Extracellular Dopamine In Striatum Research Articles

Increased novelty-induced locomotion, sensitivity to amphetamine, and extracellular dopamine in striatum of Zdhhc15-deficient mice

Novelty-seeking behaviors and impulsivity are personality traits associated with several psychiatric illnesses including attention deficits hyperactivity disorders. The underlying neural mechanisms remain poorly understood. We produced and characterized a line of knockout mice for zdhhc15, which encodes a neural palmitoyltransferase. Genetic defects of zdhhc15 were implicated in intellectual disability and behavioral anomalies in humans. Zdhhc15-KO mice showed normal spatial learning and working memory but exhibited a significant increase in novelty-induced locomotion in open field. Striatal dopamine content was reduced but extracellular dopamine levels were increased during the habituation phase to a novel environment. Administration of amphetamine and methylphenidate resulted in a significant increase in locomotion and extracellular dopamine levels in the ventral striatum of mutant mice compared to controls. Number and projections of dopaminergic neurons in the nigrostriatal and mesolimbic pathways were normal. No significant change in the basal palmitoylation of known ZDHHC15 substrates including DAT was detected in striatum of zdhhc15 KO mice using an acyl-biotin exchange assay. These results support that a transient, reversible, and novelty-induced elevation of extracellular dopamine in ventral striatum contributes to novelty-seeking behaviors in rodents and implicate ZDHHC15-mediated palmitoylation as a novel regulatory mechanism of dopamine in the striatum.

What Mechanisms Are Responsible for the Reuptake of Levodopa-Derived Dopamine in Parkinsonian Striatum?

Levodopa is the most effective medication for motor symptoms in Parkinson's disease. However, various motor and non-motor complications are associated with levodopa treatment, resulting from altered levodopa-dopamine metabolism with disease progression and long-term use of the drug. The present review emphasizes the role of monoamine transporters other than the dopamine transporter in uptake of extracellular dopamine in the dopamine-denervated striatum. When dopaminergic neurons are lost and dopamine transporters decreased, serotonin and norepinephrine transporters compensate by increasing uptake of excessive extracellular dopamine in the striatum. Organic cation transporter-3 and plasma membrane monoamine transporter, low affinity, and high capacity transporters, also potentially uptake dopamine when high-affinity transporters do not work normally. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are often administered to patients with Parkinson's disease presenting with depression, pain or other non-motor symptoms. Thus, it is important to address the potential of these drugs to modify dopamine metabolism and uptake through blockade of the compensatory function of these transporters, which could lead to changes in motor symptoms of Parkinson's disease.

Aggregated single-walled carbon nanotubes attenuate the behavioural and neurochemical effects of methamphetamine in mice.

Methamphetamine (METH) abuse is a serious social and health problem worldwide. At present, there are no effective medications to treat METH addiction. Here, we report that aggregated single-walled carbon nanotubes (aSWNTs) significantly inhibited METH self-administration, METH-induced conditioned place preference and METH- or cue-induced relapse to drug-seeking behaviour in mice. The use of aSWNTs alone did not significantly alter the mesolimbic dopamine system, whereas pretreatment with aSWNTs attenuated METH-induced increases in extracellular dopamine in the ventral striatum. Electrochemical assays suggest that aSWNTs facilitated dopamine oxidation. In addition, aSWNTs attenuated METH-induced increases in tyrosine hydroxylase or synaptic protein expression. These findings suggest that aSWNTs may have therapeutic effects for treatment of METH addiction by oxidation of METH-enhanced extracellular dopamine in the striatum.

Innately low D2 receptor availability is associated with high novelty-seeking and enhanced behavioural sensitization to amphetamine

High novelty-seeking has been related to an increased risk for developing addiction, but the neurobiological mechanism underlying this relationship is unclear. We investigated whether differences in dopamine (DA) D2/3-receptor (D2/3R) function underlie phenotypic divergence in novelty-seeking and vulnerability to addiction. Measures of D2/3R availability using the D2R-preferring antagonist [18F]Fallypride, and the D3R-preferring agonist [3H]-(+)-PHNO and of DA-related gene expression and behaviours were used to characterize DA signalling in Roman high- (RHA) and low-avoidance (RLA) rats, which respectively display high and low behavioural responsiveness both to novelty and psychostimulant exposure. When compared to RLA rats, high novelty-responding RHAs had lower levels of D2R, but not D3R, binding and mRNA in substantia nigra/ventral tegmental area (SN/VTA) and showed behavioural evidence of D2-autoreceptor subsensitivity. RHA rats also showed a higher expression of the tyrosine hydroxylase gene in SN/VTA, higher levels of extracellular DA in striatum and augmentation of the DA-releasing effects of amphetamine (Amph), suggesting hyperfunctioning of midbrain DA neurons. RHA rats also exhibited lower availabilities and functional sensitivity of D2R, but not D3R, in striatum, which were inversely correlated with individual scores of novelty-seeking, which, in turn, predicted the magnitude of Amph-induced behavioural sensitization. These results indicate that innately low levels of D2R in SN/VTA and striatum, whether they are a cause or consequence of the concomitantly observed elevated DA tone, result in a specific pattern of DA signalling that may subserve novelty-seeking and vulnerability to drug use. This suggests that D2R deficits in SN/VTA and striatum could both constitute neurochemical markers of an addiction-prone phenotype.

Quantifying the role of oxygen pressure in tissue function

it has been suggested that oxygen had reached significant levels in the earth's oceans as early as 2.5 billion years ago and has rapidly increased to near current levels about 50 million years later ([6][1]). The appearance of oxygen dramatically changed the chemical composition of the oceans and

Differential regulation of somatodendritic and nerve terminal dopamine release by serotonergic innervation of substantia nigra.

Nigrostriatal dopaminergic neurons release dopamine from dendrites in substantia nigra and axon terminals in striatum. The cellular mechanisms for somatodendritic and axonal dopamine release are similar, but somatodendritic and nerve terminal dopamine release may not always occur in parallel. The current studies used in vivo microdialysis to simultaneously measure changes in dendritic and nerve terminal dopamine efflux in substantia nigra and ipsilateral striatum respectively, following intranigral application of various drugs by reverse dialysis through the nigral probe. The serotonin releasers (+/-)-fenfluramine (100 micro m) and (+)-fenfluramine (100 micro m) significantly increased dendritic dopamine efflux without affecting extracellular dopamine in striatum. The non-selective serotonin receptor agonist 1-(m-chlorophenyl)-piperazine (100 micro m) elicited a similar pattern of dopamine release in substantia nigra and striatum. NMDA (33 micro m) produced an increase in nigral dopamine of a similar magnitude to mCPP or either fenfluramine drug. However, NMDA also induced a concurrent increase in striatal dopamine. The D2 agonist quinpirole (100 micro m) had a parallel inhibitory effect on dopamine release from dendritic and terminal sites as well. Taken together, these data suggest that serotonergic afferents to substantia nigra may evoke dendritic dopamine release through a mechanism that is uncoupled from the impulse-dependent control of nerve terminal dopamine release.

"Nonhedonic" food motivation in humans involves dopamine in the dorsal striatum and methylphenidate amplifies this effect.

The drive for food is one of the most powerful of human and animal behaviors. Dopamine, a neurotransmitter involved with motivation and reward, its believed to regulate food intake in laboratory animals by modulating its rewarding effects through the nucleus accumbens (NA). Here we assess the involvement of dopamine in "nonhedonic" food motivation in humans. Changes in extracellular dopamine in striatum in response to nonhedonic food stimulation (display of food without consumption) were evaluated in 10 food-deprived subjects (16-20 h) using positron emission tomography (PET) and [11C]raclopride (a D2 receptor radioligand that competes with endogenous dopamine for binding to the receptor). To amplify the dopamine changes we pretreated subjects with methylphenidate (20 mg p.o.), a drug that blocks dopamine transporters (mechanism for removal of extracellular dopamine). Although the food stimulation when preceded by placebo did not increase dopamine or the desire for food, the food stimulation when preceded by methylphenidate (20 mg p.o.) did. The increases in extracellular dopamine were significant in dorsal (P < 0.005) but not in ventral striatum (area that included NA) and were significantly correlated with the increases in self-reports of hunger and desire for food (P < 0.01). These results provide the first evidence that dopamine in the dorsal striatum is involved in food motivation in humans that is distinct from its role in regulating reward through the NA. In addition it demonstrates the ability of methylphenidate to amplify weak dopamine signals.

Benserazide decreases central AADC activity, extracellular dopamine levels and levodopa decarboxylation in striatum of the rat.

In Parkinsonian patients treated with levodopa, peripheral decarboxylase inhibitors like carbidopa and benserazide are used to increase the central availability of levodopa. In experimental animal studies, this clinical situation is mimicked. However, at the dose used in many animal studies, both benserazide and carbidopa pass the blood brain barrier. In this study, we investigated to what extent their presence in brain inhibits striatal aromatic amino acid decarboxylase activity. At 50 mg/kg i.p., both carbidopa and benserazide decreased striatal decarboxylase activity. At 10 mg/kg i.p., only benserazide decreased the enzyme activity, but this did not change extracellular dopamine in striatum and allowed dopamine levels to increase after levodopa administration. In contrast, the inhibition of central decarboxylase activity by 50 mg/kg benserazide decreased striatal dopamine levels and prevented the levodopa-induced increase. Therefore, it is important to carefully consider the dose of the peripheral decarboxylase inhibitor used when the central effects of levodopa are studied.

Stress-induced increase in extracellular dopamine in striatum: role of glutamatergic action via N-methyl- d-aspartate receptors in substantia nigra

There is considerable support for an influence of excitatory amino acids released from corticofugal neurons on dopaminergic activity in the basal ganglia. However, the relative importance of cortico-striatal and cortico-mesencephalic projections remains unclear, particularly with respect to the nigro-neostriatal pathway. We have therefore examined the influence of endogenous excitatory amino acids in substantia nigra on stress-induced dopaminergic activity in neostriatum. Microdialysis probes were implanted unilaterally into substantia nigra and ipsilateral neostriatum, and dopamine release in neostriatum was monitored by measuring changes in extracellular dopamine. In separate animals, neostriatal dopamine synthesis was assessed by measuring extracellular DOPA in the presence of 3-hydroxylbenzylhydrazine (NSD-1015; 100 μM), an inhibitor of aromatic amino acid decarboxylase. Thirty minutes of intermittent foot shock increased both dopamine release (+41%) and synthesis (+37%) in neostriatum. Infusion of 2-amino-5-phosphonovalerate (APV; 100 μM), an inhibitor of N-methyl- d-aspartate (NMDA) receptors, into substantia nigra greatly attenuated the stress-induced increase in neostriatal dopamine release, while having no effect on the apparent increase in stress-induced dopamine synthesis. These data suggest that excitatory amino acids such as glutamate act on NMDA receptors in substantia nigra to increase striatal dopamine release produced by exposure to stress, but that the increase in dopamine synthesis is mediated through a separate mechanism.

Role of high-affinity dopamine uptake and impulse activity in the appearance of extracellular dopamine in striatum after administration of exogenous L-DOPA: studies in intact and 6-hydroxydopamine-treated rats.

The differential behavioral and neurochemical effects of exogenous L-DOPA in animals with intact versus dopamine (DA)-denervated striata raise questions regarding the role of DA terminals in the regulation of dopaminergic neurotransmission after administration of exogenous L-DOPA. In vivo microdialysis was used to monitor the effect of exogenous L-DOPA on extracellular DA in intact and DA-denervated striata of awake rats. In intact striatum, a small increase in extracellular DA was observed after administration of L-DOPA (50 mg/kg i.p.) but in DA-denervated striatum a much larger increase in extracellular DA was elicited. Additional experiments assessed the role of high-affinity DA uptake and impulse-dependent neurotransmitter release in the effect of exogenous L-DOPA on extracellular DA in striatum. Pretreatment with GBR-12909 (20 mg/kg i.p.), a selective DA uptake inhibitor, enhanced the ability of L-DOPA to increase extracellular DA in intact striatum. However, in DA-denervated striatum, inhibition of DA uptake did not alter the extracellular DA response to L-DOPA. Impulse-dependent neurotransmitter release was blocked by the infusion of tetrodotoxin (TTX; 1 microM), an inhibitor of fast sodium channels, through the dialysis probe. Application of TTX significantly attenuated the L-DOPA-induced increase in extracellular DA observed in striatum of intact rats pretreated with GBR-12909. In a similar manner, TTX infusion significantly attenuated the increase in extracellular DA typically observed in striatum of 6-OHDA-lesioned rats after the administration of L-DOPA. The present results indicate that DA terminals, via high-affinity uptake, play a crucial role in the clearance of extracellular DA formed from exogenous L-DOPA in intact striatum. This regulatory mechanism is absent in the DA-denervated striatum. In addition, this study has shown that DA synthesized from exogenous L-DOPA primarily is released by an impulse-dependent mechanism in both intact and DA-denervated striatum. The latter result suggests an important role for a nondopaminergic neuronal element in striatum that serves as the primary source of extracellular DA formed from exogenous L-DOPA.

Anoxic and hypoxic immature rat model for measurement of monoamine using in vivo microdialysis

The immature brain is considered relatively resistant to anoxia and ischemia. Although hypoxia without ischemia has not been considered to produce brain damage in immature rats as well as in adult rats (S. Levine, Anoxic–ischemic encephalopathy in rats, Am. J. Pathol., 36 (1960) 1–17 [8]; D.E. Levy, J.B. Brieley, D.G. Silverman, F. Plum, Brief hypoxia–ischemia initially damages cerebral neurons, Arch. Neurol., 32 (1975) 450–456 [9]; J.E. Rice, R.C. Vannucci, J.B., Brieriey, The influence of immaturity on hypoxic–ischemic brain damage in rat, Ann. Neurol., 9 (1981) 131–141 [14]), hypoxia in postnatal period is possible to cause a functional brain damage (T. Hender, P. Lundborg, Regional changes in monoamine synthesis in the developing rat brain during hypoxia, Acta. Physiol. Scand., 106 (1979) 139–143 [3]; W. Ihle, J. Gross, R. Moller, Effect on chronic postnatal hypoxia on dopamine uptake by synaptosomes from striatum of adult rats, Biomed. Biochem. Acta., 44 (1985) 433–437 [7]; A. Lun, J. Gross, M. Beyer, H.D. Fischer, C. Wustmann, J. Schmidt, K. Hecht, The vulnerable period of perinatal hypoxia with regard to dopamine release and behavior in adult rats, Biomed. Biochem. Acta., 45 (1986) 619–627 [10]). Using microdialysis, we studied the anoxic or hypoxic effect on catecholamine metabolism in immature rat brain by measuring extracellular concentrations of norepinephrine (NE), dopamine (DA), and its metabolites and also 5-hydroxyindole-3-acetic acid (5-HIAA), the serotonin metabolite. DA is a well established excitatory neurotransmitter (R.C. Vannucci, Experimental biology of cerebral hypoxia–ischemia: relation to perinatal brain damage, Pediatr. Res., 27 (1990) 317–326 [16]), and in the previous report using hypoxic 7-day-old rat pups increase of DA was not detected without additional stimulations (K. Gordon, D. Johnston, M.V. Robinson, T.E. Statman, J.B. Becker, F. Silverstein, Transient hypoxia alters striatal catecholamine metabolism in immature brain: An in vivo microdialysis study, J. Neurochem., 54 (1990) 605–611 [2]). Whereas recently in newborn piglets, hypoxic hypoxia produced increase of extracellular DA (C.-C. Huang, N.S. Lajevardi, O. Tammela, A. Pastuszko, Relationship of extracellular dopamine in striatum of newborn piglets to cortical oxygen pressure, Neurochem. Res., 19 (1994) 649–655 [6]; Olano, M., Song, D., Murphy, S., Wilson, D. F. and Pastuszko, A., Relationships of dopamine, cortical oxygen pressure, and hydroxyl radicals in brain of newborn piglets during hypoxia and posthypoxic recovery, J. Neurochem., 65 (1995) 1205–1212 [13]). We consider that hypoxic ischemic brain damage of human newborns that we can treat is a damage, which does not show overt neuropathological changes. We therefore tried to show that transient anoxia and hypoxia caused biochemical alteration if the exposure did not produce marked morphological changes. This rodent model is adequate to study perinatal asphyxia and alteration of monoamine level could be useful for evaluation of brain damage, even if it is not detected histologically. Themes: Neurotransmitters, modulators, transporters, and receptors Topics: Catecholamines

Excitatory amino acid receptor antagonists decrease hypoxia induced increase in extracellular dopamine in striatum of newborn piglets

The present study tested the hypothesis that the increase in extracellular striatal dopamine during hypoxia is least partly associated with activation of N-methyl-D-aspartate (NMDA) and/or non-NMDA excitatory amino acid receptors. Studies were performed in anesthetized and mechanically ventilated 2–3 days old piglets. Hypoxic insult was induced by decreasing the oxygen fraction in inspired gas (FiO 2) from 22 to 7% for 1 h, followed by 1 h reoxygenation at 22%. Cortical oxygen pressure was measured optically by oxygen dependent quenching of phosphorescence, and extracellular striatal dopamine was measured using in vivo microdialysis. The microdialysis probes were perfused with Ringer solution ±50 μM (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) or 50 μM 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX). One hour of hypoxia decreased the cortical oxygen pressure from 46±3 Torr to 10±1.8 Torr. In striatum perfused with Ringer, statistically significant increase in extracellular dopamine, to 1050±310% of control, was observed after 20 min of hypoxia. By 40 min of hypoxia the extracellular level of dopamine increased to 4730±900% of control; by the end of the hypoxic period the values increased to 18 451±1670% of control. The presence of MK-801 in the perfusate significantly decreased the levels of extracellular dopamine during hypoxia. At 20, 40 and 60 min of hypoxia extracellular level of dopamine increased to 278±94% of control, 1530±339% of control and 14 709±1095 of control, respectively. The presence of NBQX caused a statistically significant decrease, by about 30% in the extracellular dopamine compared to control, only at the end of the hypoxic period. It can be concluded that in striatum of newborn piglets, the excitatory NMDA receptors but not the non-NMDA receptors may be modulating the changes in extracellular levels of dopamine. The NMDA receptor antagonist, MK-801, may exert part of its reported neuroprotective effect to hypoxic stress in striatum by decreasing the levels of extracellular dopamine.

Biotransformation of locally applied precursors of dopamine, serotonin and noradrenaline in striatum and hippocampus: a microdialysis study.

In vivo microdialysis in freely moving rats was used to study the biotransformation, consisting primarily of decarboxylation by aromatic amino acid decarboxylase (AAAD), of the precursors L-3,4-dihydroxyphenylalanine (L-DOPA), L-5-hydroxytryptophan (L-5HTP), and L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) on extracellular levels of dopamine (DA), serotonin (5HT) and noradrenaline (NA), respectively. The precursors were administered locally through the microdialysis probe into the striatum and into the hippocampus. The different transmitter systems were compared with respect to the ability of the precursors to elevate extracellular levels of their associated transmitter. The basal extracellular concentrations of NA and DA were found to be tetrodotoxin (TTX, a blocker of fast sodium channels) sensitive in striatum and hippocampus, indicating the neuronal origin of the measured transmitters. The extracellular concentrations of 5HT (in hippocampus) were only 60% TTX-sensitive. L-DOPA and L-5HTP showed to be effective precursors of DA and 5HT, respectively, although their formation profile was quite different. The L-DOPA-induced increase in extracellular DA was large and short-lasting, while the L-5HTP-induced increase in 5HT was slower and less pronounced. The relative increase in extracellular DA or 5HT was more pronounced in the brain region where their baseline values were lower, but the absolute amount of transmitter formed from their precursor was similar in both brain regions. L-threo-DOPS was a poor precursor for NA and also failed to influence extracellular DA in striatum, questioning its use in the treatment of freezing gait in late stages of Parkinson's disease.

Differential effects of delta- and mu-opioid receptor antagonists on the amphetamine-induced increase in extracellular dopamine in striatum and nucleus accumbens.

The specific opioid receptor antagonist naloxone attenuates the behavioral and neurochemical effects of amphetamine. Furthermore, the amphetamine-induced increase in locomotor activity is attenuated by intracisternally administered naltrindole, a selective delta-opioid receptor antagonist, but not by the irreversible mu-opioid receptor antagonist beta-funaltrexamine. Therefore, this research was designed to determine if naltrindole would attenuate the neurochemical response to amphetamine as it did the behavioral response. In vivo microdialysis was used to monitor the change in extracellular concentrations of dopamine in awake rats. Naltrindole (3.0, 10, or 30 micrograms) or vehicle was given 15 min before and beta-funaltrexamine (10 micrograms) or vehicle 24 h before the start of cumulative dosing, intracisternally in a 10-microliters volume, while the rats were lightly anesthetized with methoxyflurane. Cumulative doses of subcutaneous d-amphetamine (0.0, 0.1, 0.4, 1.6, and 6.4 mg/kg) followed pretreatment injections at 30-min intervals. Dialysate samples were collected every 10 min from either the striatum or nucleus accumbens and analyzed for dopamine content by HPLC. Amphetamine dose-dependently increased dopamine content in both the striatum and nucleus accumbens, as reported previously. Naltrindole (3.0, 10, and 30 micrograms) significantly reduced the dopamine response to amphetamine in the striatum. In contrast, 30 micrograms of naltrindole did not modify the dopamine response to amphetamine in the nucleus accumbens. On the other hand, beta-funaltrexamine (10 micrograms) had no effect in the striatum but significantly attenuated the amphetamine-induced increase in extracellular dopamine content in the nucleus accumbens. These data suggest that delta-opioid receptors play a relatively larger role than mu-opioid receptors in mediating the amphetamine-induced increase in extracellular dopamine content in the striatum, whereas mu-opioid receptors play a larger role in mediating these effects in the nucleus accumbens.

Local Influence of Endogenous Norepinephrine on Extracellular Dopamine in Rat Medial Prefrontal Cortex

Noradrenergic and dopaminergic projections converge in the medial prefrontal cortex and there is evidence of an interaction between dopamine (DA) and norepinephrine (NE) terminals in this region. We have examined the influence of drugs known to alter extracellular NE on extracellular NE and DA in medial prefrontal cortex using in vivo microdialysis. Local application of the NE uptake inhibitor desipramine (1.0 microM) delivered through a microdialysis probe increased extracellular DA (+149%) as well as NE (+201%) in medial prefrontal cortex. Furthermore, desipramine potentiated the tail shock-induced increase in both extracellular DA (stress alone, +64%; stress + desipramine, +584%) and NE (stress alone, +55%; stress + desipramine, +443%). In contrast, local application of desipramine did not affect extracellular DA in striatum, indicating that this drug does not influence DA efflux directly. Local application of the alpha 2-adrenoceptor antagonist idazoxan (0.1 or 5.0 mM) increased extracellular NE and DA in medial prefrontal cortex. Conversely, the alpha 2-adrenoceptor agonist clonidine (0.2 mg/kg; i.p.) decreased extracellular NE and DA in medial prefrontal cortex. These results support the hypothesis that NE terminals in medial prefrontal cortex regulate extracellular DA in this region. This regulation may be achieved by mechanisms involving an action of NE on receptors that regulate DA release (heteroreceptor regulation) and/or transport of DA into noradrenergic terminals (heterotransporter regulation).

Relationship of extracellular dopamine in striatum of newborn piglets to cortical oxygen pressure.

The present studies describes the relationship between extracellular dopamine in striatum of newborn piglets and cortical oxygen pressure. The extracellular level of dopamine was measured by in vivo microdialysis and the oxygen pressure in the cortex was measured by phosphorescence lifetime of oxygen probe in the blood. Controlled, graded levels of hypoxic insult to the brain of animals were generated by decreasing of the oxygen fraction in the inspired gas (FiO2) from 21% to 14%, 11%, and 9%. This resulted in decrease in the cortical oxygen pressure from 31-35 Torr to about 24 Torr, 15 Torr and 4 Torr, respectively. The changes in extracellular level of dopamine, DOPAC and HVA were dependent on changes in cortical oxygen pressure. Stepwise decrease in the cortical oxygen pressure (see above) caused increases in extracellular dopamine of about 80%, 200% and 550%, respectively. The levels of DOPAC and HVA progressively decreased and when cortical oxygen decreased to 4-6 Torr were about 50% and 70% of control, respectively. After return of FiO2 to control (21%), the cortical oxygen pressure rapidly increased to above normal, then returned to control values. The extracellular levels of dopamine, DOPAC, and HVA recovered more slowly, attaining control values in about 30 minutes. The data show that extracellular levels of dopamine increase with even very small decreases in oxygen pressure. Thus, there is no "oxygen reserve" which protects dopamine release and metabolism from decrease in oxygen pressure.

Extracellular dopamine in striatum: Influence of nerve impulse activity in medial forebrain bundle and local glutamatergic input

Microdialysis probes were used to measure dopamine in, and to administer glutamate receptor antagonists and agonists to, the striatum of unanesthetized rats. Antagonists used were: kynurenate, 2-amino-5-phosphonovalerate and 6-cyano-7-nitroquinoxaline-2,3-dione. Agonists used were: N-methyl- d-aspartate and kainate. In some rats an additional dialysis probe was implanted in medial forebrain bundle for infusion of tetrodotoxin (10μM) to block action potential propagation along dopaminergic axons in this pathway. The latter treatment reduced dopamine in striatal dialysate to below detectable levels (<0.5 pg). The quantity of dopamine in striatal dialysate was not reduced by the local application of glutamate receptor antagonists. At lower concentrations, the receptor antagonists failed to alter significantly the quantity of dopamine, whereas the highest concentration of each antagonist increased the amount of dopamine in the dialysate. At the highest concentration tested (0.75 mM or 1.0 mM), as well as at a lower concentration (0.1 mM), 2-amino-5-phosphonovalerate and 6-cyano-7-nitroquinoxaline-2,3-dione blocked the dopamine-releasing effects of exogenously applied N-methyl- d-aspartate (1.0 mM) or kainate (0.1 mM), respectively. Thus, concentrations of glutamate receptor antagonists that produced effective pharmacological blockade of the respective receptors had no effect on the basal amount of dopamine in striatal extracellular fluid. Finally, N-methyl- d-aspartate and kainate produced a significant elevation in extracellular dopamine during the infusion of tetrodotoxin into the medial forebrain bundle, indicating that impulse activity in this pathway is not necessary for dopamine release produced by glutamate receptor agonists. We conclude that the basal amount of dopamine in striatal dialysate in unanesthetized rats during quiet waking or sleep is determined by the electrophysiological activity of nigrostriatal dopamine neurons. Despite numerous reports that glutamate receptor agonists are able to stimulate dopamine release in striatum, the present data obtained using glutamate receptor antagonists suggest that endogenous glutamate exerts no tonic effect on extracellular dopamine in striatum under these conditions.

Effects of haloperidol administration on in vivo extracellular dopamine in striatum and prefrontal cortex after partial dopamine lesions

The effects of haloperidol on striatal and prefrontal cortical extracellular fluid dopamine (DA) concentrations were examined in sham-operated control rats and in rats which had received partial lesions of their dopamine systems. In control rats haloperidol administration produced increases in extracellular fluid DA concentrations in both the striatum and prefrontal cortex. However, in rats which had been partially lesioned with intracerebroventricular 6-hydroxydopamine, haloperidol produced an increase in extracellular fluid DA concentration in the prefrontal cortex but failed to alter striatal DA release. These data suggest that nigrostriatal and mesocortical DA neurons have different response capabilities following partial DA lesions.

Environmental stress increases extracellular dopamine in striatum of 6-hydroxydopamine-treated rats: in vivo microdialysis studies

Bilateral intraventricular injections of 6-hydroxydopamine depleted dopamine (DA) in striatal tissue of rats by 88%. Tail shock increased DA in striatal extracellular fluid of these rats from 10 to 17 pg/20 μl as measured by microdialysis, values less than half those seen in normal striatum. The increase was observed even in rats that were akinetic. DA in extracellular fluid after stress was negatively correlated with behavioral performance. Thus, residual nigrostriatal DA neurons are responsive to stress but do not produce normal DA levels in striatal extracellular fluid.

Effects of l-DOPA on extracellular dopamine in striatum of normal and 6-hydroxydopamine-treated rats

In vivo microdialysis was used to examine the effect of l-3,4-dihydroxyphenylalanine ( l-DOPA) administration upon dopamine (DA) in extracellular fluid both in intact striatum and in striatum of rats treated with the catecholaminergic neurotoxin 6-hydroxydopamine (6-HDA). Basal extracellular levels of DA were not significantly altered by 6-HDA unless the DA content of striatal tissue was reduced to less than 20% of control. Peripheral aromatic amino acid decar☐ylase (AADC) inhibition (RO4−4602, 50 mg/kg i.p.) followed by l-DOPA treatment (100 mg/kg i.p.) elevated extracellular DA in striatum of control rats from37 ± 5to68 ± 11pg/sample(n = 7); values corrected for recovery of the dialysis probe). In animals with severe bilateral depletions of DA in striatal tissue(mean depletion 87%; n = 6), l-DOPA increased extracellular DA in striatum from8 ± 3to266 ± 60pg/sample. In animals with large unilateral depletions of DA in striatal tissue(mean depletion 96%; n= 6), the increase in extracellular DA in striatum after l-DOPA was greater on the lesion side(from7 ± 4to245 ± 67pg/sample) than on the intact side(from28 ± 11to61 ± 8pg/sample). Animals with unilateral DA depletions showed contralateral circling behavior after l-DOPA. Increases in extracellular DA approaching the magnitude of those occuring in DA-depleted striata were observed when intact animals were treated with nomifensine(5mg/kg i.p.; n = 5), an inhibitor of high-affinity DA uptake, in addition to l-DOPA.