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1.
The aim of the study was to test whether the synthesis of substance P (SP) and that of its receptor (also known as NK1 receptor) are coordinately regulated after chronic pharmacologic intervention in two neural systems, the spinal cord and basal ganglia. In one set of experiments, capsaicin was administered subcutaneously during the early postnatal period (day 3 after birth) to induce degeneration of afferent sensory neurons in the spinal cord. In the other set of experiments, interruption of dopaminergic transmission was achieved by two methods: (a) The neurotoxin 6-hydroxydopamine was used to denervate dopaminergic neurons during the early postnatal period, and (b) haloperidol was used in adult animals to block dopaminergic transmission by receptor blockade. The spinal cord, striatum, or both were used for the quantification of tachykinin [SP and neurokinin A (NKA)] and opioid peptides [[Met5]-enkephalin (ME) and dynorphin A (1-8) (DYN)] by radioimmunoassays. The abundance of total SP-encoding preprotachykinin (PPT) mRNA and SP receptor (SPR) mRNA in spinal cord (C5 to T1 segments), striatum, or microdissected substantia nigra was determined by northern blot or solution hybridization analysis. Amines and their acid metabolites were quantified by HPLC. Capsaicin administration (subcutaneously) during the early postnatal period increased latency in a hot-plate test, decreased SP and NKA levels, increased levels of PPT mRNAs, and did not affect SPR mRNA levels in the spinal cord. Intraspinal SP systems may attempt to compensate for the loss of afferent SP input, whereas spinal cord receptor mRNA levels do not appear to be altered.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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3.
Destruction of nigrostriatal dopamine (DA) neurons with 6-hydroxydopamine (6-OHDA) early in development results in hyperinnervation of striatum by the serotonergic afferents deriving from the dorsal raphe nucleus. We have used in vivo microdialysis to investigate the degree to which serotonergic neurotransmission in striatum is altered by this increase in the density of serotonin (5-HT) terminals. The effects of several manipulations known to influence 5-HT function on extracellular 5-HT and 5-hydroxyindoleacetic acid in striatum were compared in adult rats treated neonatally with 6-OHDA and in intact adult rats. Basal levels of 5-HT in extracellular fluid (ECF) of striatum were similar in neonatally DA-depleted rats and in intact rats. Perfusion with the 5-HT reuptake blocker, fluoxetine (100 microM), increased 5-HT in striatal ECF of neonatally DA-depleted rats to levels that were threefold greater than those achieved in intact rats. Likewise, K(+)-depolarization of the 5-HT terminals (100 mM in perfusate) or systemic administration of the 5-HT releaser, (+/-)-fenfluramine (10 mg/kg i.p.), increased the concentration of 5-HT in striatal ECF of neonatally DA-depleted rats to levels approximately threefold greater than those observed in striatum of intact rats. These findings indicate that the 5-HT hyperinnervation of striatum that takes place in rats depleted of DA at infancy is associated with an increased capacity for neurotransmitter release in this system. Concomitant increased in high-affinity 5-HT uptake may prevent the occurrence of any measurable changes in the resting concentration of 5-HT in striatal ECF. 相似文献
4.
用6-OHDA损毁大鼠一侧黑质—纹状体通路可引起PD模型鼠脑纹状体内多巴胺匿乏.同时,亦可导致脑啡肽mRNA过度表达。我们用地高辛标记的cRNA探针对纹状体内脑啡肽mRNA含量进行了斑点杂交定量研究,发现损伤侧脑啡肽mRNA含量较健侧增高80%,胎中脑移植到失神经支配的纹状体内,脑啡肽mRNA过度表达得以矫正至正常水平,说明胎多巴胺能神经元脑内移植能够调节脑啡肽基因表达,提供了移植物能与宿主发生神经整合、建立突触联系的间接证据。 相似文献
5.
Effects of Adrenal Steroids on Basal Ganglia Neuropeptide mRNA and Tyrosine Hydroxylase Radioimmunoreactive Levels in the Adrenalectomized Rat 总被引:4,自引:0,他引:4
Louis R. Lucas Pierluigi Pompei Jennie Ono Bruce S. McEwen 《Journal of neurochemistry》1998,71(2):833-843
Abstract: To investigate the effects of type I (mineralocorticoid) and type II (glucocorticoid) receptor activation on striatal neuropeptide [preproenkephalin (PPE), preprotachykinin (PPT), and preprodynorphin (DYN)] mRNA and midbrain cholecystokinin (CCK) mRNA as well as striatal tyrosine hydroxylase radioimmunoreactivity (TH-RIC) levels, we administered either replacement levels of corticosterone (CORT; 0.5 mg/kg/day, s.c.) or pharmacological levels of deoxycorticosterone acetate (DOCA; a mineralocorticoid steroid with ability to bind to type I and type II receptors; 5 mg/kg, s.c.) to adrenalectomized adult male rats. After 1 week of recovery from adrenalectomy surgery, animals were injected daily with sesame oil or CORT for 1, 3, or 7 days or DOCA for 3 or 7 days and killed 16 h after the last injection. Adrenalectomy resulted in a decrease in all three striatal neuropeptide mRNA levels, compared with sham-operated rats. CORT replacement resulted in recovered PPE and PPT mRNA levels after 1 day and elevated PPE mRNA levels over those in sham-operated controls after 3 days. In contrast, DYN mRNA levels showed recovery after 7 days of CORT replacement. Results after DOCA treatment largely paralleled those after CORT replacement. There were no significant treatment effects on indirect markers of midbrain dopaminergic activity, i.e., CCK mRNA and TH-RIC. From these results we conclude that compared with striatal tachykinin and dynorphinergic neurons, enkephalinergic cells show greater sensitivity, whereas the dopaminergic system, including mesencephalic CCK, demonstrates an insensitivity to physiological CORT and to pharmacological DOCA treatment. 相似文献
6.
Aguiar LM Macedo DS de Freitas RM de Albuquerque Oliveira A Vasconcelos SM de Sousa FC de Barros Viana GS 《Life sciences》2005,76(19):2193-2202
The present work studied in vivo neuroprotective effects of n-acetylserotonin (NAS), the immediate precursor of melatonin, on the dopaminergic system, in rats lesioned with the unilateral intrastriatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA). Two weeks after the lesion, the dopamine receptor agonist, apomorphine, produced rotational asymmetry, and the NAS treatment significantly reduced the motor deficit following the apomorphine challenge. The apomorphine-induced rotational behavior was blocked by 84, 86 and 53% after NAS, at doses of 2, 5 and 10 mg/kg, i.p., respectively. The injection of 6-OHDA significantly decreased DA, DOPAC and HVA levels in the rat striatum. In contrast, the NAS (2, 5 and 10 mg/kg, i.p., daily for 7 days) treatment partially reversed the decreases caused by 6-OHDA, and the neurotransmitter levels were brought to approximately 50% of that observed in the contralateral sides. NAS was more efficient at the smaller doses. NAS (5 mg/kg) produced an up-regulation of D1 (37%) and D2 (37%) receptors associated with a decrease in Kd values. 相似文献
7.
Ferraz AC Matheussi F Szawka RE Rizelio V Delattre AM Rigon P Hermel Edo E Xavier LL Achaval M Anselmo-Franci JA 《Neurochemical research》2008,33(7):1238-1246
Studies involving estrogen treatment of ovariectomized rats or mice have attributed to this hormone a neuroprotective effect on the substantia nigra pars compacta (SNpc) neurons. We investigated the effect of estradiol replacement in ovariectomized rats on the survival of dopaminergic mesencephalic cell and the integrity of their projections to the striatum after microinjections of 1 microg of 6-hydroxydopamine (6-OHDA) into the right SNpc or medial forebrain bundle (MFB). Estradiol replacement did not prevent the reduction either in the striatal concentrations of DA and metabolites or in the number of nigrostriatal dopaminergic neurons following lesion with 1 microg of 6-OHDA into the SNpc. Nevertheless, estradiol treatment reduced the decrease in striatal DA following injection of 1 microg of 6-OHDA into the MFB. Results suggest therefore that estrogen protect nigrostriatal dopaminergic neurons against a 6-OHDA injury to the MFB but not the SNpc. This may be due to the distinct degree of lesions promoted in these different rat models of Parkinson's disease. 相似文献
8.
C. Anthony Altar Carolyn B. Boylan Michelle Fritsche Bruce E. Jones Carl Jackson Stanley J. Wiegand Ronald M. Lindsay Carolyn Hyman 《Journal of neurochemistry》1994,63(3):1021-1032
Abstract: Brain-derived neurotrophic factor (BDNF) promotes the survival of dopamine (DA) neurons, enhances expression of DA neuron characteristics, and protects these cells from 6-hydroxydopamine (6-OHDA) toxicity in vitro. We tested the ability of BDNF or neurotrophin-3 (NT-3) to exert similar protective effects in vivo during chronic delivery of 6-OHDA to the rat neostriatum. Chronic infusions of BDNF or NT-3 (12 µg/day) above the substantia nigra were started 6 days before and continued during an 8-day chronic intrastriatal infusion of 6-OHDA. In control and neurotrophin-treated animals, 6-OHDA treatment selectively depleted 50–60% of nigrostriatal DA nerve terminals but produced little if any loss of pars compacta DA cell bodies. This partial DA lesion resulted in three rotations per minute toward the lesioned hemisphere after treatment with the DA release-inducing drug d-amphetamine. Compared with supranigral infusions of vehicle, BDNF and NT-3 decreased the number of these ipsiversive rotations by 70 and 48% and increased by 20- and 10-fold, respectively, the number of contraversive rotations observed after amphetamine injection. When challenged with the DA receptor agonist apomorphine, BDNF- and NT-3-treated animals also exhibited a seven- and 3.5-fold increase in the number of contraversive rotations relative to the vehicle group, respectively. Compared with vehicle, BDNF increased striatal levels of homovanillic acid (HVA; 86%), 3,4-dihydroxyphenylacetic acid (DOPAC; 42%), and 5-hydroxyindoleacetic acid (5-HIAA; 32%) and the HVA/DA (43%) and 5-HIAA/serotonin (34%) ratios in the DA-denervated striatum. NT-3 augmented only striatal 5-HIAA levels (24%). Neither factor altered the 6-OHDA-induced decrease in striatal DA levels or high-affinity DA uptake and thus did not protect against the destruction of DA terminals and did not alter striatal D1 or D2 ligand binding. Choline, GABA, and glutamate uptake in the striatum were not altered by the lesion or neurotrophin treatment. Thus, BDNF and to a lesser extent NT-3 reverse rotational behavioral deficits and augment striatal DA and 5-HT metabolism in a partial DA lesion model. 相似文献
9.
In this paper we review the detailed mechanisms underlying the modulation of enkephalinergic neurons by dopaminergic neurons in rat striatum. Several lines of evidence, which showed that striatal levels of [Met5]enkephalin (ME) increase after the nigrostriatal dopaminergic pathway was interrupted by hemitransection or direct administration of 6-hydroxydopamine to the substantia nigra, or after repeated injections of either reserpine or haloperidol, suggest that dopamine (DA) plays an important role in regulating the metabolism of ME-containing neurons in the striatum. The increase in ME content after repeated injections of haloperidol was found in areas heavily innervated by DA neurons such as striatum or nucleus accumbens but not in hypothalamus, brain stem, and hippocampus. Further studies suggest that striatal cholinergic interneurons may partially mediate the action of haloperidol on enkephalinergic neurons. Several studies have been carried out to determine whether the elevation of striatal ME content after haloperidol treatment was caused by an increase in the synthesis or by a decrease in the utilization of ME. The rate of decline of striatal ME content in haloperidol-treated rats was steeper than that of controls after intraventricular injection of cycloheximide, which indicated that haloperidol accelerates the turnover of ME. This hypothesis was confirmed by our recent findings that the level of mRNA coding for preproenkephalin A, determined by cell-free translation and blot hybridization with cDNA clones, is increased after repeated injections of haloperidol. 相似文献
10.
Marc Morissette Richard Grondin Martin Goulet Paul J. Bédard Thérèse Di Paolo 《Journal of neurochemistry》1999,72(2):682-692
Abstract : Studies in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys and in parkinsonian patients show elevated preproenkephalin (PPE) mRNA levels, unaltered by chronic l -DOPA therapy, whereas preprotachykinin (PPT) mRNA levels are decreased by the lesion and corrected by l -DOPA. The relative contributions of the dopamine D1 and D2 receptors for PPE mRNA regulation were investigated in the present study and compared with those for PPT mRNA. In situ hybridization was used to measure peptide mRNA levels in the striatum of MPTP cynomolgus monkeys after chronic 1-month treatment with the D1 agonist SKF-82958, administered subcutaneously in pulsatile or continuous mode, compared with the long-acting D2 agonist cabergoline. Normal as well as untreated MPTP animals were also studied. PPE mRNA levels were elevated in the caudate nucleus and putamen of untreated MPTP monkeys compared with control animals with a more pronounced increase in the lateral as compared with the medial part of both structures. PPT mRNA levels showed a rostrocaudal gradient, with higher values in the middle of the caudate-putamen and more so in the medial versus the lateral parts. PPT mRNA levels were decreased in the caudate and putamen of untreated MPTP monkeys compared with control animals, and this was observed in the middle and posterior parts of these brain areas. Elevated PPE and decreased PPT mRNA levels observed after MPTP exposure were corrected after treatment with cabergoline (0.25 mg/kg, every other day), a dose that had antiparkinsonian effects and did not give sustained dyskinesia. In contrast, elevated PPE mRNA levels observed in untreated MPTP monkeys were markedly increased by pulsatile administration of SKF-82958 (1 mg/kg, three times daily) in two monkeys in which the parkinsonian symptoms were improved and dyskinesias developed, whereas it remained close to control values in a third one that did not display dyskinesias despite a sustained improvement in disability ; a shorter duration of motor benefit (wearing off) over time was observed in these three animals. By contrast, pulsatile administration of SKF-82958 corrected the decreased PPT level observed in untreated MPTP monkeys. Continuous treatment with SKF-82958 (equivalent daily dose) produced no clear antiparkinsonian and dyskinetic responses and did not alter the denervation-induced elevation of PPE or decrease of PPT mRNA levels. The present data suggest an opposite contribution of the dopamine D1 receptors (stimulatory) as compared with the dopamine D2 receptors (inhibitory) on PPE mRNA, whereas a similar stimulatory contribution of D1 or D2 receptors is observed for PPT mRNA. An increase in PPE expression could be involved in the induction of dyskinesias and wearing off, whereas our data do not support this link for PPT. The antiparkinsonian response was associated with a correction of the lesion-induced decrease of PPT. 相似文献
11.
P Nowak R M Kostrzewa A Kwieciński A Bortel ? Labus R Brus 《Journal of physiology and pharmacology》2005,56(2):325-333
To determine whether behavioral sensitization produced by prolonged D-amphetamine administration affects susceptibility of nigrostriatal dopaminergic neurons to the neurotoxic actions of 6-hydroxydopamine (6-OHDA), rats were treated daily from the 23 rd day after birth for 11 consecutive days with D-amphetamine (1.0 mg/kg s.c.) or saline. On the last day of treatment, one group primed with D-amphetamine and one control group of rats were tested to confirm behavioral sensitization development. The remaining animals were additionally treated on the 34 th day (one day after the last D-amphetamine injection) with 6-OHDA HBr (300 microg in 10 microl i.c.v., salt form, half in each lateral ventricle) or its vehicle. Four weeks later the levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-metoxytyramine (3-MT), as well as 5-hydroxytrypatmine (5-HT) and its metabolite 5-hydroxyindoleacteic acid (5-HIAA) were assayed in the striatum, by HPLC/ED. In rats with behavioral sensitization, 6-OHDA reduced endogenous dopamine and its metabolites content to a comparable degree in comparison to controls. This finding indicates that presumed up-regulation of the dopamine transporter in the behaviorially sensitized rats did not increase the neurotoxicity of a high dose of 6-OHDA. 相似文献
12.
Calcitriol has been implicated as an agent that has neuroprotective effects in various animal models of diseases, possibly by upregulating glial cell line-derived neurotrophic factor (GDNF). The present study examined the neuroprotective effects of calcitriol in a model of early Parkinson’s disease. Rats were treated daily with calcitriol or saline for 7 days before an intraventricular injection of 6-hydroxydopamine (6-OHDA), and then for 1 day or daily for 3½ to 4 weeks after lesioning. Evoked overflow and tissue content of dopamine (DA) were determined 3½ to 4 weeks post lesion. The 8-day calcitriol treatment did not attenuate 6-OHDA-induced decreases in evoked overflow of DA, nor did it protect against 6-OHDA-induced reductions in tissue levels of DA in the striatum or substantia nigra. However, the long-term calcitriol treatment did significantly increase evoked overflow of DA, as well as the amount of DA in the striatum, compared to saline treated animals. GDNF was significantly increased in the substantia nigra, but not in the striatum, of non-lesioned, calcitriol treated rats. These results suggest that long-term treatment with calcitriol can provide partial protection for dopaminergic neurons against the effects of intraventricularly administered 6-OHDA. 相似文献
13.
Neuroinflammation and blood brain barrier (BBB) dysfunction have been implicated in the pathogenesis of Parkinson's disease (PD). The neuropeptide substance P (SP) is an important mediator of both neuroinflammation and BBB dysfunction through its NK1 receptor in a process known as neurogenic inflammation. Increased SP content has previously been reported following 6-OHDA treatment in vitro, with the levels of SP correlating with cell death. The present study used an in vivo 6-OHDA lesion model to determine if dopaminergic degeneration was associated with increased SP in the substantia nigra and whether this degeneration could be prevented by using a SP, NK1 receptor antagonist. Unilateral, intrastriatal 6-OHDA lesions were induced and SP (10 μg/2 μL) or the NK1 receptor antagonists, N-acetyl-L-tryptophan (2 μL at 50 nM) or L-333,060 (2 μL at 100 nM), administered immediately after the neurotoxin. Nigral SP content was then determined using immunohistochemical and ELISA methods, neuroinflammation and barrier integrity was assessed using Iba-1, ED-1, GFAP and albumin immunohistochemistry, while dopaminergic cell loss was assessed with tyrosine hydroxylase immunohistochemistry. Motor function in all animals was assessed using the rotarod task. Intrastriatal 6-OHDA lesioning produced an early and sustained increase in ipsilateral nigral SP content, along with a breakdown of the BBB and activation of microglia and astrocytes. Further exacerbation of SP levels accelerated disease progression, whereas NK1 receptor antagonist treatment protected dopaminergic neurons, preserved barrier integrity, reduced neuroinflammation and significantly improved motor function. We propose that neurogenic inflammation contributes to dopaminergic degeneration in early experimental PD and demonstrate that an NK1 receptor antagonist may represent a novel neuroprotective therapy. 相似文献
14.
There are previous evidences of biochemical and functional interhemispheric asymmetry for central dopaminergic systems. The purpose of the current study was to establish an evidence of the existence of mechanisms for interhemispheric regulation of dopaminergic systems. The initial hypothesis was that to compensate the spontaneous interhemispheric asymmetry, the brain side with lower dopamine (DA) concentration show a higher DA turnover. The ratio of metabolite/neurotransmitter was computed as an index of presynaptic turnover rate. Both striatum and hippocampus showed a DOPAC/DA index higher in the brain side with a lower DA concentration. In addition, we found an inverse relation between the interhemispheric index of DA and interhemispheric index of DA turnover. Taken together the present data provide evidence of an interhemispheric regulation for the DA-innervation of both striatum and hippocampus in normal unlesioned rats. 相似文献
15.
Neurotransmitter, opiodergic system, steroid-hormone interaction and involvement in the replacement therapy of sexual disorders 总被引:1,自引:0,他引:1
G Frajese R Lazzari A Magnani C Moretti V Sforza D Nerozzi 《The Journal of steroid biochemistry and molecular biology》1990,37(3):411-419
Dopamine (DA) and serotonin (5-HT) are the neurotransmitters most directly involved in sexual activity. DA plays a stimulatory role while 5-HT has an inhibitory effect. The two monoaminergic systems modulate the secretion of many hormones (GnRH, LH, testosterone, prolactin and endorphins) involved in sexual functional capacity. Furthermore, hormones influence synthesis and storage of brain neurotransmitters. Impotence can often be associated to clinical depression and altered neurotransmitter function. Moreover, stress represents an unbalance between various neurotransmitter systems and can induce impotence especially when disorders of the endorphinic system are present. Replacement therapy is based upon the understanding of these basic concepts. Impotence due to an underlying depressive illness must be treated with dopaminergic antidepressant drugs; while in stressful conditions a good response to the naloxone test is the preliminary criterion to subsequent naltrexone treatment. When a hormonal deficiency has been proved, the hormone replacement therapy is of course highly effective (gonadotropins in hypogonadotropic syndromes, testosterone in aging, etc.). Finally, idiopathic impotence could be treated by DA agonist and/or 5-HT antagonist drugs either alone or better yet in association with psychotherapy. 相似文献
16.
Parkinson disease (PD) is characterized by the progressive degeneration of substantia nigra dopaminergic neurons projecting to the striatum. Since the deficit in striatal dopamine is the main cause of PD symptoms, it appears critical to preserve axon terminals. Significant axon protection from peripheral nerve Wallerian degeneration is observed in Wlds mice, a phenotype conferred by a spontaneous dominant mutation. To assess any Wlds-mediated rescue of dopamine fibers in a PD model, the nigrostriatal pathway of Wlds mice was lesioned with 6-hydroxydopamine (6-OHDA), a catecholaminergic neurotoxin. Following 6-OHDA injection in the medial forebrain bundle, Wlds mice showed remarkable dopamine fiber protection in the striatum. Drug-induced rotational behavior confirmed the nigrostriatal fiber ability to release dopamine, although revealing an abnormal neurotransmitter control presumably due to disrupted axonal transport. Following 6-OHDA injection in the midstriatum, only a protection trend was observed. Strikingly, no protection of Wlds nigral dopaminergic cell bodies was obtained following either nigrostriatal lesion. Besides showing subtle differences in the degeneration process between subcellular compartments, the reported Wlds-mediated protection of the dopamine axon terminals in an animal model of PD may lead to the understanding of mechanisms underlying axon loss and to the development of new therapeutic approaches. 相似文献
17.
The mechanism of action of drugs of abuse like cocaine and amphetamines has been studied extensively in the dopamine terminal field areas of the caudate-putamen (CPu) and the nucleus accumbens (NAc) of the rodent brain. These brain regions contain several neuropeptides that must play important roles in the normal physiological functions of these brain regions. The study of neuropeptide physiology in the context of the neurobiological responses to drugs of abuse may shed some light on the intrinsic mechanism of action of neuropeptides of the CPu and the NAc. The neuropeptides substance P (SP) and cholecystokinin (CCK) are present in the striatum where they could play an important role regulating the effects of psychostimulants like cocaine and amphetamines (methamphetamine [METH] is a long acting derivative of d-amphetamine). These highly addictive agents induce the release of dopamine (DA) (and other catecholamines) from dopaminergic terminals of the striatum. The excessive release of DA in the striatum and the NAc has been implicated in the habit-forming properties of these drugs. In order to study the contribution of SP and CCK in the striatum during psychostimulant treatment, we employed selective non-peptide neurokinin-1 (NK-1) and cholecystokinin-2 (CCK-2) receptor antagonists that readily cross the blood brain barrier. We infused the neurokinin-1 receptor (NK-1R) antagonist, L-733,060, into the striatum of freely moving rats via a microdialysis probe in order to assess the effects of SP on cocaine-induced DA overflow in the striatum. Infusion of the NK-1R antagonist prior to a systemic injection of cocaine (10 mg/kg i.p.) significantly attenuated DA overflow in the striatum. Conversely, infusion of a CCK-2 receptor (CCK-2R) antagonist, L-369,293, through the microdialysis probe evoked DA overflow in the striatum in the absence of cocaine and potentiated DA overflow after a single injection of cocaine (10 mg/kg i.p.). Exposure to METH (10 mg/kg 4x at two-hour intervals) produced deficits of dopamine transporters (DAT) in mice striatum that are detectable three days after the treatment and are long lasting. Pre-treatment (i.p. injections) with the NK-1R antagonist, WIN-51,708 30 minutes before the 1st and 4th injections of METH prevented the loss of DAT in the striatum. Moreover, pre-treatment with the NK-1R antagonist prevents METH-induced cell death. Taken together, these results demonstrate that the NK-1R and the CCK-2R are important modulators of the actions of the psychostimulants cocaine and METH. Neuropeptide receptors represent an important control point mediating the effects of the neurotransmitter DA in the striatum of the rodent brain. 相似文献
18.
Périer C Marin C Jimenez A Bonastre M Tolosa E Hirsch EC 《Journal of neurochemistry》2003,86(6):1328-1337
Inactivation of the subthalamic nucleus (STN) or the internal segment of the pallidum (GPi)/entopeduncular nucleus (EP) by deep brain stimulation or lesioning alleviates clinical manifestations of Parkinson's disease (PD) as well as reducing the side-effects of levodopa treatment. However, the effects of STN or entopeduncular nucleus (EP) lesion on levodopa-related motor fluctuations and on neurochemical changes induced by levodopa remain largely unknown. The effects of such lesions on levodopa-induced motor alterations were studied in 6-hydroxydopamine (6-OHDA)-lesioned rats and were assessed neurochemically by analyzing the functional activity of the basal ganglia nuclei, using the expression levels of the mRNAs coding for glutamic acid decarboxylase and cytochrome oxidase as molecular markers of neuronal activity. At the striatal level, preproenkephalin (PPE) mRNA levels were analyzed. We found in 6-OHDA-lesioned rats that a unilateral STN or EP lesion ipsilateral to the 6-OHDA lesion had no effect on either the shortening in the duration of the levodopa-induced rotational response or the levodopa-induced biochemical changes in the basal ganglia nuclei. In contrast, overexpression of PPE mRNA due to levodopa treatment was reversed by the STN or EP lesion. Our study thus shows that lesion of the EP or STN may counteract some of the neurochemical changes induced by levodopa treatment within the striatum. 相似文献
19.
Illicit use of p-methoxyamphetamine (PMA) is rapidly increasing. However, little is known about the acute effects of PMA on neurotransmission in vivo. High-speed chronoamperometry was used to monitor neurotransmitter release and clearance in anesthetized rats after local application of PMA or 3,4-methylenedioxymethamphetamine (MDMA). In striatum, PMA caused less neurotransmitter release than MDMA. PMA-evoked release could be partially blocked by pre-treatment with a serotonin (5-HT) reuptake inhibitor, suggesting that evoked 5-HT release contributed to the electrochemical signal and was mediated by the 5-HT transporter (SERT). MDMA-evoked release was not blocked by a SERT inhibitor, suggesting that primarily DA was released. To study the effect of these amphetamines on clearance of 5-HT mediated specifically by the SERT, clearance of exogenously applied 5-HT was measured in the CA3 region of the hippocampus. In contrast to the striatum where 5-HT is cleared by both the SERT and the dopamine transporter (DAT), 5-HT is cleared primarily by the SERT in the CA3 region. This is also a region where neither PMA nor MDMA evoked release of neurotransmitter. The maximal inhibition of 5-HT clearance was greater after PMA than MDMA. These data demonstrate in vivo (1) brain region variability in the ability of PMA and MDMA to evoke release of neurotransmitter; (2) that clearance of 5-HT in the striatum is mediated by both the SERT and the DAT; (3) distinct differences in the amount and nature of neurotransmitter released in the striatum after local application of PMA and MDMA and (4) that PMA is a more efficacious inhibitor of 5-HT clearance in the hippocampus than MDMA. These fundamental differences may account for the more severe adverse reactions seen clinically after PMA, compared to MDMA. 相似文献
20.
Oscar Diaz-Ruiz Agustin Zapata Lufei Shan YaJun Zhang Andreas C. Tomac Nasir Malik Fidel de la Cruz Cristina M. B?ckman 《PloS one》2009,4(9)
The widespread distribution of the tumor suppressor PTEN in the nervous system suggests a role in a broad range of brain functions. PTEN negatively regulates the signaling pathways initiated by protein kinase B (Akt) thereby regulating signals for growth, proliferation and cell survival. Pten deletion in the mouse brain has revealed its role in controlling cell size and number. In this study, we used Cre-loxP technology to specifically inactivate Pten in dopamine (DA) neurons (Pten KO mice). The resulting mutant mice showed neuronal hypertrophy, and an increased number of dopaminergic neurons and fibers in the ventral mesencephalon. Interestingly, quantitative microdialysis studies in Pten KO mice revealed no alterations in basal DA extracellular levels or evoked DA release in the dorsal striatum, despite a significant increase in total DA tissue levels. Striatal dopamine receptor D1 (DRD1) and prodynorphin (PDyn) mRNA levels were significantly elevated in KO animals, suggesting an enhancement in neuronal activity associated with the striatonigral projection pathway, while dopamine receptor D2 (DRD2) and preproenkephalin (PPE) mRNA levels remained unchanged. In addition, PTEN inactivation protected DA neurons and significantly enhanced DA-dependent behavioral functions in KO mice after a progressive 6OHDA lesion. These results provide further evidence about the role of PTEN in the brain and suggest that manipulation of the PTEN/Akt signaling pathway during development may alter the basal state of dopaminergic neurotransmission and could provide a therapeutic strategy for the treatment of Parkinson''s disease, and other neurodegenerative disorders. 相似文献