丘脑底核脑深部电刺激对纹状体区细胞外液谷氨酸含量的影响

目的 探讨长期丘脑底核脑深部电刺激(DBS)对猴偏侧帕金森病模型纹状体区细胞外液中谷氨酸含量的影响.方法 在猴偏侧帕金森病模型的基础上植入DBS系统,刺激电极位于病侧丘脑底核.在给予DBS前后不同时间微透析检测双侧壳核、尾状核细胞外液谷氨酸的含量变化.结果 与开机前比较,DBS后双侧尾状核和壳核的谷氨酸含量均明显升高,1周时升高最显著,1个月以后含量保持稳定;DBS后12个月电极侧壳核谷氨酸含量仍比开机前和非电极侧升高明显(P＜0.05),而尾状核电极侧谷氨酸含量已接近非电极侧(P＞0.05).结论 对猴偏侧帕金森病模型行丘脑底核DBS后,纹状体区细胞外液中谷氨酸的含量明显升高.     

在体检测偏侧帕金森病猴模型尾核区多巴胺含量

本实验应用1-甲基-1,2,3,6-四氢吡啶(MPTP)制备偏侧帕金森病(PD)猴模型,采用颅内微透析技术结合高效液相色谱-电化学法(HPLC-EC)在体检测双侧尾核区多巴胺(DA)及其代谢产物的含量。结果发现,注射侧与注射对侧相比,尾核区DA、二羟苯乙酸(DOPAC)及高香草酸(HVA)的含量分别减少70％、34％和38％。结果表明:颅内微透析技术是在体检测脑内神经递质含量的最有效方法,可以直接反映与PD样症状有关的细胞外液神经递质的变化。     

丘脑底核电刺激对猴偏侧帕金森病纹状体神经递质的影响

目的 探讨应用微透析技术在慢性STN—DBS对纹状体细胞外液多巴胺及代谢产物的影响。方法 选择已经成功安装脑深部刺激电极的偏侧PD猕猴模型2只，分别在打开脉冲发生器前、后的不同时间点取样（开机后8h、1周、1个月、2个月）。应用高效液相电化学方法检测开机前后的尾状核和壳核细胞外液的多巴胺（DA）及其代谢产物含量。结果 电极侧壳核和尾状核的DA在开机后8h、1周、1个月、2个月相应地分别较各自开机前的DA含量增高了39％、91％、111％、114％和31％、91％、106％、102％（P〈0．05）。电极侧壳核和尾状核HVA／DA在开机后8h分别较各自开机前增高了186％和91％（P〈0．05），而开机后1周、1个月、2个月HVA／DA较开机前无明显变化（P〉0．05）。电极侧的多巴胺周转率在开机后的各时间点均显著低于非电极侧（P〈0．01）。结论 STN—DBS可有效的改善猴偏侧PD模型的症状，应用微透析取样技术结合高效液相色谱测，定法发现在给予有效电刺激后可增加刺激侧纹状体细胞外液的多巴胺及其代谢产物含量。为STN—DBS治疗帕金森病提供理论依据。     

STN—DBS对纹状体细胞外液牛磺酸含量的影响

目的探讨丘脑底核脑深部电刺激对猴帕金森病模型纹状体区细胞外液巾牛磺酸含量的影响。方法猴偏侧帕金森病模型,在患侧丘脑底核植入人用脑深部刺激电极,同期猴背部皮下植入脉冲发生器和皮下导线,通过测试后给予有效高频电刺激,利用微透析技术分别在打开脉冲发生器前和开机后的不同时间点在双侧壳核、尾状核头部细胞外液进行取样。对取样标本应用高效液相色谱荧光法检测其中牛磺酸的含量变化。结果电极侧壳核和尾状核的牛磺酸含量在开机后较开机前明显增加（P〈0．05）。结论丘脑底核脑深部刺激后可引起纹状体区细胞外液中牛磺酸的含量明显升高,这可能是丘脑底核脑深部电刺激的作用机制之一。     

Tremor is associated with PET measures of nigrostriatal dopamine function in MPTP-lesioned monkeys

Unilateral intracarotid artery (ICA) MPTP infusion, along with sequential systemic doses of MPTP, produces near complete degeneration of the nigrostriatal pathway on the side of infusion (ipsilateral) and variable levels of damage in the contralateral hemisphere accompanied by varying levels of parkinsonism (overlesioned hemiparkinsonian model). Positron emission tomography and the dopamine (DA) metabolism tracer [(18)F]6-fluoro-l-m-tyrosine (FMT) were used to evaluate the relationship between DA metabolism and clinical features of parkinsonism in 14 overlesioned hemiparkinsonian monkeys. Monkeys were rated on a parkinsonian scale that included ratings of bradykinesia, fine motor skills (FMS), and rest tremor. Because the monkeys tended to show more severe clinical signs on the side of the body contralateral to ICA MPTP infusion, we calculated asymmetry scores for each of the clinical features as well as for FMT uptake (K(i)) in the caudate and putamen. Tremor asymmetry was associated with FMT uptake asymmetry in the putamen. No such relationship was observed for FMS or bradykinesia. The overall severity of tremor (mild, moderate/severe) was associated with FMT uptake in the caudate and putamen. Postmortem biochemical analysis for a subset of monkeys showed that the monkeys with moderate/severe tremor had significantly lower DA levels in both caudate and putamen than those with mild tremor. In addition, K(i) values were significantly correlated with DA levels in both caudate and putamen. These findings support the idea that nigrostriatal degeneration contributes to rest tremor.     

Local cerebral glucose utilization in monkeys with hemiparkinsonism induced by intracarotid infusion of the neurotoxin MPTP

Quantitative 2-[14C]deoxyglucose autoradiography was used to map the pattern of alterations in local cerebral glucose utilization associated with unilateral lesions of the substantia nigra pars compacta produced by the infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into one internal carotid artery of rhesus monkeys. These monkeys become hemiparkinsonian, displaying rigidity, bradykinesia, and tremor of the limbs contralateral to the side of MPTP infusion; during spontaneous activity they turn toward the side of the lesion. Eighty-two brain areas were examined, and statistically significant metabolic changes were confined mainly to basal ganglia structures ipsilateral to the side of the lesion. Glucose utilization was reduced in the substantia nigra pars compacta and ventral tegmental area, i.e., in the areas of cell loss. Increases in glucose utilization in regions normally innervated by the lesioned area were observed in the post-commissural portions of the putamen and dorsolateral caudate. Other structures showing statistically significant metabolic changes were the external segment of the globus pallidus (+40%), subthalamic nucleus (-17%), and pedunculopontine nucleus (+15%). There were also smaller changes in portions of the thalamus (ventral anterior nucleus, parafascicular nucleus) and premotor cortex. All significant metabolic changes were confined to the side of the substantia nigra lesion and were essentially restricted to regions involved in the production of movement or maintenance of posture.     

Methodology of microdialysis of neostriatum in hemiparkinsonian nonhuman primates

In vivo biochemical microdialysis in primate brain would greatly expand our understanding of functional neuronal systems. This work describes our efforts to establish a microdialysis system in primate brain. Seven anesthetized rhesus monkeys underwent magnetic resonance imaging (MRI) with the head fixed in a compatible stereotaxic frame. This allowed stereotaxic localization of the caudate nucleus and putamen. Guide cannulae were implanted and fixed to the skull. Microdialysis probes made from polyethylene and fused silica were inserted into the caudate and putamen through the guide cannulae and perfused at the rate of 1.3 microliters/min. The putamens were approached horizontally, while the caudate nuclei were reached via a 30 degrees-45 degrees angle from the vertical. Postdialysis MRI and histologic evaluation proved that all probes accurately arrived at the predetermined region. Our data show that MRI guided stereotaxis allows accurate placement of dialysis probes and that implantation of guide cannulae is a reliable and convenient way to perform repeated brain microdialysis procedures.     

偏侧猴帕金森病模型的脑深部电刺激研究

目的 探讨丘脑底核脑深部电刺激(STN DBS)对纹状体多巴胺代谢的影响.方法 2只偏侧帕金森病(PD)模型猴,在电极植入术前及电刺激后1、3个月分别行单光子放射计算机断层扫描(SPECT)测定脑内多巴胺转运体(DAT)及多巴胺D2受体(D2R)的含量;利用高效液相色谱分析(HPLE-ECD)检测脑脊液中多巴胺及其代谢产物的含量和变化.结果 偏侧PD模型猴在深部脑刺激下症状明显缓解,SPECT显示在有效刺激后纹状体区DAT特异性摄取率增高,D2R特异性摄取率下降.脑脊液中多巴胺及其代谢产物的含量与术前相比无明显差异.结论 STN DBS可有效改善偏侧PD模型猴的症状.SPECT提示有效电刺激STN提高了纹状体区多巴胺代谢活性.     

GDNF improves dopamine function in the substantia nigra but not the putamen of unilateral MPTP-lesioned rhesus monkeys

Microdialysis measurements of dopamine (DA) and DA metabolites were carried out in the putamen and substantia nigra of unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rhesus monkeys that received intraventricular injections of vehicle or glial-derived neurotrophic factor (GDNF, 300 μg) 3 weeks prior to the microdialysis studies. Following behavioral measures in the MPTP-lesioned monkeys, they were anesthetized with isoflurane and placed in a stereotaxic apparatus. Magnetic resonance imaging (MRI)-guided sterile stereotaxic procedures were used for implantations of the microdialysis probes. Basal extracellular levels of DA and the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were found to be decreased by >95% in the right putamen of the MPTP-lesioned monkeys as compared to normal animals. In contrast, basal DA levels were not significantly decreased, and DOPAC and HVA levels were decreased by only 65% and 30%, respectively, in the MPTP-lesioned substantia nigra. Significant reductions in -amphetamine-evoked DA release were also observed in the MPTP-lesioned substantia nigra and putamen of the monkeys as compared to normal animals. A single intraventricular administration of GDNF into one group of MPTP-lesioned monkeys elicited improvements in the parkinsonian symptoms in these animals at 2–3 weeks post-administration. In addition, -amphetamine-evoked overflow of DA was significantly increased in the substantia nigra but not the putamen of MPTP-lesioned monkeys that had received GDNF. Moreover, post-mortem brain tissue studies showed increases in whole tissue levels of DA and DA metabolite levels primarily within the substantia nigra in MPTP-lesioned monkeys that had received GDNF. Taken together, these data support that single ventricular infusions of GDNF produce improvements in motoric behavior in MPTP-lesioned monkeys that correlate with increases in DA neuronal function that are localized to the substantia nigra and not the putamen.     

Neurochemical architecture of the human striatum

The striatum of the human brain has a highly differentiated neurochemical architecture visible in stains for many of the neurotransmitter-related molecules present in the striatum. The distributions for these chemical markers have never been analyzed comprehensively. We compared the distributions of multiple neurochemical markers in a serial-section analysis of the caudate nucleus, the putamen, and the ventral striatum in normal human brains. The cholinergic system was identified with choline acetyltransferase (ChAT). The organization of the cholinergic fiber system was compared with that of striatal systems expressing immunoreactivity for calbindin D28k, met-enkephalin, substance P, tyrosine hydroxylase, and parvalbumin. Each striatal region analyzed displayed a unique neurochemical organization. In the dorsal caudate nucleus, the distribution of all markers followed the classical striosome/matrix organization as previously reported. In the dorsal putamen, ChAT-staining was less intense, and striosomes were delineated primarily by unstained fiber bundles. In the ventral caudate nucleus/nucleus accumbens region, the boundaries of ChAT-stained regions were not always visible with stains for calbindin, enkephalin, and substance P. The ventral putamen displayed a similar organization, except in its lateral part, where ChAT-poor regions were often found adjacent to, rather than in register with, regions expressing low levels of the other markers (calbindin, enkephalin, substance P, and tyrosine hydroxylase). Our findings suggest that, in addition to the classical striosome-matrix organization visible in the dorsal caudate nucleus and putamen, there is further neurochemical differentiation in a large ventral part of the caudate nucleus and putamen and in the ventral striatum-nucleus accumbens proper. The more complex relationships among the different neurochemical systems in the ventral striatum may reflect the increase in size in the primate of striatal regions associated with association and limbic cortex. J. Comp. Neurol. 384:1–25, 1997. © 1997 Wiley-Liss, Inc.     

Chronic haloperidol-induced changes in regional dopamine release and metabolism and neurotensin content in rats

Chronic neuroleptic administration has previously been shown to alter in vivo measures of dopaminergic function and lead to regionally selective increases in neurotensin levels. In the current study, female rats were administered chronic haloperidol for 6 months via subcutaneous silastic implants. After 24 weeks of administration, microdialysis probes were inserted into the lateral caudate putamen and the medial prefrontal cortex. Basal samples were collected prior to infusion of a high K⁺ concentration (100 mM KCI). Extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid were assessed using HPLC. Chronic haloperidol-treated rats showed increased basal dopamine metabolite levels in the caudate putamen and an altered response to the effects of high K⁺ on 3,4-dihydroxyphenylacetic acid; no significant differences were seen with other analytes in the caudate putamen. Although basal concentrations were not different between groups in the prefrontal cortex, haloperidol-treated rats showed a significant attenuation of response to the effects of high K⁺ infusion on dopamine metabolite concentrations. Radioimmunoassay measurement of tissue neurotensin content showed highly significant elevations of neurotensin concentrations in the caudate putamen and nucleus accumbens, but not in other brain regions analyzed. These results suggest a confluence of altered dopamine and neurotensin function in the caudate putamen which may be related to motor side effects of haloperidol, whereas changes in prefrontal dopamine function are not associated with altered neurotensin levels.     

Prevention of dyskinesia by an NMDA receptor antagonist in MPTP monkeys: effect on adenosine A2A receptors

Adenosine A(2A) receptors (A(2A)R) have received increasing attention for the treatment of L-DOPA-induced dyskinesias in Parkinson disease. In the present study, A(2A)R messenger RNA (mRNA) and receptor-specific binding in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys were studied after treatment with L-DOPA and a selective NR1A/2B NMDA receptor antagonist, CI-1041. Four MPTP monkeys received L-DOPA/benserazide and all developed dyskinesias, whereas among the four MPTP monkeys who additionally received CI-1041, only one developed mild dyskinesias. Four normal monkeys and four MPTP-treated monkeys were also studied. All MPTP monkeys had similar striatal dopamine (DA) denervation. A(2A)R mRNA levels, measured by in situ hybridization, were increased in the rostral lateral caudate and putamen of saline-treated MPTP monkeys as well as in the caudal lateral and medial putamen when compared with those of controls. A(2A)R mRNA levels remained elevated in the rostral caudate and putamen of L-DOPA-treated MPTP monkeys when compared with those of controls. A(2A)R mRNA levels of L-DOPA + CI-1041-treated monkeys were at control levels and decreased in the lateral rostral caudate and caudal putamen when compared with those of L-DOPA-treated and saline-treated MPTP monkeys respectively. No change was measured in the caudal medial putamen and caudate nucleus. A(2A)Rs labeled by autoradiography with [(3)H]SCH-58261 had lower level in the L-DOPA + CI-1041-treated MPTP monkeys compared with saline- or L-DOPA-treated MPTP and control monkeys in the rostral lateral and medial caudate and the putamen. No effect of lesion or L-DOPA treatment was measured on [(3)H]SCH-58261-specific binding. These findings suggest that blockade of NMDA receptors could prevent the development of dyskinesias by altering A(2A)Rs.     

Altered striatal dopaminergic metabolism 36 hours after unilateral trauma to the human mesencephalon

Markers of dopaminergic synaptic activity and choline acetyltransferase (CAT) were measured in the putamen and caudate nucleus of a patient who lived 36 hours after a unilateral mechanical lesion of the mesencephalon. After cessation of impulse flow along the nigrostriatal tract, dopamine was elevated, dihydroxyphenylacetic acid was diminished, and CAT and tyrosine hydroxylase activity were enhanced in the putamen ipsilateral to the lesion. [3H]-spiperone binding indicated an increase in D2-dopamine receptor density in the caudate nucleus. These findings indicate that the changes predicted from experimental neurochemical models occur in human nigrostriatal systems.     

Effect of chronic "binge cocaine" on basal levels and cocaine-induced increases of dopamine in the caudate putamen and nucleus accumbens of C57BL/6J and 129/J mice

In vivo microdialysis was used to measure the effect of chronic "binge" pattern cocaine administration on basal and cocaine-induced dopamine levels in the caudate putamen and nucleus accumbens of C57BL/6J and 129/J mice. Mice were implanted with a guide cannula in the caudate putamen or nucleus accumbens and after 4 days recovery, one group received "binge" pattern cocaine administration for 13 days (15 mg/kg x 3, i.p. at hourly intervals) while another group received saline in the same pattern. On the day before microdialysis, dialysis probes were lowered into the caudate putamen and nucleus accumbens. The next morning, after baseline dopamine collection, all animals received "binge" cocaine administration. Dialysates were collected every 20 min and dopamine content was determined by HPLC with electrochemical detection. In the basal condition, the mean level of dopamine in the dialysate from both brain regions of mice pretreated with "binge" pattern cocaine administration was significantly lower than that of the mice pretreated with saline administration. The absolute levels of dopamine achieved following "binge" pattern cocaine challenge were lower in the mice that had received chronic cocaine administration. However, when expressed as percent increase over baseline, the dopamine response to cocaine in the nucleus accumbens was significantly higher in mice that received chronic than in mice that received acute cocaine administration. Chronic cocaine administration led to a lowering of both basal dopamine and the absolute levels of cocaine-induced increases of dopamine in the two brain regions, but enhanced the percent increases over the baseline in response to cocaine in the nucleus accumbens of both mouse strains.     

Molecular alterations in the neostriatum of human cocaine addicts

Molecular changes in the neostriatum of human subjects who died with a history of cocaine abuse were revealed in discrete cell populations by means of the techniques of in situ hybridization histochemistry and in vitro receptor binding and autoradiography. Cocaine subjects had a history of repeated cocaine use and had cocaine and/or cocaine metabolites on board at the time of death. These subjects were compared to control subjects that had both a negative history and toxicology of cocaine use. Selective alterations in mRNA levels of striatal neuropeptides were detected in cocaine subjects compared to control subjects, especially for the opioid peptides. Marked reductions in the levels of enkephalin mRNA and μ opiate receptor binding were found in the caudate and putamen, concomitant with elevations in levels of dynorphin mRNA and κ opiate receptor binding in the putamen and caudate, respectively. Dopamine uptake site binding was reduced in the caudate and putamen of cocaine subjects. The greater magnitude of changes in the dorsolateral striatum (caudate and putamen) as opposed to the ventromedial striatum (nucleus accumbens) suggests that cocaine abuse preferentially alters the biosynthetic activity of striatal systems associated with sensorimotor functioning. Additionally, an imbalance in the activity of the two major striatal output pathways in cocaine users is implicated because peptide mRNA levels were reduced in enkephalinergic striatopallidal neurons and increased in dynorphinergic striatonigral neurons. Another imbalance, that of reductions of transmitter mRNA and receptor expression associated with euphoria (enkephalin and μ opiate receptors), together with elevations in mRNAs of transmitter systems associated with dysphoria (dynorphin and κ opiate receptors), suggests a model of dysphoria and craving in the human cocaine addict brain. © 1993 Wiley-Liss, Inc.     

Quantitative imaging of tyrosine hydroxylase and calmodulin in the human brain

The distributions of tyrosine hydroxylase and calmodulin in adult normal postmortem human brain were analyzed quantitatively. Consecutive coronal sections were obtained from the anterior area of the right hemisphere and were stained immunohistochemically for tyrosine hydroxylase and calmodulin. Stained sections were divided into approximately 3 million microareas at 50 microm intervals, and the immunohistochemical fluorescence intensity in each area was measured by a human brain mapping analyzer, which is a microphotometry system for analysis of the distribution of neurochemicals in a large tissue slice. Immunoreactive staining of tyrosine hydroxylase and calmodulin was observed in almost all brain regions, but its intensity varied. Relatively high levels of calmodulin were observed in brain regions with high levels of tyrosine hydroxylase, though high levels of tyrosine hydroxylase were not always observed in brain regions where high levels of calmodulin were distributed. In particular, high levels of both of tyrosine hydroxylase and calmodulin were distributed in the caudate nucleus and putamen. Previously it was shown that tyrosine hydroxylase was activated and dopamine synthesis was enhanced in the neostriatum region in mice and rats by the intracerebroventricular administration of calcium through a calmodulin-dependent system. The present results combined with these previous findings suggest that the activity of tyrosine hydroxylase in the caudate nucleus and putamen of humans may also be regulated by a calcium/calmodulin-dependent system.     

Presynaptic dopaminergic function is largely unaltered in mesolimbic and mesostriatal terminals of adult rats that were prenatally exposed to cocaine

Fast-scan cyclic voltammetry in brain slices and postmortem tissue content assessment were used to evaluate presynaptic dopaminergic function in the caudate putamen and nucleus accumbens of adult male rats (180+ days old) that were prenatally treated with either cocaine or saline. Experiments were carried out to test whether there were differences in dopamine release, reuptake, autoreceptor function or the tissue levels of dopamine and its metabolites between cocaine- and saline-exposed rats. We report that presynaptic dopaminergic function remains largely intact in adult rats that were prenatally exposed to cocaine. The ability of terminals in the caudate putamen and nucleus accumbens to release and regulate dopamine is unaltered by prenatal cocaine exposure. However the tissue content of dopamine in the caudate putamen was decreased, representing a diminution in the dopamine storage pool. We conclude, therefore, that behavioral changes that have previously been observed in rats that were prenatally exposed to cocaine are not mediated through alteration of presynaptic dopaminergic mechanisms in these brain regions.     

Autoradiographic studies in animal models of hemi-parkinsonism reveal dopamine D2 but not D1 receptor supersensitivity. II. Unilateral intra-carotid infusion of MPTP in the monkey (Macaca fascicularis)

The selective dopaminergic antagonist ligands [3H]SCH 23390 and [3H]sulpiride were used to reveal autoradiographically dopamine D1 and D2 receptors, respectively, in brain sections from monkeys which had received unilateral intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causing loss of dopamine-containing neurones of the substantia nigra pars compacta. The monkeys developed hemi-parkinsonian symptoms (tremor, bradykinesia) in limbs contralateral to the side of the toxin infusion. Administration of apomorphine (0.05-0.25 mg/kg) caused contralateral rotational behaviour, and reversal of the parkinsonian symptoms. Loss of forebrain dopaminergic terminals was assessed autoradiographically using [3H]mazindol to label dopamine uptake sites. A reduction in these sites of 97% (mean brain value) in the caudate nucleus, and 91% in the putamen, as compared with binding values from untreated control monkeys, was accompanied by a significant increase in the binding of [3H]sulpiride (D2) in these structures. In contrast, in the same animals there was no similar increase in [3H]SCH 23390 binding to D1 receptors in the denervated areas. These results suggest that in the parkinsonian brain, where the dopaminergic innervation of the caudate nucleus and putamen has been lost, D2 receptors may be more susceptible than D1 receptors to changes, revealed here as an increase in [3H]sulpiride binding sites.     

Effect of acute binge cocaine on levels of extracellular dopamine in the caudate putamen and nucleus accumbens in male C57BL/6J and 129/J mice

Levels of dopamine, both basal and after binge-pattern cocaine administration, were measured in the caudate putamen and nucleus accumbens of C57BL/6J and 129/J mice by in vivo microdialysis. Six-week old males were surgically implanted with a CMA guide cannula into the caudate putamen or nucleus accumbens. After 4 days recovery, dialysis probes were lowered into the caudate putamen or the nucleus accumbens and mice were placed in individual microdialysis chambers. The next morning experiments were carried out on freely moving animals. Experimental animals received 1-day binge cocaine administration (15 mg/kgx3, i.p. at hourly intervals) while control animals received saline in the same pattern. Dialysates were collected every 20 min and dopamine content was determined by HPLC with electrochemical detection. Basal levels of dopamine in the dialysate of the caudate putamen were 4.2+/-0.2 nM in C57BL/6J mice and 5.0+/-0.3 nM in 129/J mice. In the nucleus accumbens, basal levels of dopamine were 0.65+/-0.04 nM in the C57BL/6J mice and 0.75+/-0.03 nM in 129/J mice, with no significant differences between strains in either region. Binge cocaine administration significantly increased mean dopamine levels in the caudate putamen in the C57BL/6J mice (with a 3-h mean of 6.80 nM) and in the 129J mice (9.94 nM). In this region, 129/J mice had significantly higher levels of cocaine-induced dopamine than did C57BL/6J mice. In the nucleus accumbens, administration of cocaine also significantly increased dopamine levels in both strains (1.32 nM in C57BL/6J and 1.43 nM in 129/J), but with no difference between strains.     

Glutamate decarboxylase (GAD67 and GAD65) gene expression is increased in a subpopulation of neurons in the putamen of parkinsonian monkeys

The cellular distribution of the mRNAs encoding for the two isoforms of glutamate decarboxylase, GAD67 and GAD65, was analyzed by in situ hybridization histochemistry in the caudate nucleus and putamen of control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian squirrel monkeys. On brain sections processed with a radioactive and a digoxigenin-labeled cRNA probe, the GAD67 and GAD65 mRNAs were colocalized in virtually all labeled neurons of the caudate nucleus and putamen, in both control and MPTP-treated monkeys. Furthermore, neurons labeled with the GAD cRNAs constituted at least 90% of all striatal neurons, as estimated on adjacent Nissl-stained sections. In the two groups of monkeys, double-labeling experiments using a combination of radioactive GAD67 or GAD65 and digoxigenin-labeled preproenkephalin (PPE) cRNA probes showed that roughly half of all neurons labeled with the GAD cRNAs were also labeled with the PPE cRNA probe. When compared to controls, GAD67 and GAD65 mRNA levels were higher in the putamen, and to a lesser extent in the caudate nucleus, of MPTP-treated monkeys. Further analysis of labeling at the cellular level in a dorsolateral sector of the putamen revealed that GAD67 and GAD65 mRNA levels in MPTP-treated monkeys were increased in PPE-labeled (presumed striato-pallidal) neurons but not in PPE-unlabeled (presumed striato-nigral) neurons. Our results demonstrate that most neurons in the caudate nucleus and putamen of squirrel monkeys contain the mRNAs encoding for the two GAD isoforms. In addition, the selective increase in GAD mRNA levels in PPE-labeled neurons provides further evidence that striato-pallidal GABAergic neurons are hyperactive in MPTP-treated parkinsonian monkeys. Synapse 27:122–132, 1997. © 1997 Wiley-Liss, Inc.