Involvement of cholinergic neurons in the release of dopamine elicited by stimulation of μ-opioid receptors in striatum

The involvement of striatal cholinergic neurons in the release of dopamine (DA) elicited by the (μ-opioid receptor agonist DAGO [d-Ala², NMePhe⁴-Gly⁵(ol)]enkephalin) was explored. The striatal release of DA was measured by microdialysis in rats anesthetized with chloral hydrate. When infused in the striatum, through the microdialysis probe, DAGO increased the extracellular levels of DA. The previous injection in striatum of AF 64-A, a toxin for cholinergic neurons, or the concomitant infusion of the M₂-muscarinic antagonist methoctramine abolished the effect of DAGO on the DA release. It is concluded that stimulation of μ-opioid receptors, by inhibiting the acetylcholine release which stimulates tonically M₂-muscarinic receptors likely associated with dopaminergic nerve endings, indirectly increases the striatal DA release.     

Roles of the M4 acetylcholine receptor in the basal ganglia and the treatment of movement disorders

Acetylcholine (ACh) released from cholinergic interneurons acting through nicotinic and muscarinic acetylcholine receptors (mAChRs) in the striatum have been thought to be central for the potent cholinergic regulation of basal ganglia activity and motor behaviors. ACh activation of mAChRs has multiple actions to oppose dopamine (DA) release, signaling, and related motor behaviors and has led to the idea that a delicate balance of DA and mAChR signaling in the striatum is critical for maintaining normal motor function. Consistent with this, mAChR antagonists have efficacy in reducing motor symptoms in diseases where DA release or signaling is diminished, such as in Parkinson's disease and dystonia, but are limited in their utility because of severe adverse effects. Recent breakthroughs in understanding both the anatomical sites of action of ACh and the mAChR subtypes involved in regulating basal ganglia function reveal that the M₄ subtype plays a central role in regulating DA signaling and release in the basal ganglia. These findings have raised the possibility that sources of ACh outside of the striatum can regulate motor activity and that M₄ activity is a potent regulator of motor dysfunction. We discuss how M₄ activity regulates DA release and signaling, the potential sources of ACh that can regulate M₄ activity, and the implications of targeting M₄ activity for the treatment of the motor symptoms in movement disorders. © 2019 International Parkinson and Movement Disorder Society     

Cholinergic control of striatal neurons to modulate L‐dopa‐induced dyskinesias

L‐dopa induced dyskinesias (LIDs) are a disabling motor complication of L‐dopa therapy for Parkinson's disease (PD) management. Treatment options remain limited and the underlying network mechanisms remain unclear due to a complex pathophysiology. What is well‐known, however, is that aberrant striatal signaling plays a key role in LIDs development. Here, we discuss the specific contribution of striatal cholinergic interneurons (ChIs) and GABAergic medium spiny projection neurons (MSNs) with a particular focus on how cholinergic signaling may integrate multiple striatal systems to modulate LIDs expression. Enhanced ChI transmission, altered MSN activity and the associated abnormal downstream signaling responses that arise with nigrostriatal damage are well known to contribute to LIDs development. In fact, enhancing M4 muscarinic receptor activity, a receptor favorably expressed on D1 dopamine receptor‐expressing MSNs dampens their activity to attenuate LIDs. Likewise, ChI activation via thalamostriatal neurons is shown to interrupt cortical signaling to enhance D2 dopamine receptor‐expressing MSN activity via M1 muscarinic receptors, which may interrupt ongoing motor activity. Notably, numerous preclinical studies also show that reducing nicotinic cholinergic receptor activity decreases LIDs. Taken together, these studies indicate the importance of cholinergic control of striatal neuronal activity and point to muscarinic and nicotinic receptors as significant pharmacological targets for alleviating LIDs in PD patients.     

Lateralization and gender differences in the dopaminergic response to unpredictable reward in the human ventral striatum

Electrophysiological studies have shown that mesostriatal dopamine (DA) neurons increase activity in response to unpredicted rewards. With respect to other functions of the mesostriatal dopaminergic system, dopamine’s actions show prominent laterality effects. Whether changes in DA transmission elicited by rewards also are lateralized, however, has not been investigated. Using [¹¹C]raclopride‐PET to assess the striatal DA response to unpredictable monetary rewards, we hypothesized that such rewards would induce an asymmetric reduction in [¹¹C]raclopride binding in the ventral striatum, reflecting lateralization of endogenous dopamine release. In 24 healthy volunteers, differences in the regional D_2/3 receptor binding potential (ΔBP) between an unpredictable reward condition and a sensorimotor control condition were measured using the bolus‐plus‐constant‐infusion [¹¹C]raclopride method. During the reward condition subjects randomly received monetary awards while performing a ‘slot‐machine’ task. The ΔBP between conditions was assessed in striatal regions‐of‐interest and compared between left and right sides. We found a significant condition × lateralization interaction in the ventral striatum. A significant reduction in binding potential (BP_ND) in the reward condition vs. the control condition was found only in the right ventral striatum, and the ΔBP was greater in the right than the left ventral striatum. Unexpectedly, these laterality effects appeared to be partly accounted for by gender differences, as our data showed a significant bilateral BP_ND reduction in women while in men the reduction reached significance only in the right ventral striatum. These data suggest that DA release in response to unpredictable reward is lateralized in the human ventral striatum, particularly in males.     

Afferent influences on striatal development in organotypic cocultures

Organotypic cocultures of striatum, cortex, and ventral mesencephalon were used to study the anatomical and physiological development of striatal neurons in the presence or absence of cortical and nigral (SN/VTA) inputs. Striatum and cortex were dissected from prenatal (E18-E22) or early postnatal (P0-P2) rats, and SN/VTA was dissected from E14-15 fetuses; pieces were maintained up to 3 weeks in static slice culture. Triple cocultures containing SN/VTA exhibited rapid and robust dopamine (DA) innervation of the striatum in a patchy pattern, and homogeneous distribution within the cortical piece, regardless of the orientations of the three pieces. DA fibers within the striatal piece overlapped striatal patch neurons, marked by DARPP-32 immunoreactivity, in striatal cultures prepared from all age rats, but development most analogous to that seen in vivo was observed with the use of late prenatal (E20-E22) striatum. The patch/matrix organization was maintained in cultures prepared from late prenatal striatum in the presence of cortical and nigrostriatal DA afferents. In addition, a more complete transition to a patchy organization was observed in E18/19 striatal cultures in the presence of cortical and DA innervation. Electrophysiological recording demonstrated the presence of both spontaneous and cortically evoked activity in striatal medium spiny neurons; this activity was greatly influenced by the presence of DA innervation. These findings demonstrate the importance of afferent innervation in the maturation of striatal neurons in organotypic cultures.     

Estrous cycle-dependent variation in amphetamine-induced behaviors and striatal dopamine release assessed with microdialysis

Estrous cycle-dependent variation in amphetamine (AMPH)-stimulated behaviors and striatal dopamine (DA) release were determined for freely moving rats undergoing intracerebral microdialysis. There was greater AMPH-stimulated striatal DA release in the striatum of rats in estrus, during the period from 20 min to 100 min post-AMPH, compared with the response of rats in diestrus (P less than 0.05). Animals in estrus also showed less general activity and greater intensity of stereotyped behaviors than did animals in diestrus (P less than 0.05). Independent experiments examining estrous cycle-dependent differences in AMPH-stimulated striatal DA release in vitro also found that AMPH-stimulated striatal DA release was greater on estrus than on diestrus (P less than 0.05). Thus, striatal DA release and behaviors induced by AMPH are modulated by ovarian hormones. The heightened responsiveness to AMPH during estrus suggests that estrogen and/or progesterone potentiate the striatal DA response to AMPH.     

DRD2 Genotype-Based Variation of Default Mode Network Activity and of Its Relationship With Striatal DAT Binding

The default mode network (DMN) comprises a set of brain regions with “increased” activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([₁₂₃I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling.     

Localization of dopamine D2 receptors on cholinergic interneurons of the dorsal striatum and nucleus accumbens of the rat

Striatal cholinergic interneurons located in the dorsal striatum and nucleus accumbens are amenable to influences of the dopaminergic mesolimbic pathway, which is a pathway involved in reward and reinforcement and targeted by several drugs of abuse. Dopamine and acetylcholine neurotransmission and their interactions are essential to striatal function, and disruptions to these systems lead to a variety of clinical disorders. Dopamine regulates acetylcholine release through dopamine receptors that are localized directly on striatal cholinergic interneurons. The dopamine D2 receptor, which attenuates acetylcholine release, has been implicated in drug relapse and is targeted by therapeutic drugs that are used to treat a variety of neurological disorders including Tourette Syndrome, Parkinson's disease and schizophrenia. The present study provides the first direct evidence for the localization of dopamine D2 receptors on striatal cholinergic interneurons of the rat brain using dual labeling immunocytochemistry procedures. Using light microscopy, dopamine D2 receptors were localized on the cell somata and dendritic and axonal processes of striatal cholinergic interneurons in the dorsal striatum and nucleus accumbens of the rat brain. These findings provide a foundation for understanding the specific roles that cholinergic neuronal network systems and interacting dopaminergic signaling pathways play in striatal function and in a variety of clinical disorders including drug abuse and addiction.     

Species-specific patterns of glycoprotein expression in the developing rodent caudoputamen: Association of 5′-nucleotidase activity with dopamine islands and striosomes in rat,but with extrastriosomal matrix in mouse

The glycoprotein 5′-nucleotidase is a cell surface phosphatase and represents a new marker for striosomes in the adult rat caudoputamen. We report here on its developmental expression in the rat and mouse striatum, and show an unexpected converse 5′-nucleotidase chemoarchitecture of the caudoputamen in these closely related species. In the rat, 5′-nucleotidase activity was first visible as neuropil staining in tyrosine hydroxylase-positive dopamine islands of the midstriatum on postnatal day 1, and by the end of the first postnatal week, 5′-nucleotidase-positive dopamine islands also appeared rostrally. This compartmental pattern persisted thereafter, so that in adult animals, in all but the caudal caudoputamen, zones of enhanced 5′-nucleotidase staining were restricted to calbindin-D_28k-poor striosomes. Weak 5′-nucleotidase activity also emerged in the matrix. In striking contrast, in the mouse striatum, enhanced 5′-nucleotidase activity was preferentially associated with extrastriosomal tissue. Enzymatic reaction first appeared on embryonic day 18, and developed over the first postnatal week into a mosaic pattern in which the matrix was stained but the dopamine islands were unstained. The matrix staining itself was heterogeneous. After the second postnatal week, most of the caudoputamen was stained, and in adult mice only rostral striosomes expressed low 5′-nucleotidase activity. We conclude that in rats, 5′-nucleotidase represents one of the few substances that maintains a preferential dopamine island/striosome distribution during striatal development. In mice, 5′-nucleotidase activity is expressed preferentially in the matrix during development, and its compartmental pattern is gradually lost with maturation, except very rostrally. These findings do not suggest an instructive role of the enzyme in striatal compartment formation in either species, but do suggest the possibility that 5′-nucleotidase contributes to the differentiation of striatal compartments during development. © 1993 Wiley-Liss, Inc.     

Methamphetamine-Induced Neurotoxicity Disrupts Pharmacologically Evoked Dopamine Transients in the Dorsomedial and Dorsolateral Striatum

Phasic dopamine (DA) signaling, during which burst firing by DA neurons generates short-lived elevations in extracellular DA in terminal fields called DA transients, is implicated in reinforcement learning. Disrupted phasic DA signaling is proposed to link DA depletions and cognitive-behavioral impairment in methamphetamine (METH)-induced neurotoxicity. Here, we further investigated this disruption by assessing effects of METH pretreatment on DA transients elicited by a drug cocktail of raclopride, a D2 DA receptor antagonist, and nomifensine, an inhibitor of the dopamine transporter (DAT). One advantage of this approach is that pharmacological activation provides a large, high-quality data set of transients elicited by endogenous burst firing of DA neurons for analysis of regional differences and neurotoxicity. These pharmacologically evoked DA transients were measured in the dorsomedial (DM) and dorsolateral (DL) striatum of urethane-anesthetized rats by fast-scan cyclic voltammetry. Electrically evoked DA levels were also recorded to quantify DA release and uptake, and DAT binding was determined by means of autoradiography to index DA denervation. Pharmacologically evoked DA transients in intact animals exhibited a greater amplitude and frequency and shorter duration in the DM compared to the DL striatum, despite similar pre- and post-drug assessments of DA release and uptake in both sub-regions as determined from the electrically evoked DA signals. METH pretreatment reduced transient activity. The most prominent effect of METH pretreatment on transients across striatal sub-region was decreased amplitude, which mirrored decreased DAT binding and was accompanied by decreased DA release. Overall, these results identify marked intrastriatal differences in the activity of DA transients that appear independent of presynaptic mechanisms for DA release and uptake and further support disrupted phasic DA signaling mediated by decreased DA release in rats with METH-induced neurotoxicity.     

Adolescent Maturation of Cortical Dopamine

Dopamine is a critical modulator of prefrontal cortical function, and it is known to be dysfunctional in schizophrenia. Current hypotheses on schizophrenia highlight developmental aspects and genetic predisposition for the disease; yet, symptom onset typically occurs during adolescence. Several aspects of prefrontal cortical circuits and their modulation by dopamine mature postnatally, as late as during adolescence. Here we review studies assessing the postnatal trajectory of dopamine control of GABA interneurons, a neuronal population that has been long suspected to be critical for schizophrenia pathophysiology. Dopamine modulation of fast-spiking interneurons changes dramatically during adolescence (postnatal day 45–50 in rats) with D2 agonists switching from being mildly inhibitory in prepubertal rats to strongly excitatory in young adult rats. In vivo recordings in adult rats reveal that deep-layer pyramidal neurons respond to endogenous DA release with suppression of firing while interneurons are activated. In adult rats with a neonatal ventral hippocampal lesion (NVHL), an extensively studied developmental model of schizophrenia, the maturation in the D2 modulation of interneuron physiology fails to occur, rendering a disinhibited prefrontal cortex. Abnormal interneuron maturation may therefore impair cognitive function in the adult animal.     

Postnatal rearing conditions influence ontogeny of adult dopamine transporter (DAT) immunoreactivity of the striatum in gerbils

Summary. In the present study, the influence of postnatal rearing conditions on the structural maturation of the striatum of adult male gerbils (Meriones unguiculatus) was investigated. For that purpose, animals were bred and reared either grouped in an object-filled environment (EC) or isolated under restricted environmental conditions (IC). At the age of postnatal day 90, dopamine fibers were stained immunocytochemically using an antibody against the dopamine transporter (DAT). Innervation density was determined along the entire rostrocaudal axis of the ventromedial and dorsolateral part of the striatum. As a result, restricted rearing produced a significant restraint of the maturation of striatal dopamine (DA) innervation, leading to adult fiber densities which were approximately 9% below those in semi-naturally reared gerbils. Results are discussed with structural and functional alterations observed in the brain of IC animals. Received May 9, 2001; accepted June 3, 2002 Published online July 26, 2002     

Development of striatal compartmentalization following pre- or postnatal dopamine depletion.

Nigrostriatal dopamine (DA) projections terminate in distinct patches during the late prenatal and early postnatal period in the rat. During the first postnatal week, patches of DA fibers overlap with clusters of striatal neurons that share several identified characteristics. The early segregation of striatal cell types into either these patches or the surrounding matrix becomes a permanent organizational feature of the striatum. In order to determine whether the heterogeneous distribution of DA influences the formation of cellular patches, the developmental organization of chemically identifiable cell types was examined in normal rats and in rats DA depleted as infants (0 or 3 d) or in utero (embryonic days 17-18). During the first postnatal week, corresponding patches of DA afferents and substance P (SP)-immunoreactive neurons existed in the striatum of normal animals, and AChE-positive zones overlapped these patches in the lateral striatum. Injection of 6-hydroxydopamine into the lateral ventricles of fetal or infant rats produced a dramatic loss of striatal DA terminals. Neither the patchy distribution of SP-immunoreactive neurons nor the distinctive pattern of AChE staining present during the first 2 postnatal weeks was disrupted. During the third postnatal week, cells immunoreactive for leu-enkephalin or calbindin-D28k were confined to the matrix compartment, and this compartmentalization was also not noticeably changed by pre- or postnatal DA depletion. In adult animals, overlapping patches of leu-enkephalin- and SP-immunoreactive fibers were observed, regardless of whether any DA terminals remained. Thus, the basic organization of the striatal patch and matrix compartments develops normally in the absence of DA innervation through much of the formative period. Although these observations do not completely dismiss the possibility that the first DA afferents to appear in the striatal primordia influence contracted striatal cells to develop the patch phenotype, they suggest that the patchy distribution of DA afferents may be secondary to the early clustering of striatal neurons forming the patch compartment.     

Cocaine cue–induced dopamine release in the human prefrontal cortex

BackgroundAccumulating evidence indicates that drug-related cues can induce dopamine (DA) release in the striatum of substance abusers. Whether these same cues provoke DA release in the human prefrontal cortex remains unknown.MethodsWe used high-resolution positron emission tomography with [¹⁸F]fallypride to measure cortical and striatal DA D2/3 receptor availability in the presence versus absence of drug-related cues in volunteers with current cocaine dependence.ResultsTwelve individuals participated in our study. Among participants reporting a craving response (9 of 12), exposure to the cocaine cues significantly decreased [¹⁸F]fallypride binding potential (BP_ND) values in the medial orbitofrontal cortex and striatum. In all 12 participants, individual differences in the magnitude of craving correlated with BP_ND changes in the medial orbitofrontal cortex, dorsolateral prefrontal cortex, anterior cingulate, and striatum. Consistent with the presence of autoreceptors on mesostriatal but not mesocortical DA cell bodies, midbrain BP_ND values were significantly correlated with changes in BP_ND within the striatum but not the cortex. The lower the midbrain D2 receptor levels, the greater the striatal change in BP_ND and self-reported craving.LimitationsLimitations of this study include its modest sample size, with only 2 female participants. Newer tracers might have greater sensitivity to cortical DA release.ConclusionIn people with cocaine use disorders, the presentation of drug-related cues induces DA release within cortical and striatal regions. Both effects are associated with craving, but only the latter is regulated by midbrain autoreceptors. Together, the results suggest that cortical and subcortical DA responses might both influence drug-focused incentive motivational states, but with separate regulatory mechanisms.     

Biochemical and behavioral effects of serotonin neurotoxins on the nigrostriatal dopamine system: Comparison of injection sites

Unilateral injections of the serotonin neurotoxin, 5,7-dihydroxytryptamine (DHT), at various points along the 5-HT pathway to the forebrain produce a turning syndrome associated with alterations of dopamine synthesis in the ipsilateral striatum. Unilateral injections of DHT into the SN produced an ipsilateral increase in striatal dopamine (DA) turnover and contralateral rotation in response to amphetamine or apomorphine. Injection of DHT into the MFB produced an ipsilateral decrease in striatal DA turnover and tyrosine hydroxylase (TOH) activity, and ipsilateral rotation in response to amphetamine or apomorphine. After the injection of DHT into the SN or MFB, there was a significant correlation between the rates of drug-induced rotation, the decrease in cortical 5-HT turnover, and the change in striatal DA turnover, suggesting that the unilateral change in DA turnover (and, presumably, the increased stimulation of DA receptors) is causally linked to turning. Injection of DHT into the zones of the striatum and GP richest in 5-HT terminals produced the same responses as the MFB-lesioned rats: ipsilateral rotation and a decrease in striatal TOH activity. Injection of DHT into the area of the striatum richest in DA terminals failed to produce rotation or a significant change in TOH activity. We suggest that 5-HT neurons from the raphe nuclei exert a tonic inhibition on the nigrostriatal pathway at the level of the SN through direct synapses on DA neurons, whereas their neostriatal terminals have an indirect effect on DA terminals, perhaps via interaction with cholinergic and GABA-ergic neurons.     

The role of opioid receptor agonists and antagonists in the treatment of Parkinson’s disease

A possible mechanism underlying the role of opioids in the treatment of Parkinson’s disease and L-dopa-induced dyskinesias is suggested. This role is based on the reorganization of neuronal firing in the motor cortico-basal ganglia-thalamocortical loop as a consequence of opioid-mediated LTD induction in the spiny cells of the input basal ganglia nucleus, striatum. Analysis of existing data allowed us to propose that the striatonigral cells in the striosomes and matrix that release dynorphin mainly express μ and κ opioid receptors, respectively, whereas striatopallidal cells that release enkephalin express δ opioid receptors. The proposed mechanism implies that in addition to agonists of dopamine receptors and antagonists of muscarinic receptors, μ and δ receptor agonists and/or κ receptor antagonists might alleviate the symptoms of Parkinson’s disease and allow recovery of locomotor activity. Recurrent collaterals of striatal spiny cells innervating their dendrites and bodies, as well as those of striatal cholinergic interneurons, form negative feedback loops that allow opioid peptides and substance P to regulate and stabilize striatal output pathways. Therefore, in the absence of activation of the D2 and D1 receptors on striatal spiny cells, increased enkephalin concentration and decreased dynorphin and substance P level promote the suppression of acetylcholine release (due to modulation of cholinergic interneuron firing through κ opioid and NK receptors), thus reducing the impact of a dopamine deficit on basal ganglia functioning. Opposing changes in opioid concentrations, due to L-dopa treatment and reorganization of activity in the same neuronal loops, may reduce dyskinesias. The text was submitted by the author in English.     

Bilateral effects of unilateral GDNF administration on dopamine- and GABA-regulating proteins in the rat nigrostriatal system

Dopamine (DA) affects GABA neuronal function in the striatum and together these neurotransmitters play a large role in locomotor function. We recently reported that unilateral striatal administration of GDNF, a growth factor that has neurotrophic effects on DA neurons and enhances DA release, bilaterally increased striatal neuron activity related to locomotion in aged rats. We hypothesized that the GDNF enhancement of DA function and resulting bilateral enhancement of striatal neuronal activity was due to prolonged bilateral changes in DA- and GABA-regulating proteins. Therefore in these studies we assessed dopamine- and GABA-regulating proteins in the striatum and substantia nigra (SN) of 24 month old Fischer 344 rats, 30 days after a single unilateral striatal delivery of GDNF. The nigrostriatal proteins investigated were the DA transporter (DAT), tyrosine hydroxylase (TH), and TH phosphorylation and were examined by blot-immunolabeling. The striatal GABA neuron-related proteins were examined by assay of the DA D₁ receptor, DARPP-32, DARPP-32 Thr³⁴ phosphorylation, and glutamic acid decarboxylase (GAD). Bilateral effects of GDNF on TH and DAT occurred only in the SN, as 30 μg GDNF increased ser19 phosphorylation, and 100 μg GDNF decreased DAT and TH protein levels. GDNF also produced bilateral changes in GAD protein in the striatum. A decrease in DARPP-32 occurred in the ipsilateral striatum, while increased D₁ receptor and DARPP-32 phosphorylation occurred in the contralateral striatum. The 30 μg GDNF infusion into the lateral striatum was confined to the ipsilateral striatum and substantia nigra. Thus, long-lasting bilateral effects of GDNF on proteins regulating DA and GABA neuronal function likely alter physiological properties in neurons, some with bilateral projections, associated with locomotion. Enhanced nigrostriatal excitability and DA release by GDNF may trigger these bilateral effects.     

Early postnatal hypoxia induces long-term changes in the dopaminergic system in rats

Summary A rat model of a mild, chronic, early postnatal hypoxia, characterized by long-term consequences in the behavioural outcome, was used to study longterm consequences in the dopaminergic system. Exposure of newborn rats to an early postnatal hypoxia (hypobaric hypoxia, 11 kPa pO₂ in the inspiratory air, 2nd–10th day of life, 10 hours daily) brings about the following lasting neurochemical changes: an increased stimulated dopamine release rate from striatum slices by about 30%, an increased low affinity, high capacity dopamine uptake into striatum synaptosomes by about 100%. The critical period to produce an increased release rate of dopamine was estimated as day 2–6 postnatally. There are no long-term changes in the concentration of dopamine and its metabolites and in the tyrosine hydroxylase activity in consequences of this early postnatal hypoxia. Treatment of newborn animals with L-DOPA (10–50 g/g body weight) previous to hypoxia normalizes the DA release rate.     

Classification of H2O2 as a Neuromodulator that Regulates Striatal Dopamine Release on a Subsecond Time Scale

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