouse

Summary Evidence exists for a negative correlation between Parkinson's disease and smoking. The present and previous studies indicate that nicotine treatment can markedly alter the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in the black mouse based on biochemical determinations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in neostriatum and substantia nigra 2 weeks after MPTP injection. Acute intermittent treatment with (–)nicotine starting 10 min before the MPTP injection partly protected against MPTP-induced neurotoxicity in the neostriatum and substantia nigra. Also, a partial protection was observed in the substantia nigra when (–)nicotine was given together with MPTP in an acute intermittent treatment schedule. Conversely, chronic infusion of (–)nicotine via minipumps produced a dose-related enhancement of MPTP-induced DA neurotoxicity in the neostriatum. It is suggested that the protective activity of nicotine in the MPTP model is related to a blockade of MPP + uptake into the DA cells via increased DA release. Conversely, the nicotine enhancement of MPTP-induced DA toxicity is suggested to be caused by a failure of the nicotinic cholinoceptors to desensitize to the chronic (–)nicotine exposure, leading to increased chronic influx of Na⁺ and Ca²⁺ ions via the ion channels of the nicotinic cholinoceptors located on the DA neurons with associated increased Ca ion toxicity and increased energy demands.Abbreviations DA dopamine - DOPAC 3,4-dihydroxyphenylacetic acid - HPLC high performance liquid chromatography - HVA homovanillic acid - MPP⁺a 1-methyl-4-phenyl-pyridinium ion - MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine     

Sexual behavior increases dopamine transmission in the nucleus accumbens and striatum of male rats: comparison with novelty and locomotion.

Extracellular concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were examined concurrently, using in vivo microdialysis, in the nucleus accumbens and dorsal striatum of sexually active male rats during tests of locomotor activity, exposure to a novel chamber, exposure to sex odors, the presentation of a sexually receptive female, and copulation. DA increased significantly in the nucleus accumbens when the males were presented with a sexually receptive female behind a screen and increased further during copulation. Although DA also increased significantly in the dorsal striatum during copulation, the magnitude of the effect was significantly lower than that observed in the nucleus accumbens. In contrast, forced locomotion on a rotating drum, exposure to a novel chamber, and exposure to sex odors did not increase DA significantly in either region, although both DOPAC and HVA increased significantly in both regions during the locomotion test. These results indicate that novelty or locomotor activity alone cannot account for the increased extracellular DA concentrations observed in the nucleus accumbens of male rats during the presentation of a sexually receptive female behind a screen, nor can they account for the increased DA concentrations observed in both the nucleus accumbens and dorsal striatum of male rats during copulation. The preferential increase in DA transmission in the nucleus accumbens, compared with that in the striatum, suggests that anticipatory and consummatory aspects of sexual activity may belong to a class of naturally occurring events with reward values that are mediated by DA release in the nucleus accumbens.     

Regulatory aspects of nigrostriatal dopaminergic neurons

Summary In the urethane-anesthetized rat, electrical stimulation (10 Hz, 30 s, 250 A) of the medial forebrain bundle (MFB), at 20-min intervals over an 8-h period, combined with intracerebral microdialysis in the striatum caused: an undiminished increase in the release of dopamine (DA) with each stimulation episode; a decreased efflux of 3,4-dihydroxyphenylacetic acid (DO-PAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA) after the first stimulation only; a delayed increased efflux of DOPAC with no change in HVA; and a poststimulation depression of firing of dopaminergic neurons in the substantia nigra (before, 3.1±0.7 Hz; after, 1.9±1.0 Hz; P<0.05). After the last stimulation episode, the release of DA declined to prestimulation values, while the increased efflux of DOPAC persisted for three more hours. After the infusion of tetrodotoxin (4.0×10^-7 M, 1.5 l, 1.0 l/min) into the MFB, the basal release of DA was reduced (P<0.05), while the efflux of DOPAC and HVA was increased (P<0.05). A model is proposed suggesting that: (1) during increased release of DA in the striatum, the metabolism of DA is decreased; (2) inhibition of nigrostriatal dopaminergic neurons is the usual cause of increased synthesis and metabolism of DA in the striatum; and (3) increased release of DA, and increased synthesis and metabolism of DA in the striatum are not causally linked and are noncoupled processes.