Fetal striatal transplants restore electrophysiological sensitivity to dopamine in the lesioned striatum of rats with experimental Huntington's disease

Dopamine (DA), a major neurotransmitter used in the striatum, is involved in movement disorders such as Parkinson's disease and Huntington's chorea. With the loss of neurons in the striatum of patients with Huntington's disease (HD), there is an associated downregulation of DA receptors, which may alter DA-mediated responses. In the present study, DA-mediated electrophysiological depression was studied in animals with quinolinic acid (QA)-induced experimental HD. QA was directly applied to the right striatum of adult female Sprague-Dawley rats. Animals receiving QA developed ipsilateral rotation after the application of apomorphine. Fetal striatal tissue transplants grafted 1 month after lesioning attenuated apomorphine-induced rotation. Six months after lesioning, the animals were anesthetized with urethane for electrophysiological study. DA, applied directly to neurons by pressure microejection, inhibited spontaneous single-unit activity in the striatal neurons of nonlesioned, lesioned and lesioned/grafted rats. QA lesioning reduced responses to DA in the striatal neurons. The dose of DA required to inhibit striatal neuron activity in the lesioned rats was significantly increased compared to that in the nonlesioned rats. Transplantation of fetal striatal tissue restored the electrophysiological sensitivity to DA in the lesioned striatum. The dose of DA used to suppress striatal neuron activity was reduced after grafting. Immunohistostaining showed survival of gamma-aminobutyric acid neurons at the graft site. Tyrosine hydroxylase-positive terminals were found innervating the striatal grafts. In conclusion, our data demonstrate that fetal striatal transplants restore electrophysiological sensitivity to DA in the lesioned striatum of animals with experimental HD.     

Differential responsiveness to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in sub-regions of the primate substantia nigra and striatum

After treatment with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), there was a severe loss of dopamine (DA) at all examined sites in the striatum, both in those monkeys which remained asymptomatic (77-99%) and in one monkey which developed severe parkinsonian disability (94-99%). However, the asymptomatic animals had normal DA concentration in the substantia nigra (SN); yet in the symptomatic animal DA was largely depleted in the central (86%) and medial (94%), but not lateral (8%) regions of the SN. The HVA/DA ratio was raised in the striatum of all MPTP-treated animals. In the SN though, this ratio was elevated only in the symptomatic animal, in the central and medial, but not lateral regions. The contralateral half of these brains were examined for DA histofluorescence. The SN of asymptomatic animals had a slight increase in lipofuscin fluorescence within dopaminergic neurons and a small reduction in the number of dopaminergic cells, while fluorescent intensity of individual neurons was unchanged. The SN of the symptomatic animal displayed a sharp decline in the number of DA neurons along with an increase in autofluorescent pigment granules; these changes were most pronounced in the central and medial regions of the SN. These data suggest that after MPTP the terminals of the nigrostriatal pathway are affected before the cell bodies. In the one symptomatic animal emergence of parkinsonian disability corresponded with a marked loss of DA neurons and DA concentration in the central and medial regions of the SN. In the control monkeys a gradient in the concentration of amines and metabolites was observed within the SN; the lateral region contained the highest and the medial region the lowest concentration.     

帕金森病黑质多巴胺神经元易损伤性的内在因素

帕金森病（Parkinson’s disease,PD）主要症状是由中脑黑质致密部（substantia nigra compact,SNc）的多巴胺（dopamine,DA）神经元死亡引起。帕金森病发病过程中,路易小体病理（Lewy pathology,LP）和线粒体功能障碍最为突出,但SNc 多巴胺神经元为什么特别易遭受这两种病理损害尚不清楚。研究表明,与脑内其他神经元相比,SNc 多巴胺神经元具有特殊的解剖形态、生理和生化表型。SNc 多巴胺神经元具有高分支无髓鞘轴突和众多的突触终端,突触末梢物质和能量代谢的高要求需要大量的线粒体,巨大突触终端增加了突触蛋白质的表达、转运和降解的负担。SNc 多巴胺神经元具有独特的自主起搏电活动和缓慢钙振荡特性,Cav1-3钙通道活动及后续的级联反应增加了SNc 多巴胺神经元线粒体负担,增加了基础氧化应激、线粒体损伤和自噬,降低了处理错误折叠蛋白质的能力。SNc 多巴胺神经元特有的神经递质--多巴胺易被氧化成为反应性醌,具有潜在毒性,可破坏葡糖脑苷脂酶导致其活性降低,引起线粒体氧化应激和溶酶体功能障碍。总之,SNc 多巴胺神经元具有的这些内在因素综合起来,可能导致了其对线粒体功能障碍和路易小体病理损伤的易感性,并且SNc 多巴胺神经元所处的神经网络障碍也促使了帕金森病的进展。认识到这些特征会对研究帕金森病相关病理学机制和阻止疾病进展创造新的机会。     

帕金森病黑质多巴胺神经元易损伤性的内在因素

帕金森病（Parkinson’s disease,PD）主要症状是由中脑黑质致密部（substantia nigra compact,SNc）的多巴胺（dopamine,DA）神经元死亡引起。帕金森病发病过程中,路易小体病理（Lewy pathology,LP）和线粒体功能障碍最为突出,但SNc 多巴胺神经元为什么特别易遭受这两种病理损害尚不清楚。研究表明,与脑内其他神经元相比,SNc 多巴胺神经元具有特殊的解剖形态、生理和生化表型。SNc 多巴胺神经元具有高分支无髓鞘轴突和众多的突触终端,突触末梢物质和能量代谢的高要求需要大量的线粒体,巨大突触终端增加了突触蛋白质的表达、转运和降解的负担。SNc 多巴胺神经元具有独特的自主起搏电活动和缓慢钙振荡特性,Cav1-3钙通道活动及后续的级联反应增加了SNc 多巴胺神经元线粒体负担,增加了基础氧化应激、线粒体损伤和自噬,降低了处理错误折叠蛋白质的能力。SNc 多巴胺神经元特有的神经递质——多巴胺易被氧化成为反应性醌,具有潜在毒性,可破坏葡糖脑苷脂酶导致其活性降低,引起线粒体氧化应激和溶酶体功能障碍。总之,SNc 多巴胺神经元具有的这些内在因素综合起来,可能导致了其对线粒体功能障碍和路易小体病理损伤的易感性,并且SNc 多巴胺神经元所处的神经网络障碍也促使了帕金森病的进展。认识到这些特征会对研究帕金森病相关病理学机制和阻止疾病进展创造新的机会。     

Leptin Acts via Leptin Receptor-Expressing Lateral Hypothalamic Neurons to Modulate the Mesolimbic Dopamine System and Suppress Feeding

The lateral hypothalamic area (LHA) acts in concert with the ventral tegmental area (VTA) and other components of the mesolimbic dopamine (DA) system to control motivation, including the incentive to feed. The anorexigenic hormone leptin modulates the mesolimbic DA system, although the mechanisms underlying this control have remained incompletely understood. We show that leptin directly regulates a population of leptin receptor (LepRb)-expressing inhibitory neurons in the LHA and that leptin action via these LHA LepRb neurons decreases feeding and body weight. Furthermore, these LHA LepRb neurons innervate the VTA, and leptin action on these neurons restores VTA expression of the rate-limiting enzyme in DA production along with mesolimbic DA content in leptin-deficient animals. Thus, these findings reveal that LHA LepRb neurons link anorexic leptin action to the mesolimbic DA system.     

Involvement of Ventral Periaqueductal Gray Dopaminergic Neurons in Propofol Anesthesia

It has been reported that central dopaminergic system is implicated in the mechanism underlying general anesthesia. Whether dopamine (DA) neurons in midbrain ventral periaqueductal gray (vPAG) are involved in general anesthesia and how general anesthetics affect these neurons remain sparsely documented. To determine the role of vPAG DA neurons in propofol-induced anesthesia, we performed microinjection of 6-hydroxydopamine (6-OHDA) into vPAG to damage DA neurons and investigated the alteration in somatosensory electroencephalogram (EEG), as well as the induction and recovery time of propofol anesthesia. Subsequently, we examined the effect of propofol on the electrophysiological activity of DA neurons in vPAG using whole-cell patch clamp. Two weeks after 6-OHDA microinfusion, DA neurons in the vPAG were markedly reduced by 63.6% in the 6-OHDA-treated rats compared with vehicle rats. This lesion significantly shortened the induction time (7.15?±?3.97 s vs. 11.18?±?2.83 s, P?<?0.05) and prolonged the recovery time of propofol anesthesia (780.26?±?150.86 s vs. 590.68?±?107.97 s, P?<?0.05). Meanwhile, EEG in somatosensory cortex revealed that delta power (0–4 Hz) was significantly higher in 6-OHDA-treated rats than vehicle rats. In the electrophysiological experiment, propofol decreased the frequency of spontaneous excitatory postsynaptic currents rather than the amplitude and decay time. In addition, propofol preferentially increased the frequency and prolonged the decay time of spontaneous inhibitory postsynaptic currents without affecting the amplitude. Significance: Propofol can promote presynaptic GABA release, inhibit presynaptic glutamate release and increase postsynaptic GABA_A receptor sensitivity, which eventually inhibits the activity of vPAG DA neurons and thereby influences the state of consciousness.     

Excitation of nigral dopamine neurons by the GABA(A) receptor agonist muscimol is mediated via release of glutamate

Previous electrophysiological studies have shown that the GABA(A)-receptor agonist muscimol is able to markedly increase the firing rate of rat nigral dopamine (DA) neurons. This action of the drug is paradoxical since local microiontophoretic application of the drug is associated with a clearcut inhibition of this neurons. In the present electrophysiological study, an attempt was made to analyze the mechanism of this action of the drug. Administration of muscimol (0.25-4.0 mg/kg, i.v.) was associated with a dose-dependent increase in firing rate as well as an increased bursting activity of the nigral DA neurons. Both these effects of muscimol were clearly antagonised by intravenous administration of the NMDA receptor antagonist MK 801(1 mg/kg) or by intracerebroventricular administration of the broad-spectrum excitatory amino acid receptor antagonist kynurenic acid. Furthermore, pretreatment with PNU 156561A (40 mg/kg, i.v., 5-8h), a compound that raised endogenous kynurenic acid levels about 9 times, also clearly antagonised the actions of muscimol. Indeed, this treatment reversed the excitatory action of muscimol into an inhibitory effect on the nigral DA neurons. Here, we report that the excitatory action of muscimol is mediated indirectly by release of glutamate.     

Functional diversity of ventral midbrain dopamine and GABAergic neurons

Recent findings indicate that VTA and SN dopaminergic (DA) and GABAergic neurons form subpopulations that are divergent in their electrophysiological features, vulnerability to neurodegeneration, and regulation by neuropeptides. This diversity can be correlated with the anatomical organization of the VTA and SN and their inputs and outputs. In this review we describe the heterogeneity in ion channels and firing patterns, especially burst firing, in subpopulations of dopamine neurons. We go on to describe variations in vulnerability to neurotoxic damage in models of Parkinson’s disease in subgroups of DA neurons and its possible relationship to developmental gene regulation, the expression of different ion channels, and the expression of different protein markers, such as the neuroprotective marker calbindin. The electrophysiological properties of subgroups of GABAergic midbrain neurons, patterns of expression of protein markers and receptors, possible involvement of GABAergic neurons in a number of processes that are usually attributed exclusively to dopaminergic neurons, and the characteristics of a subgroup of neurons that contains both dopamine and GABA are also discussed.     

Changes in somatodendritic but not terminal dopamineregulation in aged rhesus monkeys

For these studies, young (8-9 years), middle-aged (14-17 years) and aged (23-28 years) rhesus monkeys were used as a model of normal aging in humans to investigate changes in dopamine (DA)-containing neurons in senescence. Aged monkeys exhibited significant age-related motoric declines as compared to the young animals. In vivo microdialysis studies showed that basal levels of the DA metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were diminished by 44% and 79%, respectively, in the substantia nigra (SN) of aged monkeys. In addition, d-amphetamine-evoked overflow of DA in the SN was diminished by 30% in the middle-aged animals and 67% in the aged monkeys. Post-mortem measures of DA and DA metabolites showed significant decreases in DA (20%), DOPAC (47%) and HVA (22%) levels in the putamen and a 25% decline in HVA tissue levels in the SN of the aged monkeys as compared to the young animals. Unbiased stereological cell counting of tyrosine hydroxylase (TH)-immunoreactive neurons in the SN showed a small (15-20%) but significant age-related decline in TH-positive neurons. In addition, there was a small (15-20%) but significant decline in TH-positive fiber density and TH-positive cell size. In comparison to the massive loss of DA neurons responsible for the movement dysfunctions seen in Parkinson's disease, pronounced functional changes in DA release in the SN and putamen may significantly contribute to the motoric dysfunctions characterizing normal aging in rhesus monkeys.     

Fibroblast growth factor receptor signaling affects development and function of dopamine neurons - inhibition results in a schizophrenia-like syndrome in transgenic mice

Developing and mature midbrain dopamine (DA) neurons express fibroblast growth factor (FGF) receptor-1 (FGFR1). To determine the role of FGFR1 signaling in the development of DA neurons, we generated transgenic mice expressing a dominant negative mutant [FGFR1(TK-)] from the catecholaminergic, neuron-specific tyrosine hydroxylase (TH) gene promoter. In homozygous th(tk-)/th(tk-) mice, significant reductions in the size of TH-immunoreactive neurons were found in the substantia nigra compacta (SNc) and the ventral tegmental area (VTA) at postnatal days 0 and 360. Newborn th(tk-)/th(tk-) mice had a reduced density of DA neurons in both SNc and VTA, and the changes in SNc were maintained into adulthood. The reduced density of DA transporter in the striatum further demonstrated an impaired development of the nigro-striatal DA system. Paradoxically, the th(tk-)/th(tk-) mice had increased levels of DA, homovanilic acid and 3-methoxytyramine in the striatum, indicative of excessive DA transmission. These structural and biochemical changes in DA neurons are similar to those reported in human patients with schizophrenia and, furthermore, these th(tk-)/th(tk-) mice displayed an impaired prepulse inhibition that was reversed by a DA receptor antagonist. Thus, this study establishes a new developmental model for a schizophrenia-like disorder in which the inhibition of FGF signaling leads to alterations in DA neurons and DA-mediated behavior.     

B-HT 920 stimulates postsynaptic D2 dopamine receptors in the normal rat: electrophysiological and behavioral evidence

The putative autoreceptor-selective dopamine (DA) agonist B-HT 920 was tested using electrophysiological and behavioral models thought to reflect actions at postsynaptic D2 DA receptors. Direct iontophoretic application of B-HT 920 onto nucleus accumbens neurons caused a current-dependent inhibition of firing which could be attenuated by pretreatment with alpha-methyl-p-tyrosine (to deplete DA) and reinstated (enabled) by concurrent administration of the selective D1 DA receptor agonist SKF 38393. These findings suggest that, like other selective D2 DA receptor agonists, the postsynaptic effects of B-HT 920 require concurrent stimulation of D1 DA receptors. Behavioral indices of postsynaptic D2 DA receptor stimulation (stereotyped sniffing and rearing) were also evident following combined treatment with B-HT 920 and SKF 38393. Moreover, similar "low-level" stereotyped behaviors were also observed when B-HT 920 was administered alone following pretreatment with the alpha-2 adrenoceptor antagonists idazoxane and piperoxane, suggesting that alpha-2 agonist actions of B-HT 920, in some way, mask the expression of D2 receptor-mediated stereotyped responses. When B-HT 920 was combined with SKF 38393 following pretreatment with idazoxane, both the intensity and form (continual licking and gnawing) of stereotyped behavior was enhanced. Taken together, these electrophysiological and behavioral findings indicate that B-HT 920 possesses the properties of a selective D2 DA receptor agonist and cannot be considered as a DA autoreceptor-selective compound.     

Brain-derived neurotrophic factor facilitates maturation of mesenchymal stem cell-derived dopamine progenitors to functional neurons

The generation of dopamine (DA) neurons from stem cells holds great promise in the treatment of Parkinson's disease and other neural disease associated with dysfunction of DA neurons. Mesenchymal stem cells (MSCs) derived from the adult bone marrow show plasticity with regards to generating cells of other germ layers. In addition to reduced ethical concerns, MSCs could be transplanted across allogeneic barriers, making them desirable stem cells for clinical applications. We have reported on the generation of DA cells from human MSCs using sonic hedgehog (SHH), fibroblast growth factor 8 and basic fibroblast growth factor. Despite the secretion of DA, the cells did not show evidence of functional neurons, and were therefore designated DA progenitors. Here, we report on the role of brain-derived neurotrophic factor (BDNF) in the maturation of the MSC-derived DA progenitors. 9-day induced MSCs show significant tropomyosin-receptor-kinase B expression, which correlate with its ligand, BDNF, being able to induce functional maturation. The latter was based on Ca²⁺ imaging analyses and electrophysiology. BDNF-treated cells showed the following: increases in intracellular Ca²⁺ upon depolarization and after stimulation with the neurotransmitters acetylcholine and GABA and, post-synaptic currents by electrophysiological analyses. In addition, BDNF induced increased DA release upon depolarization. Taken together, these results demonstrate the crucial role for BDNF in the functional maturation of MSC-derived DA progenitors.     

Molecular cloning and characterization of crustacean type-one dopamine receptors: D1alphaPan and D1betaPan

Dopamine (DA) differentially modulates identified neurons in the crustacean stomatogastric nervous system (STNS). While the electrophysiological actions of DA have been well characterized, little is known about the dopaminergic transduction cascades operating in this system. As a first step toward illuminating the molecular underpinnings of dopaminergic signal transduction in the crustacean STNS, we have cloned and characterized two type-one DA receptors (DARs) from the spiny lobster (Panulirus interruptus): D(1alphaPan) and D(1betaPan). We found that the structure and function of these arthropod DARs are well conserved across species. Using a heterologous expression system, we determined that DA, but not serotonin, octopamine, tyramine or histamine activates these receptors. When stably expressed in HEK cells, the D(1alphaPan) receptor couples with Gs, and DA elicits an increase in [cAMP]. The D(1betaPan) receptor responds to DA with a net increase in [cAMP] that is mediated by Gs and Gz.     

Target-specific glutamatergic regulation of dopamine neurons in the ventral tegmental area

Dopamine (DA) neurons in the ventral tegmental area (VTA) are thought to play a critical role in affective, motivational, and cognitive functioning. There are fundamental target-specific differences in the functional characteristics of subsets of these neurons. For example, DA afferents to the prefrontal cortex (PFC) have a higher firing and transmitter turnover rate and are more responsive to some pharmacological and environmental stimuli than DA projections to the nucleus accumbens (NAc). These functional differences may be attributed in part to differences in tonic regulation by glutamate. The present study provides evidence for this mechanism: In freely moving animals, blockade of basal glutamatergic activity in the VTA by the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate antagonist LY293558 produced an increase in DA release in the NAc while significantly decreasing DA release in the PFC. These data support an AMPA receptor-mediated tonic inhibitory regulation of mesoaccumbens neurons and a tonic excitatory regulation of mesoprefrontal DA neurons. This differential regulation may result in target-specific effects on the basal output of DA neurons and on the regulatory influence of voltage-gated NMDA receptors in response to phasic activation by behaviorally relevant stimuli.     

The electrophysiological actions of neurotensin in the central nervous system

The endogenous neuropeptide, neurotensin (NT) alters the firing frequencies of certain neurons in the central nervous system (CNS). This is one of the findings that support the hypothesis that NT is a neurotransmitter substance. The direct application of NT on CNS neurons causes predominantly excitatory effects. These effects occur in a dose-related fashion via a calcium-dependent postsynaptic mechanism. The C-terminal hexapeptide fragment, NT 8-13 exerts similar electrophysiological effects to NT, while the N-terminal octapeptide fragment, NT 1-8 is devoid of such activity. NT produces a significant increase in the firing rates of individual neurons in the substantia nigra (SN), ventral tegmental area (VTA), medial prefrontal cortex (MPF), hypothalamus, and periaqueductal grey (PAG). This excitation occurs with a rapid onset and is readily reversible after cessation of NT application. In contrast, NT has no effect or weak inhibitory effects on the firing rates of neurons in the locus coeruleus (LC) and cerebellum. These electrophysiological actions of NT appear to be unique and not shared by other neurotransmitter and neuropeptide receptor antagonists and agonists that have been studied via direct co-application. NT attenuates dopamine (DA)-induced inhibition associated with direct application onto neurons in the SN and VTA both in vivo and in vitro. Intracellular recordings suggest that direct application of higher concentrations of NT appears to produce 'depolarization block' on individual neurons in the SN, VTA, MPF, and hypothalamus. The electrophysiological consequences of NT application not only show similarities to clinically efficacious antipsychotic medications, but also demonstrate the ability of NT to modulate the activity of dopamine (DA) neurons at the cellular level via specific NT binding sites. These findings further underscore the possibility that NT may play a pre-eminent role in the pathogenesis of, and psychopharmacological management of neurological and psychiatric disorders purportedly related to perturbation of CNS DA systems including schizophrenia.     

Firing properties of substantia nigra dopaminergic neurons in freely moving rats

Single unit recordings were obtained from putative dopaminergic neurons in the substantia nigra of awake, freely moving rats. The cells exhibited waveforms, range of firing rates and types of firing patterns identical to those of identified DA neurons of anesthetized or paralyzed rats. Two firing patterns were observed: single spike activity and a bursting mode with spikes of progressively diminished amplitude and increased duration within each burst. The degree of burst firing varied considerably among the cells and individual cells sometimes switched from one pattern of firing (e.g. predominantly single spike) to another (e.g. bursting), although the determinants of these transitions are, at this time, unclear. Putative DA neurons were inhibited by i.v. apomorphine and excited by i.v. haloperidol. Haloperidol also reversed the apomorphine-induced inhibition of firing. Inhibitions and excitations were associated with a reduction and elevation, respectively, in burst firing. The effects of the two drugs were identical to their effects in immobilized rats. In several cases, a putative DA neuron was observed to fire all of its spikes in near coincidence with at least one other cell with identical electrophysiological characteristics. This form of interaction (i.e. presumed electrical coupling) between DA cells is only rarely observed in anesthetized or paralyzed rats and may play a significant role in the normal functioning of the nigrostriatal DA system.     

Inhibitory and activatory effects of dopamine on neurons in slices of the compact zone of theSubstantia nigra of rats

Effects of dopamine on the background spike activity of functionally (according to their electrophysiological characteristics) identified dopaminergic (DA) or non-dopaminergic (non-DA) neurons of the compact zone of thesubstantia nigra were studied on slices of the midbrain of adult rats. In the majority of DA neurons, dopamine suppressed the background activity in a dose-dependent manner. Sensitivity of these cells to dopamine varied within a wide range: IC₅₀, the concentration providing the 50% maximum effect, equalled from 3 to 3,000 µM in different units. A part of DA neurons responded to dopamine with an increase in their activity. Mixed responses, in which an initial suppression of impulsation was replaced by a slow-developing activation, was observed in some neurons. Non-DA neurons usually responded to dopamine by an enhancement of impulsation; yet, the cells with inhibitory or mixed responses similar to those of DA neurons could be found in this population as well. Sensitivity of non-DA neurons to dopamine was about the same as that of DA-cells, without the dependence on the direction of responses. S(–)-suipiride, a blocker of D₂ receptors, decreased the inhibitory component of all tested responses to dopamine both in DA and non-DA neurons and evoked no changes in the excitatory component. At the same time, R(+)-SCH 23390 HC1, a blocker of D₁ receptors, suppressed the activatory component of responses with no effect on the inhibitory component. We conclude that both types of DA receptors, D₂ and D₁ receptors, can be present on the DA and non-DA neurons. Dopamine, influencing these receptors, suppresses or facilitates, respectively, the spike activity of these cells. The relative amount of such receptors is the main factor determining the pattern and dynamics of the integral response to dopamine application. The possible functional role of the presence of both D₁ and D₂ receptors on the membrane of a single neuron is discussed.Neirofiziologiya/Neurophysiology, Vol. 27, No. 4, pp. 268–277, July–August, 1995.     

Pharmacological elevation of endogenous kynurenic acid levels activates nigral dopamine neurons

Summary. Inhibitors of kynurenine 3-hydroxylase have previously been used to increase endogenous levels of kynurenic acid, an excitatory amino acid receptor antagonist. In the present electrophysiological study PNU 156561A was utilized to elevate endogenous concentrations of kynurenic acid and subsequent effects on the firing pattern of dopamine (DA) neurons of rat substantia nigra (SN) were analyzed. Pretreatment with PNU 156561A (40 mg/kg, i.v., 5–7 h) caused a five-fold increase in endogenous kynurenic acid levels in whole brain five to seven hours after administration and also evoked a significant increase in firing rate and bursting activity of nigral DA neurons. The results of the present study show that a moderate increase in endogenous kynurenic acid levels produces significant actions on the tonic glutamatergic control of the firing pattern of nigral DA neurons, and implicate kynurenine 3-hydroxylase inhibitors as novel antiparkinsonian agents. Received April 3, 2000 Accepted July 2, 2000     

Cocaine withdrawal and neuro-adaptations in ion channel function

Chronic exposure to psychostimulants induces neuro-adaptations in ion channel function of dopamine (DA)-innervated cells localized within the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). Although neuroplasticity in ion channel function is initially found in drug-sensitized animals, it has recently been believed to underlie the withdrawal effects of cocaine, including craving that leads to relapse in human addicts. Recent studies have also revealed remarkable differences in altered ion channel activities between mPFC pyramidal neurons and medium spiny NAc neurons in cocaine-withdrawn animals. In response to psychostimulant or certain “excitatory” stimuli, increased intrinsic excitability is found in mPFC pyramidal neurons, whereas decreased excitability is observed in medium spiny NAc cells in drug-withdrawn animals compared to drug-free control animals. These changes in ion channel function are modulated by interrupted DA/Ca²⁺ signaling with decreased DA D2 receptor function but increased D1 receptor signaling. More importantly, they are correlated to behavioral changes in cocaine-withdrawn human addicts and sensitized animals. Based on growing evidence, researchers have proposed that cocaine-induced neuro-adaptations in ion channel activity and DA/Ca²⁺ signaling in mPFC pyramidal neurons and medium spiny NAc cells may be the fundamental cellular mechanism underlying the cocaine withdrawal effects observed in human addicts.