Dopaminergic processes in the striatum mediating corticoliberin effect on behavior of active and passive rats

The action of intranasal corticotropin-releasing hormone (CRH) administration on open field behavior and striatal and hypothalamic levels of dopamine, noradrenaline and their metabolites has been studied in rats with different behavior strategies (KHA and KLA strains). In KLA rats, CRH administration resulted in increased locomotor and exploratory activity, while KHA rats demonstrated decreased that. The analysis of catecholamine levels did not detect any strain differences in hypothalamus, but in striatum the dopamine levels have been twice higher, while the metabolite levels (DOPAC and HVA) were significantly lower in KLA rats as compared to KHA rats. The CRH administration led to increased dopamine and noradrenaline levels in hypothalamus and decreased those in striatum in rats of both strains, but in KLA the decrease was more evident. It is probably a result of intensified mediator turnover induced by the neurohormone in KLA rats, as supported by a fact of increased dopamine metabolite levels in this structure.     

Different action on dopamine catabolic pathways of two endogenous 1,2,3,4-tetrahydroisoquinolines with similar antidopaminergic properties.

The effect of single and multiple 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) administration on concentrations of dopamine and its metabolites: homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3MT) in three brain areas was studied HPLC with electrochemical detection in Wistar rats. The rate of dopamine catabolism in the striatum along the N-oxidative and O-methylation pathways was assessed by calculation of the ratio of appropriate metabolites to dopamine concentration. In addition, the spontaneous and apomorphine-stimulated locomotor activity, and muscle rigidity was studied after acute administration of 1MeTIQ and 1BnTIQ. We have found that 1MeTIQ did not change the level of dopamine and HVA in all investigated structures both after a single and chronic administration. However, the levels of intermediary dopamine metabolites, DOPAC and 3MT, were distinctly affected. The level of DOPAC was strongly depressed (by 60-70%) while the level of extraneuronal matabolite 3MT was significantly elevated (by 170-200%). In contrast to 1MeTIQ, 1BnTIQ depressed the level of dopamine (by approximately 60%) and increased the level of total metabolite, HVA, (by 40%) especially in the striatum, but the levels of DOPAC and 3MT remained unchanged. The paper has shown that 1MeTIQ and 1BnTIQ produced different effects on dopamine catabolism. Potential neuroprotective compound 1MeTIQ did not change the rate of total dopamine catabolism, it strongly inhibited the monoamine oxidase (MAO)-dependent catabolic pathway and significantly activated the catechol-O-methyltransferase (COMT)-dependent O-methylation. In contrast 1BnTIQ, a compound with potential neurotoxic activity, produced the significant increase of the rate of dopamine metabolism with strong activation of the oxidative MAO-dependent catabolic pathway. Interestingly, both compounds produced similar antidopaminergic functional effects: antagonism of apomorphine hyperactivity and induction of muscle rigidity. The results may explain the biochemical basis of the neuroprotective and of the neurotoxic properties endogenous brain tetrahydroisoquinoline derivatives.     

ON THE RELEVANCE OF PREFERENTIAL INCREASES OF MESOLIMBIC VERSUS STRIATAL DOPAMINE TURNOVER FOR THE PREDICTION OF ANTIPSYCHOTIC ACTIVITY OF PSYCHOTROPIC DRUGS

Abstract— Drugs possessing (chlorpromazine, haloperidol, clozapine, thioridazine and sulpiride) or lacking (benzoctamine and perlapine) antipsychotic activity were compared with respect to their ability to enhance x-methyl-p-tyrosine-induced dopamine disappearance from the mesolimbic area and corpus striutum of rat brain. In addition, their effects on the endogenous concentrations of homovanillic (HVA) and 3.4-dihydroxyphenylacetic (DOPAC) acids in these two brain areas were determined. Some of the drugs enhanced dopamine disappearance in the mesolimbic area more than in the striatum. The most active in this respect were sulpiride. perlapine and chlorpromazine. By contrast, haloperidol was slightly more active in the striatum than in the mesolimbic area. None of the drugs was more efficient in elevating HVA levels in the mesolimbic area than in the striatum. However, there were large differences in the relative extent of the HVA increases in the two regions. Benzoctamine, perlapine and chlorpromazine increased HVA concentrations in the mesolimbic area nearly as much as in the striatum. Thioridazine and haloperidol, however, elevated striatal HVA much more effectively. Haloperidol and clozapine increased the DOPAC concentration in both areas to about the same extent. The other drugs were more active in the striatum. The largest difference between both regions was shown by chlorpromazine. Perlapine and benzoctamine, both lacking antipsychotic activity, produced much larger increases of HVA than of DOPAC. This is in contrast to the results obtained with true neuroleptics and may reflect an involvement of release phenomena in the action of these two drugs on dopamine metabolism. These results suggest that a preferential increase of dopamine turnover in the mesolimbic area is not necessarily linked to a better ratio of antipsychotic activity vs. extrapyramidal side effects. Moreover, an antiacetylcholine component of dopamine receptor blocking drugs does not seem to be a prerequisite for preferential activity on dopamine turnover in the mesolimbic system.     

Effects of Perinatal Vitamin B6 Deficiency on Dopaminergic Neurochemistry

Long-Evans dams were fed either a vitamin B6-deficient or a control diet from day 13-14 of gestation and throughout lactation. A control pair-fed group was also included because of differences in food intake between vitamin B6-deficient and control ad libitum dams. The progeny of vitamin B6-deficient dams had all the classic symptoms of B6 deficiency. These included weight loss, ataxia, tremor, and epileptic seizures. Concentrations of the neurotransmitter dopamine (DA), and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as D-2 dopamine receptor binding, 3,4-dihydroxyphenylalanine (DOPA) decarboxylase activity, and vitamin B6 levels were measured in the corpus striatum of progeny at 7, 14, and 18 days after birth. Striatal DA and HVA levels were significantly decreased in B6-deficient animals when compared to ad libitum or pair-fed controls. Daily injections of vitamin B6 to deprived animals from the 14th to 18th day after birth improved the abnormal movement and normalized the concentration of DA but not of HVA in corpus striatum. Striatal D-2 dopamine receptor binding using [3H]spiperone as ligand was significantly reduced in 18-day-old animals as compared to ad libitum and pair-fed controls. No significant differences were found at 14 days. The administration of vitamin B6 to deprived animals did not raise the level of D-2 receptor binding during the period of observation. Scatchard plots indicated that the differences in binding were due to changes in receptor number and not in KD. Corpus striatum DOPA decarboxylase activity with and without the addition of exogenous pyridoxal phosphate was significantly reduced in 14- and 18-day-old animals when compared to pair-fed controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neonatal hyperthyroidism: alterations in behavioural activity and the metabolism of brain norepinephrine and dopamine.

Daily administration of triiodothyronine (10 μg/100 g) to newborn rats for 30 days produced signs of hyperthyroidism which included accelerated development of physical and behavioural characteristics accompanying maturation. The hyperthyroid rats displayed progressive increases in spontaneous locomotor activity between 14–35 days, which remained elevated well above control levels even at 105 days. Exposure of developing rats to triiodothyronine increased the endogenous levels of striatal tyrosine and tyrosine hydroxylase as well as the concentration of dopamine in hypothalamus, pons-medulla, mid-brain, striatum and hippocampus. The concentration of striatal homovanillic acid and 3,4-dihydroxyphenylacetic acid was also increased in hyperthyroid rats. In contrast, the steady-state levels of norepinephrine remained unaltered resulting in a significant increase in dopamine to norepinephrine ratio in several regions of the brain examined. The elevated levels of dopamine metabolites (homovanillic acid and 3,4-dihydroxyphenylacetic acid) may be due to an increased turnover of dopamine. Our data suggest that increased thyroid hormone levels may lead to an enhanced synthesis as well as utilization of brain catecholamines which in turn may underlie the observed increases in spontaneous locomotor activity.     

Brain dialysis: changes in the activities of dopamine neurons in rat striatum by perfusion of acetylcholine agonists under freely moving conditions

A dialysis cannula implanted into rat striatum was perfused with Ringer's solution containing drugs. Levels of 3,4-dihydroxyphenyl-acetic acid (DOPAC) and homovanillic acid (HVA) in the dialysate or striatal tissue were determined by HPLC with electrochemical detection. Continuous perfusion of oxotremorine, a muscarinic agonist, for 4 h gradually increased the levels of DOPAC and HVA. The maximal levels of DOPAC and HVA were 180 and 130% of the basal ones, respectively. Perfusion of lobeline, a nicotinic agonist, caused a rapid increase in DOPAC level within I h (160% of the basal level) and HVA was 120% of the basal level for 4 h. In striatal tissue 20 min after starting perfusion of oxotremorine or lobeline, there were no changes in DOPAC and HVA measured except for a decrease in dopamine after lobeline. Pretreatment with tetrodotoxin suppressed the effect of oxotremorine, but did not suppress the effect of the lobeline. These data suggest that, in the rat striatum in vivo, most of the muscarinic receptors indirectly enhance the turnover of dopamine via striatonigral or other loops, while some of the nicotinic receptors directly enhance the release or turnover of dopamine in the dopamine nerve terminals.     

Effects of an N-methyl-d-aspartate receptor agonist and its antagonist CPP on the levels of dopamine and serotonin metabolites in rat striatum collected in vivo by using a brain dialysis technique

3-((±)-2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) is an antagonist at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. In the present study, levels of dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) were measured after intracerebroventricular injection of NMDA, CPP or both in rat striatum using a brain dialysis method. The injection of NMDA produced a significant increase in DOPAC level. HVA level was also increased by NMDA injection. The level of 5-HIAA was not affected by NMDA injection. The injection of CPP had no effect on DOPAC, HVA and 5-HIAA levels. The injection of CPP restrained the increase of DOPAC and HVA levels induced by NMDA injection. The results suggest that intracerebral injection of NMDA may increase dopamine release from rat striatum, but have no effect on serotonin release. Furthermore, CPP inhibits NMDA induced release of dopamine.     

Striatal dopamine release and biphasic pattern of locomotor and motor activity under gas narcosis

Inert gas narcosis is a neurological syndrome appearing when humans or animals are exposed to hyperbaric inert gases (nitrogen, argon) composed by motor and cognitive impairments. Inert gas narcosis induces a decrease of the dopamine release at the striatum level, structure involved in the regulation of the extrapyramidal motricity. We have investigated, in freely moving rats exposed to different narcotic conditions, the relationship between the locomotor and motor activity and the striatal dopamine release, using respectively a computerized device that enables a quantitative analysis of this behavioural disturbance and voltammetry. The use of 3 MPa of nitrogen, 2 MPa of argon and 0.1 MPa of nitrous oxide, revealed after a transient phase of hyperactivity, a lower level of the locomotor and motor activity, in relation with the decrease of the striatal dopamine release. It is concluded that the striatal dopamine decrease could be related to the decrease of the locomotor and motor hyperactivity, but that other(s) neurotransmitter(s) could be primarily involved in the behavioural motor disturbances induced by narcotics. This biphasic effect could be of major importance for future pharmacological investigations, and motor categorization, on the basic mechanisms of inert gas at pressure.     

Stimulation of presynaptic dopamine autoreceptors by 4-(2-di-n-propylaminoethyl) indole (DPAI)

The dopaminergic activity of 4-(2-di-n-propylaminoethyl)indole (DPAI) was investigated. In animal models for postsynaptic dopaminergic activity DPAI showed only very weak or no effects. In rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal tract, very weak contralateral turning behavior was induced in 4/6 rats. DPAI did not induce stereotyped behavior but caused a pronounced reduction in locomotor activity. In male rats pretreated with reserpine, DPAI lowered serum prolactin levels. Levels of homovanillic acid (HVA) were monitored in the striatum of the chloral hydrate anesthetized rat by means of in vivo voltammetry. DPAI administration reduced the faradaic peak corresponding to HVA. In rats pretreated with the decarboxylase inhibitor, NSD-1015, DPAI blocked the accumulation of dopa in response to gamma-butyrolactone. The results of this study indicate that DPAI possesses a high degree of selectivity for presynaptic dopamine autoreceptors, and little or no effect on postsynaptic dopamine receptors.     

Effects of acute and subacute cocaine administration on the CNS dopaminergic system in Wistar-Kyoto and spontaneously hypertensive rats: I. Levels of dopamine and metabolites

Effects of acute and subacute cocaine administration on dopamine (DA) and its metabolites in striata and nucleus accumbens of nine week-old Wistar-Kyoto and spontaneously hypertensive rats were studied. Levels of DA,3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined by HPLC-EC. There were no differences in DA levels in striata and nucleus accumbens between control WKY and SHR. Levels of DA in two brain regions were unaffected in groups treated acutely with cocaine. Both strains showed a significant increase in striatal HVA 2 hr after cocaine injection. Seven day treatment declined DA levels in striatum of WKY and in nucleus accumbens of SHR. However, only WKY treated subacutely with cocaine showed significantly increased HVA either with or without changes in DOPAC in nucleus accumbens and striatum, respectively. Increased DOPAC/DA and HVA/DA ratios appeared only in striatum of WKY and in nucleus accumbens of SHR following subacute treatment. These results suggest that subacute cocaine administration affects DA levels in striata and nucleus accumbens differently between WKY and SHR.     

Sexually Dimorphic Effects of Catechol-O-Methyltransferase (COMT) Inhibition on Dopamine Metabolism in Multiple Brain Regions

The catechol-O-methyltransferase (COMT) enzyme metabolises catecholamines. COMT inhibitors are licensed for the adjunctive treatment of Parkinson''s disease and are attractive therapeutic candidates for other neuropsychiatric conditions. COMT regulates dopamine levels in the prefrontal cortex (PFC) but plays a lesser role in the striatum. However, its significance in other brain regions is largely unknown, despite its links with a broad range of behavioural phenotypes hinting at more widespread effects. Here, we investigated the effect of acute systemic administration of the brain-penetrant COMT inhibitor tolcapone on tissue levels of dopamine, noradrenaline, and the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). We examined PFC, striatum, hippocampus and cerebellum in the rat. We studied both males and females, given sexual dimorphisms in several aspects of COMT''s function. Compared with vehicle, tolcapone significantly increased dopamine levels in the ventral hippocampus, but did not affect dopamine in other regions, nor noradrenaline in any region investigated. Tolcapone increased DOPAC and/or decreased HVA in all brain regions studied. Notably, several of the changes in DOPAC and HVA, particularly those in PFC, were more prominent in females than males. These data demonstrate that COMT alters ventral hippocampal dopamine levels, as well as regulating dopamine metabolism in all brain regions studied. They demonstrate that COMT is of significance beyond the PFC, consistent with its links with a broad range of behavioural phenotypes. Furthermore, they suggest that the impact of tolcapone may be greater in females than males, a finding which may be of clinical significance in terms of the efficacy and dosing of COMT inhibitors.     

Effects of Apomorphine on In Vivo Release of Dopamine and Its Metabolites in the Prefrontal Cortex and the Striatum, Studied by a Microdialysis Method

The effects of apomorphine (0.1-2.5 mg/kg) on release of endogenous dopamine and extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the prefrontal cortex and the striatum were examined in vivo by a microdialysis method. Apomorphine significantly reduced release of dopamine and the extracellular levels of dopamine metabolites, DOPAC and HVA, not only in the striatum, but also in the prefrontal cortex. These findings indicate that dopamine autoreceptors modulate in vivo release of dopamine in the prefrontal cortex.     

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。     

Dopaminergic transmission in STOP null mice

Neuroleptics are thought to exert their anti-psychotic effects by counteracting a hyper-dopaminergic transmission. Here, we have examined the dopaminergic status of STOP (stable tubule only polypeptide) null mice, which lack a microtubule-stabilizing protein and which display neuroleptic-sensitive behavioural disorders. Dopamine transmission was investigated using both behavioural analysis and measurements of dopamine efflux in different conditions. Compared to wild-type mice in basal conditions or following mild stress, STOP null mice showed a hyper-locomotor activity, which was erased by neuroleptic treatment, and an increased locomotor reactivity to amphetamine. Such a behavioural profile is indicative of an increased dopaminergic transmission. In STOP null mice, the basal dopamine concentrations, measured by quantitative microdialysis, were normal in both the nucleus accumbens and the striatum. When measured by electrochemical techniques, the dopamine efflux evoked by electrical stimulations mimicking physiological stimuli was dramatically increased in the nucleus accumbens of STOP null mice, apparently due to an increased dopamine release, whereas dopaminergic uptake and auto-inhibition mechanisms were normal. In contrast, dopamine effluxes were slightly diminished in the striatum. Together with previous results, the present study indicates the association in STOP null mice of hippocampal hypo-glutamatergy and of limbic hyper-dopaminergy. Such neurotransmission defects are thought to be central to mental diseases such as schizophrenia.     

Greater Ethanol-Induced Locomotor Activation in DBA/2J versus C57BL/6J Mice Is Not Predicted by Presynaptic Striatal Dopamine Dynamics

A large body of research has aimed to determine the neurochemical factors driving differential sensitivity to ethanol between individuals in an attempt to find predictors of ethanol abuse vulnerability. Here we find that the locomotor activating effects of ethanol are markedly greater in DBA/2J compared to C57BL/6J mice, although it is unclear as to what neurochemical differences between strains mediate this behavior. Dopamine elevations in the nucleus accumbens and caudate-putamen regulate locomotor behavior for most drugs, including ethanol; thus, we aimed to determine if differences in these regions predict strain differences in ethanol-induced locomotor activity. Previous studies suggest that ethanol interacts with the dopamine transporter, potentially mediating its locomotor activating effects; however, we found that ethanol had no effects on dopamine uptake in either strain. Ex vivo voltammetry allows for the determination of ethanol effects on presynaptic dopamine terminals, independent of drug-induced changes in firing rates of afferent inputs from either dopamine neurons or other neurotransmitter systems. However, differences in striatal dopamine dynamics did not predict the locomotor-activating effects of ethanol, since the inhibitory effects of ethanol on dopamine release were similar between strains. There were differences in presynaptic dopamine function between strains, with faster dopamine clearance in the caudate-putamen of DBA/2J mice; however, it is unclear how this difference relates to locomotor behavior. Because of the role of the dopamine system in reinforcement and reward learning, differences in dopamine signaling between the strains could have implications for addiction-related behaviors that extend beyond ethanol effects in the striatum.     

Cholinergic effect on the dopamine turnover in the rat corpus striatum]

The peripheral administration of oxotremorine caused a significant increase in dihydroxyphenylacetic acid (DOPAC) in the striatum of rats, dopamine (DA) level was unaffected. Injection of oxotremorine into the substantia nigra failed to change the content of dopamine and its acid metabolites homovanillic acid (HVA) and DOPAC in striatum. Injection of oxotremorine or carbachol into the substantia nigra or into the caudate nucleus did not significantly influence the DA-turnover. The partly inconsistent results are discussed in connection with literature data in regard to the existence of excitatory as well as inhibitory cholinergic systems, which are located differently and are involved in the regulation of DA-turnover.     

Differential modulation of dopaminergic systems in the rat brain by dietary protein

Rats that consume a diet 50% rich in protein exhibit hyperactivity and hyperresponsiveness to nociceptive stimuli, in which facilitation of dopaminergic activity has been implicated. We studied the regional changes in the concentrations of dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the brains of rats that were maintained on high-protein (HP, 50% casein), normal-protein (NP, 20% casein), and low-protein (LP, 8% casein) diets for 36 weeks. Brain nuclei that represented different DAergic systems were punchdissected and analyzed using HPLC. In the substantia nigra, the striatum, and the dentate gyrus, DA concentrations decreased and increased, respectively, with a decrease and increase in dietary protein (p<0.05 compared to the NP diet). Similar trends in the effect of the HP diet were observed in the ventral tegmental area, amygdala, frontal cortex, subiculum, centromedial nucleus (CM) of the thalamus, and inferior colliculi (IC), although the differences in DA concentrations were not statistically significant. These brain areas also showed a pattern of decreased DA concentration in association with the LP diet, and the differences were statistically significant (p<0.05) in the CM and IC. DA concentrations in most regions of the midbrain and brainstem were not different between the diet groups, nor were consistent trends observed in those regions. Also, there were no consistent relationships between DOPAC/DA and HVA/DA ratios and dietary protein level. These data suggest that only discrete dopaminergic neuronal circuits in the rat forebrain were sensitive to changes in dietary protein level.     

Suanzaorentang, and anxiolytic Chinese medicine, affects the central adrenergic and serotonergic systems in rats

Previously, we found that the ancient Chinese remedy of Suanzaorentang was a promising anxiolytic drug (Chen and Hsieh, 1985; Chen and Hsieh, 1985a). We also found that Suanzaorentang decreased the turnover rate of central monoamines and central catecholaminergic activity (Hsieh, et al., 1986). In this study, we found that 5-hydroxytryptophan (5-HTP) induced decrease in locomotor activity was significantly antagonized by Suanzaorentang, p-chlorophenylalanine (p-CPA) induced increase in locomotor activity was significantly inhibited by Suanzaorentang, Suanzaorentang had no significant effects on baclofen, muscimol, aminooxyacetic acid (AOAA) and thiosemicarbazide induced changes in locomotor activity, Suanzaorentang significantly decreased vanillylmandelic acid (VMA) in striatum and hippocampus, homovanillic acid (HVA) in hippocampus and 5-hydroxyindol acetic acid (5-HIAA) in striatum and hypothalamus, Suanzaorentang significantly reversed the alpha-methyltyrosine (alpha-MT) produced decrease in DA concentrations in striatum and hippocampus, and (6) Suanzaorentang significantly reversed the p-CPA produced decrease in 5-HT concentrations on amygdala. These facts implied that Suanzaorentang might decrease the serotonergic activity but have no significant effect on GABAergic activity. The main locus of action might be in the limbic system.     

Development of Haloperidol-Induced Dopamine Release in the Rat Striatum Using Intracerebral Dialysis

Haloperidol-induced dopamine (DA) release and metabolism were studied in the rat striatum at 10-11, 21-22, and 35-36 days of age using intracerebral dialysis and HPLC with electrochemical detection. There was an age-related increase in basal DA release and extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), with the greatest increases occurring between 10-11 and 21-22 days of age. Haloperidol (0.1 mg/kg, i.p.) significantly increased DA release at each age compared to control. Also, haloperidol produced a significantly greater increase in DA release at 10-11 days than at 21-22 or 35-36 days of age when expressed as percentage of predrug release. Haloperidol increased DA release over 60 min to 235%, 138%, and 158% above baseline at 10-11, 21-22, and 35-36 days of age, respectively, after which time the levels remained relatively constant. Haloperidol significantly increased extracellular DOPAC and HVA levels at each age compared to controls, but there were no significant differences in DOPAC or HVA levels between ages in response to haloperidol. The results indicate that, at 10 days of age, DA release in the striatum is physiologically functional and that the regulatory feedback control of DA release and metabolism in the striatum develops prior to 10 days of age.