谷氨酸和MK-801对正常和帕金森模型大鼠纹状体内多巴胺代谢的影响

采用微透析和高效液相色谱一电化学(HPLC-ECD)技术研究了谷氨酸和MK-801对正常和帕金森模型人鼠纹状体内多巴胺代谢的影响。用微透析技术在大鼠纹状体内分别定位给以左旋多巴、L-谷氨酸和／或MK-801,同时收集透析液,用HPLC-ECD方法测定透析液中多巴胺代谢产物的浓度。微透析和HPL-ECD分析结果表明：纹状体内定位给以序旋多巴,正常大鼠和帕金森模型大鼠纹状体内多巴胺代谢产物的浓度均升高;纹状体内定位给以L-谷氨酸,可使正常大鼠纹状体内多巴胺代谢产物的浓度降低,但对帕金森火鼠模型纹状体内多巴胺代谢产物浓度的降低不显著;纹状体内定位给以MK-801,正常人鼠纹状体内多巴胺代谢产物的浓度升高：但对帕金森人鼠模型纹状体内多巴胺代谢产物浓度的升高不显著：纹状体内同时定位给以MK-80l和L-谷氨酸,可以有效防止L-谷氨酸所致正常人鼠纹状体内多巴胺代谢产物浓度的降低。结果提示,谷氦酸可以通过NMDA受体调节多巴胺的代谢。尽管非竞争性NMDA拈抗剂MK-801可以有效防止L-谷氨酸所敛正常人鼠纹状体内多巴胺代谢产物浓度的降低,但却不能有效地改善帕金森大鼠模型纹状体内多巴胺的代谢水平。因此存正常及帕金森病情况下,谷氮酸一多巴胺相互作用机制和MK-801改善帕金森病的机制还有待进一步研究。     

Presynaptic Modulation by Somatostatin in the Neostriatum

Medium spiny projection neurons (MSNs) are the main neuronal population in the neostriatum. MSNs are inhibitory and GABAergic. MSNs connect with other MSNs via local axon collaterals that produce lateral inhibition, which is thought to select cell assemblies for motor action. MSNs also receive inhibitory inputs from GABAergic local interneurons. This work shows, through the use of the paired pulse protocol, that somatostatin (SST) acts presynaptically to regulate GABA release from the terminals interconnecting MSNs. This SST action is reversible and not mediated through the release of dopamine. It is blocked by the SST receptor (SSTR) antagonist ciclosomatostatin (cicloSST). In contrast, SST does not regulate inhibition coming from interneurons. Because, SST is released by a class of local interneuron, it is concluded that this neuron helps to regulate the selection of motor acts. Special issue article in honor of Dr. Ricardo Tapia.     

Role of excitatory amino acids in the regulation of dopamine synthesis and release in the neostriatum

Summary We have explored the role of excitatory amino acids in the increased dopamine (DA) release that occurs in the neostriatum during stress-induced behavioral activation. Studies were performed in awake, freely moving rats, usingin vivo microdialysis. Extracellular DA was used as a measure of DA release; extracellular 3,4-dihydroxyphenylalanine (DOPA) after inhibition of DOPA decarboxylase provided a measure of apparent DA synthesis. Mild stress increased the synthesis and release of DA in striatum. DA synthesis and release also were enhanced by the intra-striatal infusion of N-methyl-D-aspartate (NMDA), an agonist at NMDA receptors, and kainic acid, an agonist at the DL-a-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA)/kainate site. Stress-induced increase in DAsynthesis was attenuated by co-infusion of 2-amino-5-phosphonovalerate (APV) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), antagonists of NMDA and AMPA/kainate receptors, respectively. In contrast, intrastriatal APV, CNQX, or kynurenic acid (a non-selective ionotropic glutamate receptor antagonist) did not block the stress-induced increase in DArelease. Stress-induced increase in DA release was, however, blocked by administration of tetrodotoxin along the nigrostriatal DA projection. It also was attenuated when APV was infused into substantia nigra. Thus, glutamate may act via ionotropic receptors within striatum to regulate DA synthesis, whereas glutamate may influence DA release via an action on receptors in substantia nigra. However, our method for monitoring DA synthesis lowers extracellular DA and this may permit the appearance of an intra-striatal glutamatergic influence by reducing a local inhibitory influence of DA. If so, under conditions of low extracellular DA glutamate may influence DA release, as well as DA synthesis, by an intrastriatal action. Such conditions might occur during prolonged severe stress and/or DA neuron degeneration. These results may have implications for the impact of glutamate antagonists on the ability of patients with Parkinson's disease to tolerate stress.     

Binding order of substrates to the sodium and potassium ion coupled L-glutamic acid transporter from rat brain

Efflux of L-glutamic acid from synaptic plasma membrane vesicles requires external potassium. This requirement is saturated by concentrations of about 15 mequiv/L potassium. In the absence of potassium, L-glutamic acid can be released from the vesicles in the presence of external L-glutamic acid. This stimulation does not require external sodium but is dependent on the external concentration of L-glutamic acid. Half-maximal effects are obtained by concentrations of about 1 microM which are very similar to the apparent Km for L-glutamic acid influx. Efflux of labeled glutamate driven by external sodium plus glutamate requires internal sodium. These findings suggest that the transporter displays an asymmetric behavior toward sodium. This ion dissociates much more slowly than L-glutamic acid on the external surface of the membrane but not on the internal surface. Furthermore, it appears that the transporter translocates potassium in a step distinct from the L-glutamic acid translocation step. The simplest explanation is that upon translocation of sodium and L-glutamic acid and their release to the inside, potassium binds to the transporter, enabling it to return to the outside to allow initiation of a new transport cycle.     

Amino Acid Levels and γ-Aminobutyric AcidA Receptors in Rat Neostriatum, Cortex, and Thalamus After Neonatal 6-Hydroxydopamine Lesion

Abstract: The amino acid γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in brain, and GABAergic neurons have been proposed to play a major role in basal ganglia physiology. In the neostriatum (caudate putamen), medium-sized aspiny interneurons, as well as neostriatal output neurons that project to several brain regions, use GABA as their neurotransmitter. Dopamine fibers arising from the substantia nigra represent a major input to the neostriatum where, besides their classic neurotransmitter role, they are seemingly involved in the regulation of amino acid neurotransmitter release. To further characterize the nature of some of the amino acid/dopamine interactions, selective dopaminergic deafferentations were produced in neonatal rats (3 days postnatal) by intraventricular administration of the neurotoxin 6-hydroxydopamine (6-OHDA); the noradrenergic neurons were protected by prior administration of desmethylimipramine. After a 3-month survival, levels of catecholamines, indoleamines, and amino acids were determined in cingulate cortex, thalamus, and neostriatum. In addition, GABA_A receptors were measured in membrane preparations from these three regions, using the specific agonist [³H]muscimol. In the 6-hydroxydopamine-lesioned rats, levels of dopamine and its metabolites homovanillic acid, 3,4-dihydroxyphenylacetic acid, and 3-methoxytyramine were decreased, as expected, in cortex and neostriatum, but remained unmodified in thalamus. In all three regions, serotonin content was increased; its metabolite, 5-hydroxyindole-3-acetic acid, was also elevated, but only in cortex and neostriatum. The levels of GABA were increased in neostriatum and thalamus, but remained unmodified in cortex. Glycine was increased in all three regions examined. There were also increases of phosphatylethanolamine and serine in thalamus, and of aspartic acid and alanine in neostriatum. The density of GABA_A binding sites was increased in neostriatum, but remained unchanged in cortex and thalamus. The changes in amino acid levels and [³H]muscimol binding sites induced by a neonatal 6-hydroxydopamine treatment differ from those found after similar lesions in adult animals, possibly because of the plastic and synaptic rearrangements that can still occur during early postnatal development. The present results also demonstrate that adaptations occur in response to a dopaminergic deafferentation at an early age and that these exhibit a regional specificity.     

Endogenous GABA Modulates Histamine Release from the Anterior Hypothalamus of the Rat

Abstract: Using a microdialysis method, we investigated the effects of the nipecotic acid-induced increase in content of endogenous GABA on in vivo release of histamine from the anterior hypothalamus (AHy) of urethane-anesthetized rats. Nipecotic acid (0.5 m M ), an inhibitor of GABA uptake, decreased histamine release to ∼60% of the basal level. This effect was partially antagonized by picrotoxin (0.1 m M ), an antagonist of GABA_A receptors, or phaclofen (0.1 m M ), an antagonist of GABA_B receptors. These results suggest that histamine release is modulated by endogenous GABA through both GABA_A and GABA_B receptors. When the tuberomammillary nucleus, where the cell bodies of the histaminergic neurons are localized, was stimulated electrically, the evoked release of histamine from the nerve terminals in the AHy was significantly enhanced by phaclofen, suggesting that GABA_B receptors may be located on the histaminergic nerve terminals and modulate histamine release presynaptically. On the other hand, picrotoxin caused an increase in histamine release to ∼170% of the basal level, and this increase was diminished by coinfusion with d (−)-2-amino-5-phosphonopentanoic acid (0.1 m M ), an antagonist of NMDA receptors. Previously, we demonstrated tonic control of histamine release by glutamate mediated through NMDA receptors located on the histaminergic terminals in the AHy. These results suggest the possible localization of GABA_A receptors on glutamatergic nerve terminals and that the receptors may regulate the basal release of histamine indirectly.     

Effects of L-glutamic acid on acid secretion and mucosal blood flow in the rat stomach

The effect of intravenous administration of L-glutamic acid (L-Glu) on gastric acid secretion and gastric mucosal blood flow (GMBF) in anesthetized rats were investigated. Infusion with synthetic L-Glu alone had no effect on spontaneous acid secretion. However, L-Glu reduced histamine- (2 mg/kg/hr) or oxotremorine- (1 microg/kg/hr) stimulated acid secretion, whereas L-Glu had no effect on acid secretion induced by pentagastrin (8 microg/kg/hr). Furthermore, this inhibitory effect of L-Glu on histamine- or oxotremorine-stimulated acid secretion was blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX), a non-NMDA receptor antagonist. The effect of L-Glu on gastric mucosal microcirculation in the anesthetized rats was evaluated by using Laser Doppler Flowmetry (LDF). The results showed that L-Glu did not significantly reduce both mucosal and serosal blood flow in stomach. No significant modulatory effect on histamine- or oxotremorine-stimulated increase in GMBF was noted after infusion with L-Glu. It is concluded that L-glutamic acid is capable of the modulating of gastric acid secretion via ionotropic non-NMDA receptors, but do not affect on GMBF. However, L-glutamic acid showed no effect on acid secretion by itself.     

Effects of some putative amino acid neurotransmitters on the stimulated TSH secretion in male rats

The importance of several amino acids (glycine, L-glutamic acid, L-serine, taurine and beta-alanine) in the regulation of the stimulated secretion of TSH was studied in male rats using both peripheral and central administration of the amino acids. Glycine (10-200 mg/kg i.p.), L-glutamic acid (10-500 mg/kg i.p.) and L-serine (500 mg/kg i.p.) decreased significantly the cold-induced TSH secretion whereas beta-alanine (1-500 mg/kg i.p.) and taurine (10-100 mg/kg i.p.) were not effective. The effect of L-glutamic acid (100 mg i.p.) was partially antagonized by bicuculline (1 mg/kg i.p.) but not by picrotoxin (1 or 2 mg/kg i.p.). Only glycine (50 and 100 mg/kg i.p.) inhibited the TRH-stimulated TSH secretion. When the intracerebroventricular route was used, L-serine (50 micrograms/rat) decreased the TSH could response whereas glycine and L-glutamic acid (1-50 micrograms/rat) had no clear effect. We conclude that glycine, glutamate and serine inhibit the cold-induced TSH secretion in the male rat. The action of serine and glycine is possibly mediated through the periventricular hypothalamus and the anterior pituitary, respectively. The inhibition caused by glutamate seems to be partially mediated through the bicuculline-sensitive GABA receptors in the hypothalamus. Taurine and beta-alanine play no role in the control of rat TSH secretion.     

Amphetamine Promotes Neostriatal Ascorbate Release via a Nigro-Thalamo-Cortico-Neostriatal Loop

Abstract: In the neostriatum, amphetamine and other dopamine agonists elevate the extracellular level of ascorbate, which is known to modulate neostriatal function. Although both D₁ and D₂ receptors have been linked to neostriatal ascorbate release, ample evidence suggests it is controlled by areas outside the neostriatum. The present series of experiments used selective lesions and intracerebral drug infusions to probe the involvement of the ventromedial thalamus and substantia nigra pars reticulata. Our results implicate both of these sites in amphetamine-induced increases in the release of neostriatal ascorbate. Thus, whereas unilateral electrolytic lesions of the substantia nigra pars reticulata completely abolished the ability of systemic amphetamine (2.5 mg/kg) to increase extracellular ascorbate in ipsilateral neostriatum, intranigral infusions of this drug (10 and 30 µg/µl) elevated neostriatal ascorbate release. This infusion effect, moreover, was blocked by electrolytic lesions of the ipsilateral ventromedial thalamus, which receives input from the substantia nigra pars reticulata and projects to the cerebral cortex. These results, combined with previous evidence implicating cortical projections to neostriatum as the source of extracellular ascorbate, suggest that neostriatal ascorbate release is regulated, at least in part, by a nigro-thalamo-cortico-neostriatal pathway.     

Presynaptic regulation of dopamine release by beta-phenylethylamine

Experiments with local perfusion of the rat neostriatum and subsequent chromatography of the perfusate have shown that addition of beta-phenylethylamine (beta-PEA) to the perfusion medium in a concentration of 10(-3) M enhanced spontaneous and inhibited the K+-induced release of 3H-dopamine preliminarily applied to the neostriatum. The stimulating effect of beta-PEA was Ca2+-dependent and was potentiated in sodium-free media. The inhibitory effect of beta-PEA on the K+-induced release of 3H-DA was abolished by haloperidol, a blocker of dopamine receptors. This fact allows one to suggest that this effect of beta-PEA is mediated by presynaptic dopamine autoreceptors. The data obtained indicate that beta-PEA can modulate the dopaminergic synaptic transmission depending on functional activity of dopaminergic neurons.     

pH-dependent heterogeneity of acidic amino acid transport in rabbit jejunal brush border membrane vesicles.

Initial rates of Na(+)-dependent L-glutamic and D-aspartic acid uptake were determined at various substrate concentrations using a fast sampling, rapid filtration apparatus, and the resulting data were analyzed by nonlinear computer fitting to various transport models. At pH 6.0, L-glutamic acid transport was best accounted for by the presence of both high (Km = 61 microM) and low (Km = 7.0 mM) affinity pathways, whereas D-aspartic acid transport was restricted to a single high affinity route (Km = 80 microM). Excess D-aspartic acid and L-phenylalanine served to isolate L-glutamic acid flux through the remaining low and high affinity systems, respectively. Inhibition studies of other amino acids and analogs allowed us to identify the high affinity pathway as the X-AG system and the low affinity one as the intestinal NBB system. The pH dependences of the high and low affinity pathways of L-glutamic acid transport also allowed us to establish some relationship between the NBB and the more classical ASC system. Finally, these studies also revealed a heterotropic activation of the intestinal X-AG transport system by all neutral amino acids but glycine through an apparent activation of Vmax.     

Monoaminergic influences of the caudate nucleus on conditioned food-getting reactions in rats]

Influence of microinjections of monoamines and glutamic acid into the caudate nucleus head on conditioned food-procuring reaction was studied in experiments on rats. Dopamine, noradrenaline and glutamic acid prolong the latency of the reflex, while serotonin reduces it. However, all the drugs tested reduce the number of conditioned food-procuring movements. The effects of dopamine are achieved through neurone receptors of the caudate nucleus which are sensitive to haloperidol and chlorpromazine; effects of serotonin are mediated through the D-serotoninoreactive systems, and those of noradrenaline, through the alpha-adrenoreactive systems of the neostriatum neurones. The inhibitory effect of glutamic acid is not due to the action on the serotonino-, adreno-, or dopamine receptors of caudate units.     

Glutamate: A major neuroendocrine excitatory signal mediating steroid effects on gonadotropin secretion

The preovulatory gonadotropin surge is induced by progesterone in the cycling female rat or in the ovariectomized estrogen-treated female rat after adequate estrogen-priming activity is present. The source of progesterone under physiological conditions could be the ovary and/or the adrenal. Since the GnRH neuron does not possess estrogen and progesterone receptors, its function is modulated by other CNS neurotransmitters and neurosecretory products. Among these, excitatory amino acids (EAAs) have now been shown to play an important role in the regulation of pulsatile gonadotropin release, induction of puberty and preovulatory and steroid-induced gonadotropin surges. Glutamate, the major endogenous EAA exerts its action through ionotropic and metabotropic receptors. The ionotropic receptors consist of two major classes, the NMDA (N-methyl-D-aspartate) and non-NMDA: kainate and AMPA ( --amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. EAA receptors are found in hypothalamic areas involved with reproduction. While both NMDA and non-NMDA receptors are involved in the regulation of LH secretion, the NMDA receptors appear to be involved with the regulation of puberty and FSH secretion as well. Steroids increase the release rates of glutamate and aspartate in the preoptic area during the gonadotropin surge. Steroids may also regulate the hypothalamic AMPA receptors.     

Specific [3H]SCH23390 Binding to Dopamine D1 Receptors in Cerebral Cortex and Neostriatum: Evidence for Heterogeneities in Affinity States and Cortical Distribution

The tritiated antagonist SCH23390 was used to identify dopamine D1 receptors in the cerebral cortex and neostriatum. The kinetic properties of binding were investigated in parallel experiments with membrane preparations from both tissues. The densities of receptors (Bmax) and the dissociation constants (KD) were determined from saturation curves, and the specificity of binding verified in competition experiments using agonists and antagonists. The cortical D1 receptor displays the same pharmacological selectivity (including stereospecificity) and kinetic properties as the neostriatal D1 receptor. From both the dissociation kinetics by dilution and the competition curves, it could be established that there is an heterogeneity of binding probably due to high- and low-affinity states. Endogenous dopamine, 4-hydroxy-3-methoxyphenylacetic acid, 3,4-dihydroxyphenylacetic acid, and 3-methoxytyramine contents, as well as D1 receptor distribution, were measured for the neostriatum and four localized cortical areas: anterior cingulate, primary somatosensory, primary visual, and piriform-entorhinal. For the regions examined, the distribution of D1 receptors is heterogeneous, but correlates very well (r greater than 0.98) with the endogenous levels of dopamine and its major metabolites.     

细胞内贮存钙释放的机制

细胞内贮存钙的释放主要由１,４,５－三磷酸肌醇（ＩＰ３）受体系统和ｒｙａｎｏｄｉｎｅ受体系统调控。前通过ＩＰ３与其受体结合后,诱发细胞内钙释放;后通过复杂的机制调节环腺苷二磷酸核糖含量,由ｃＡＤＰＲ直接或间接作用于ｒｙａｎｏｄｉｎｅ受体,进而启动由Ｃａ＾２＋诱发的Ｃａ＾２＋释放机制。上述两系统之间相互作用,共同调节细胞内贮存钙的释放。     

Neuronal dependence of extracellular dopamine,acetylcholine, glutamate,aspartate and gamma-aminobutyric acid (GABA) measured simultaneously from rat neostriatum using in vivo microdialysis: reciprocal interactions

Summary The neuronal origin of extracellular levels of dopamine (DA), acetylcholine (ACh), glutamate (Glu), aspartate (Asp) and gamma-aminobutyric acid (GABA) simultaneously collected from the neostriatum of halothane anaesthetized rats with in vivo microdialysis was studied. The following criteria were applied (1) sensitivity to K⁺-depolarization; (2) sensitivity to inhibition of synaptic inactivation mechanisms; (3) sensitivity to extracellular Ca²⁺; (4) neuroanatomical regionality; sensitivity to selective lesions and (5) sensitivity to chemical stimulation of the characterized pathways.It was found that: (1) Extracellular DA levels found in perfusates collected from the neostriatum fulfills all the above criteria and therefore the changes in extracellular DA levels measured with microdialysis reflect actual release from functionally active nerve terminals, and so reflect ongoing synaptic transmission. (2) Changes in neostriatal ACh levels reflect neuronal activity, provided that a ACh-esterase inhibitor is present in the perfusion medium. (3) Extracellular Glu, Asp and GABA could be measured in different perfusion media in the rat neostriatum and probably reflect metabolic as well as synaptic release. However, (4) the majority of the extracellular GABA levels found in perfusates collected from the neostriatum may reflect neuronal release, since GABA levels were increased, in a Ca²⁺-dependent manner, by K⁺-depolarization, and could be selectively decreased by an intrinsic neostriatal lesion. (5) It was not possible to clearly distinguish between the neuronal and the metabolic pools of Glu and Asp, since neostriatal Glu and Asp levels were only slightly increased by K⁺-depolarization, and no changes were seen after decortication. A blocker of Glu re-uptake, DHKA, had to be included in the perfusion medium in order to monitor the effect of K⁺-depolarization on Glu and Asp levels. Under this condition, it was found (6) that neostriatal Glu and Asp levels were significantly increased by K⁺-depolarization, although only increases in the Glu levels were sensitive to Ca²⁺ in the perfusion medium, suggesting that Glu but not Asp is released from vesicular pools. (7) Evidence is provided that selective stimulations of nigral DA cell bodies may lead to changes in release patterns from DA terminals in the ipsilateral neostriatum, which are in turn followed by discrete changes in extracellular levels of GABA and Glu in the same region. Finally, some methodological considerations are presented to clarify the contribution of neuronal release to extracellular levels of amino acid neurotransmitters in the rat neostriatum.     

Stress-Induced Dopamine Release in the Neostriatum: Evaluation of the Role of Action Potentials in Nigrostriatal Dopamine Neurons or Local Initiation by Endogenous Excitatory Amino Acids

Abstract: It has been hypothesized that excitatory amino acids can initiate dopamine release in neostriatum. We examined whether the increase in extracellular dopamine in neostriatum produced by acute stress reflects presynaptic initiation of dopamine release by endogenous excitatory amino acids. Thirty minutes of intermittent tail-shock stress significantly elevated extracellular concentrations of dopamine, glutamate, aspartate, and γ-aminobutyric acid in neostriatum of freely moving rats as measured with in vivo microdialysis. Local infusion of the N -methyl- d -aspartate receptor antagonist 2-amino-5-phosphonovaler-ate or the non- N -methyl- d -aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione via the dialysis probe did not attenuate the stress-induced increase in extra cellular dopamine. In fact, the increase was prolonged in rats treated with specific excitatory amino acid receptor antagonists. Infusion of tetrodotoxin into medial forebrain bundle increased extra cellular glutamate and aspartate in neostriatum yet reduced basal dopamine in extra cellular fluid to below the limit of detection of the assay and eliminated the stress-induced increase in extra cellular dopamine. These findings fail to support the hypothesis that the stress-induced increase in extra cellular dopamine in neostriatum is initiated locally by excitatory amino acids. Rather, the effects of stress on extra cellular dopamine seem to be determined by impulse propagation in dopamine neurons.     

The molecular aspects of the functional heterogeneity of the GABA receptors

It is generally accepted that gamma-aminobutyric acid (GABA) is one of the main inhibitory transmitter in the mammalian brain. There are three types of GABA receptors in the vertebrata central nervous system: the GABAA, GABAB and GABAC receptors. The GABAA receptor is a GABA-gated Cl- channel and is the tetramer ore the pentamer made of some classes of subunit (alpha, beta, gamma, delta). GABAB receptors are not affiliated with Cl(-) ionophore. GABAB receptors appear to be coupled to Ca2+ and K+ channels of presynaptic membranes. It seems they regulate the release of neurotransmitters release. The structural and functional properties of GABA receptors are discussed.     

The Ontogeny of Apomorphine-Induced Alterations of Neostriatal Dopamine Release: Effects on Spontaneous Release

The effects of apomorphine (0.05, 0.1, and 1.0 mg/kg, s.c.) on the extracellular levels of dopamine and the dopamine metabolite 3, 4-dihydroxyphenylacetic acid were studied through the use of in vivo microdialysis in the neostriatum of developing and adult rats. Fifteen-minute samples were collected from urethane-anesthetized rats 5, 10–11, 21–22, and 35–36 days old and adults and quantified by HPLC with electrochemical detection. Apomorphine attenuated extracellular levels of dopamine in all age groups, suggesting that the dopamine autoreceptor modulating release in the neostriatum is functional by 5 days of age. A dose-response effect of apomorphine on extracellular dopamine was observed in all age groups except at 10–11 days of age. Extracellular levels of 3, 4-dihydroxyphenylacetic acid were also significantly decreased in all age groups, consistent with the hypothesis that synthesis-modulating dopamine autoreceptors in the neostriatum are functional by 5 days of age. Apomorphine had a significantly greater effect on extracellular 3, 4-dihydrpxyphenylacetic acid levels at the 0.05 and 0.1 mg/kg doses in the 5- and 10–11-day-old age groups compared with the other ages. Absolute levels of extracellular dopamine were significantly attenuated at 5 days of age compared with the other ages, and absolute levels of extracellular 3, 4-dihydroxyphenylacetic acid monotonically increased with age.