Basal Extracellular Dopamine Research Articles

Functional significance of aldehyde dehydrogenase ALDH1A1 to the nigrostriatal dopamine system

Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of a superfamily of detoxification enzymes found in various tissues that participate in the oxidation of both aliphatic and aromatic aldehydes. In the brain, ALDH1A1 participates in the metabolism of catecholamines including dopamine (DA) and norepinephrine, but is uniquely expressed in a subset of dopaminergic (DAergic) neurons in the ventral mesencephalon where it converts 3,4-dihydroxyphenylacetaldehyde, a potentially toxic aldehyde, to 3,4-dihydroxyphenylacetic acid, a non toxic metabolite. Therefore, loss of ALDH1A1 expression could be predicted to alter DA metabolism and potentially increase neurotoxicity in ventral mesencephalic DA neurons. Recent reports of reduced levels of expression of both Aldh1a1 mRNA and protein in the substantia nigra (SN) of Parkinson's disease patients suggest possible involvement of ALDH1A1 in this progressive neurodegenerative disease. The present study used an Aldh1a1 null mouse to assess the influence of ALDH1A1 on the function and maintenance of the DAergic system. Results indicate that the absence of Aldh1a1 did not negatively affect growth and development of SN DA neurons nor alter protein expression levels of tyrosine hydroxylase, the DA transporter or vesicular monoamine transporter 2. However, absence of Aldh1a1 significantly increased basal extracellular DA levels, decreased KCl and amphetamine stimulated DA release and decreased DA re-uptake and resulted in more tyrosine hydroxylase expressing neurons in the SN than in wildtype animals. These data suggest that in young adult animals with deletion of the Aldh1a1 gene there is altered DA metabolism and dysfunction of the DA transporter and DA release mechanisms.

Decreased reuptake of dopamine in the dorsal striatum in the absence of alpha-synuclein

The presynaptic protein alpha-synuclein (α-syn) plays a role in dopaminergic neurotransmission in the nigrostriatal dopaminergic system. Mutations in this protein have been linked to pathogenesis of Parkinson's disease. However, the details of regulation of dopamine homeostasis by α-syn and its molecular targets are generally unknown. We investigated the effect of α-syn deletion on striatal dopaminergic homeostasis. Two α-syn deficient mouse lines, one carrying a spontaneous deletion of α-syn locus and the other a transgenic α-syn knockout, were used in the study. Stimulated and basal extracellular dopamine levels were determined in the dorsal striatum by in vivo voltammetry and in vivo microdialysis, respectively. Dopamine transporter expression was studied by immunohistochemistry. Stimulated dopamine overflow and basal extracellular dopamine levels were higher in mice lacking α-syn with a concomitant decrease in dopamine transporter expression and reuptake in the dorsal striatum. We show that α-syn deletion produces significant adaptive changes in the striatal dopaminergic system via modulation of reuptake.

Evidence for coupling between steady‐state and dynamic extracellular dopamine concentrations in the rat striatum

A previous study from our laboratory demonstrated the presence within the rat striatum of dopaminergic terminals in different dynamical states, determined at least in part by the extent to which terminals are subject to autoinhibition. The present study is designed to test the hypothesis that heterogeneity in the basal tonic extracellular dopamine concentration contributes to the variable extent of autoinhibition. We probed basal extracellular dopamine concentrations using a previously demonstrated strategy that utilizes intrastriatal microinfusion of kynurenate, a substance that according to voltammetric measurements decreases extracellular dopamine from its basal concentration. In the striatum, however, we find that the response to kynurenate infusion is itself heterogeneous, allowing a broad classification of sites within the striatum as kynurenate-insensitive and kynurenate-sensitive, respectively. These newly identified kynurenate-insensitive and sensitive sites yield substantially and significantly different evoked dopamine release as measured by voltammetry during electrical stimulation of the medial forebrain bundle. Our findings confirm the hypothesis that heterogeneity in the local basal concentration of dopamine is responsible for the variable extent of autoinhibition within the striatum and support the conclusion that the steady state and dynamical components of extracellular dopamine in this brain region are coupled.

Gonadectomy and Hormone Replacement Affects In Vivo Basal Extracellular Dopamine Levels in the Prefrontal Cortex but Not Motor Cortex of Adult Male Rats

Gonadectomy in adult male rats is known to impair performance on dopamine (DA)-dependent prefrontal cortical tasks and selectively dysregulate end points in the mesoprefrontal DA system including axon density. In this study, in vivo microdialysis and high-pressure liquid chromatography were used to determine whether short (4 day)- and/or long-term (28 day) gonadectomy and hormone replacement might also influence the more functionally relevant metric of basal extracellular DA level/tone. Assessments in medial prefrontal cortex revealed that DA levels were significantly lower than control in 4-day gonadectomized rats and similar to control in 4-day gonadectomized animals supplemented with both testosterone and estradiol. Among the long-term treatment groups, DA levels were significantly higher than control in gonadectomized rats and gonadectomized rats given estradiol but were similar to control in rats given testosterone. In contrast, extracellular DA levels measured in motor cortex were unaffected by long- or short-term gonadectomy. The effects of gonadectomy and hormone replacement on prefrontal cortical DA levels observed here parallel previously identified effects on prefrontal DA axon density and could represent hormone actions relevant to the modulation of DA-dependent prefrontal cortical function and perhaps its dysfunction in disorders such as schizophrenia, attention deficit hyperactivity disorder, and autism where males are disproportionately affected relative to females.

Hyperactivity of the dopaminergic system in NTS1 and NTS2 null mice

Neurotensin (NT) is a tridecapeptide that acts as a neuromodulator in the central nervous system mainly through two NT receptors, NTS1 and NTS2. The functional-anatomical interactions between NT, the mesotelencephalic dopamine system, and structures targeted by dopaminergic projections have been studied. The present study was conducted to determine the effects of NT receptor subtypes on dopaminergic function with the use of mice lacking either NTS1 (NTS1(-/-)) or NTS2 (NTS2(-/-)). Basal and amphetamine-stimulated locomotor activity was determined. In vivo microdialysis in freely moving mice, coupled with HPLC-ECD, was used to detect basal and d-amphetamine-stimulated striatal extracellular dopamine levels. In vitro radioligand binding and synaptosomal uptake assays for the dopamine transporters were conducted to test for the expression and function of the striatal pre-synaptic dopamine transporter. NTS1(-/-) and NTS2(-/-) mice had higher baseline locomotor activity and higher basal extracellular dopamine levels in striatum. NTS1(-/-) mice showed higher locomotor activity and exaggerated dopamine release in response to d-amphetamine. Both NTS1(-/-) and NTS2(-/-) mice exhibited lower dopamine D(1) receptor mRNA expression in the striatum relative to wild type mice. Dopamine transporter binding and dopamine reuptake in striatum were not altered. Therefore, lack of either NTS1 or NTS2 alters the dopaminergic system. The possibility that the dysregulation of dopamine transmission might stem from a deficiency in glutamate neurotransmission is discussed. The data strengthen the hypothesis that NT receptors are involved in the pathogenesis of schizophrenia and provide a potential model for the biochemical changes of the disease.

Low or High Cocaine Responding Rats Differ in Striatal Extracellular Dopamine Levels and Dopamine Transporter Number

Both humans and animals exhibit marked individual differences in cocaine responsiveness. By using the median split of cocaine-induced locomotor activity, we have classified outbred male Sprague-Dawley rats as either low or high cocaine responders (LCRs or HCRs, respectively). LCR/HCR classification predicts differences in cocaine inhibition of striatal dopamine (DA) transporters (DATs), cocaine-induced locomotor sensitization, cocaine-conditioned place preference, and motivation to self-administer cocaine. In this study, we used in vivo microdialysis to investigate whether the differential cocaine inhibition of DATs in LCRs and HCRs is translated into differential extracellular DA levels. Paralleling their locomotor profiles, LCRs and HCRS had similar basal extracellular DA levels in dorsal striatum (dSTR) and nucleus accumbens (NAc); after acute cocaine injection (10 mg/kg i.p.), HCRs showed greater cocaine-induced increases in DA than LCRs, with more pronounced differences in NAc. After repeated cocaine injection, LCRs and HCRs no longer differed in cocaine-induced locomotor activity or extracellular DA. To further explore the differential susceptibility of LCR/HCR DATs to cocaine, we used in vitro [(3)H]2-carbomethoxy-3-(4-fluorophenyl)tropane ([(3)H]WIN 35,428) binding and quantitative autoradiography to measure the number of DAT binding sites and cocaine's affinity for them. After acute cocaine administration, HCRs had fewer DAT binding sites in dSTR and NAc shell, compared to LCRs. No LCR/HCR differences were observed in DAT number after repeated cocaine injection or in cocaine's affinity. Our findings suggest that levels of striatal extracellular DA and DATs both make important contributions to initial differences in cocaine activation, which in LCRs/HCRs predict differential cocaine reward and reinforcement.

Ethanol induces stronger dopamine release in nucleus accumbens (shell) of alcohol-preferring (bibulous) than in alcohol-avoiding (abstainer) rats

Several studies on the differences between ethanol-preferring versus non-preferring rat lines suggest an innate deficit in the mesolimbic dopaminergic system as an underlying factor for ethanol volition. Rats would try to overcome such deficit by engaging in a drug-seeking behaviour, when available, to drink an ethanol solution over water. Thus, in the present study we compared the effect of a single dose of ethanol (1 g/kg, i.p.) on the extracellular levels of monoamines measured by microdialysis in the shell of nucleus accumbens of University of Chile bibulous (UChB) and University of Chile Abstainer (UChA) rats, bred for 79 and 88 generations to prefer or reject ethanol, respectively. It is reported that under basal conditions extracellular dopamine levels are lower in the bibulous than in the abstainer rats, while ethanol induced a 2-fold greater increase of dopamine release in bibulous than in abstainer rats. The greater effect of ethanol in bibulous rats was not associated to differences in blood ethanol levels, since the concentration and elimination of ethanol were virtually identical in both rat lines, indicating that bibulous rats are more sensitive to the stimulation of dopamine release by ethanol than abstainer rats. No differences were observed in 5-hydroxytryptamine or metabolites measured simultaneously under basal or ethanol-stimulating conditions in bibulous and abstainer rats. Overall, the present results suggest that a low dopaminergic tone and a strong mesolimbic dopamine response to ethanol are concerted neurochemical features associated to an ethanol-seeking behaviour in rats.

EFFECT OF COMT VAL108/158MET GENOTYPE ON EXECUTIVE FUNCTIONING IN SCHIZOPHRENIA

In the present study, using in vivo brain microdialysis, we investigated the basal extracellular dopamine (DA) and serotonin (5-HT) release in the caudal striatum (cSTR) of young (4–6 months old) and aged (10–12 months old) zitter mutant rats. The basal extracellular levels of DA release in both young and aged zitter rats were significantly lower than that of age-matched Sprague-Dawley (SD) rats, whereas only aged zitter rats showed a significant difference in the basal 5-HT release. Dopaminergic neurons were more vulnerable than serotonergic neurons in the cSTR of zitter mutant rats during aging. Perfusion of 60 mM potassium (K+) enhanced the extracellular levels of cSTR DA in the young zitter rats and the extracellular levels of both DA and 5-HT in the cSTR of the aged zitter rats. The firing rate of K+-stimulated monoamine release in the cSTR was significantly higher in the zitter rats than in the age-matched SD rats. These findings suggest that there are innate quantitative differences in the releasable pool and the availability of monoamines in the cSTR of zitter mutant rats.

Evidence for defective mesolimbic dopamine exocytosis in obesity‐prone rats

The association between dietary obesity and mesolimbic systems that regulate hedonic aspects of feeding is currently unresolved. In the present study, we examined differences in baseline and stimulated central dopamine levels in obesity-prone (OP) and obesity-resistant (OR) rats. OP rats were hyperphagic and showed a 20% weight gain over OR rats at wk 15 of age, when fed a standard chow diet. This phenotype was associated with a 50% reduction in basal extracellular dopamine, as measured by a microdialysis probe in the nucleus accumbens, a projection site of the mesolimbic dopamine system that has been implicated in food reward. Similar defects were also observed in younger animals (4 wk old). In electrophysiology studies, electrically evoked dopamine release in slice preparations was significantly attenuated in OP rats, not only in the nucleus accumbens but also in additional terminal sites of dopamine neurons such as the accumbens shell, dorsal striatum, and medial prefrontal cortex, suggesting that there may be a widespread dysfunction in mechanisms regulating dopamine release in this obesity model. Moreover, dopamine impairment in OP rats was apparent at birth and associated with changes in expression of several factors regulating dopamine synthesis and release: vesicular monoamine transporter-2, tyrosine hydroxylase, dopamine transporter, and dopamine receptor-2 short-form. Taken together, these results suggest that an attenuated central dopamine system would reduce the hedonic response associated with feeding and induce compensatory hyperphagia, leading to obesity.

Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum.

Acute systemic administration of salvinorin A, a naturally occurring kappa-opioid receptor (KOPr) agonist, decreases locomotion and striatal dopamine (DA) overflow. Conventional and quantitative microdialysis techniques were used to determine whether salvinorin A infusion into the dorsal striatum (DSTR) decreases DA overflow by altering DA uptake or release. The influence of repeated salvinorin A administration on basal DA dynamics and cocaine-evoked alterations in DA overflow and locomotion was also assessed. Salvinorin A was administered via the dialysis probe (0; 20-200 nM) or via intraperitoneal (i.p.) injection (1.0 or 3.2 mg/kg per day x 5 days). The effects of a challenge dose of cocaine were examined 48 h after repeated salvinorin treatment. Retrodialysis of salvinorin A produced a dose-related, KOPr antagonist reversible, decrease in DA levels. Extracellular DA levels were decreased whereas DA extraction fraction, which provides an estimate of DA uptake, was unaltered. In contrast to its acute administration, repeated salvinorin A administration did not modify dialysate DA levels. Similarly, neither basal extracellular DA levels nor DA uptake was altered. Unlike synthetic KOPr agonists, prior repeated administration of salvinorin A did not attenuate the locomotor activating effects of an acute cocaine (20 mg/kg, i.p.) challenge. However, cocaine-evoked DA overflow was enhanced. These data demonstrate that acute, but not repeated, salvinorin A administration decreases mesostriatal neurotransmission and that activation of DSTR KOPr is sufficient for this effect. Differences in the interaction of salvinorin and synthetic KOPr agonists with cocaine suggest that the pharmacology of these agents may differ.

Characterization of the striatal dopaminergic neurotransmission in MEN2B mice with elevated cerebral tissue dopamine

The Ret receptor tyrosine kinase is the common signaling receptor for the glial cell line-derived neurotrophic factor (GDNF) family ligands. The Met918Thr mutation leads to constitutive activation of Ret and is responsible for dominantly inherited cancer syndrome MEN2B. Previously, we found that the mice carrying the mutation (MEN2B mice) have profoundly increased tissue dopamine (DA) concentrations in the striatum as well as increased striatal levels of tyrosine hydroxylase (TH) and dopamine transporter. The aim of this study was to characterize the striatal dopaminergic neurotransmission in MEN2B mice and to clarify the mechanisms by which they compensate their over-production of DA. We found that tyrosine hydroxylase activity and DA synthesis are increased in MEN2B mice. Augmented effects of alpha-methyl-para-tyrosine (alphaMT, an inhibitor of TH) and tetrabenazine (VMAT2 blocker) on DA levels suggest that also storage of DA is increased in MEN2B mice. There was no difference in the basal extracellular DA concentrations or potassium-evoked DA release between the genotypes. The effects of cocaine and haloperidol were also similar between the genotypes as assessed by in vivo microdialysis. However, with in vivo voltammetry we found increase in stimulated DA release in MEN2B mice and detailed analysis of DA overflow showed that uptake of DA was also enhanced in MEN2B mice. Thus, our data show that enhanced synthesis of DA leading to increased storage and releasable pools in pre-synaptic terminals in MEN2B mice apparently also leads to increased DA release, which in turn is compensated by higher dopamine transporter activity.

Amphetamine effects in microtine rodents: A comparative study using monogamous and promiscuous vole species

We compared amphetamine-induced dopamine release in the nucleus accumbens of vole species that exhibit differing mating systems to examine potential interactions between social organization and substance abuse. We found no species or regional differences in basal extracellular dopamine, however, monogamous voles had greater and longer-lasting increases in extracellular dopamine after amphetamine treatment than did promiscuous voles. We then examined whether amphetamine-induced increase in extracellular dopamine could induce pair bonds in monogamous voles. We found that, despite increasing dopamine in the nucleus accumbens, amphetamine administration did not induce pair-bonds in male prairie voles unless the animals were pretreated to preclude D1 receptor activation, which is known to inhibit pair-bond formation. These results support suggestions that social attachment and substance abuse share a common neural substrate.

Deficiency of central dopamine in multiple obesity models.

The contribution of mesolimbic dopamine to the development of dietary obesity is not yet well understood. Because this system responds to feeding, dietary and/or genetic obesity could be linked to central dopamine deficiencies. In this study, we use inbred obesity-prone and obesity-resistant Sprague-Dawley adult female rats (Charles River Laboratories) to show that obesity-prone animals have lower basal extracellular dopamine levels in the nucleus accumbens shell in vivo (0.029±0.002 vs. 0.040±0.001 pg/sample, p p p p

Extracting the basal extracellular dopamine concentrations from the evoked responses: Re-analysis of the dopamine kinetics

Fast-scan cyclic voltammetry in conjunction with carbon fiber microelectrode has been used to study dopamine (DA) release and uptake mechanisms in rat brains because of the smaller size of the electrode and the subsecond resolution. Current voltammetry data were analyzed by a DA kinetic model assuming a zero baseline, which is in conflict with existing microdialysis findings and a recent claim of the striatal extracellular DA concentration at micromolar levels. This work applied a new analysis approach based on a modified DA kinetic model to analyze the kinetics of electrically evoked DA overflow in the caudate-putamen of anesthetized rats. The DA uptake parameters were fitted from the electrical stimulation phase, and subsequently used to calculate theoretical DA uptake rates. Comparison of the theoretical uptake rates with experimental clearance rates allows for the study of the tonic DA release process following electrical stimulations. Analyses of DA voltammetry data suggest that the locally averaged basal level of extracellular DA in the rat striatum might be confined between 95 and 220 nM. The disparate time scales in the clearance kinetics of endogenous and exogenous DA were investigated. Long-distance diffusion could only partially explain the slow clearance time course of exogenous DA. Model simulations and parameter analyses on evoked DA responses indicate that suppression of the nonevoked DA release process immediately following electrical stimulation cannot completely account for the rapid clearance of the electrically evoked DA. Inconsistency in the measured uptake strengths in the literature studying endogenous and exogenous DA remains to be investigated in the future.

Dopamine release is impaired in a mouse model of DYT1 dystonia

Early onset torsion dystonia, the most common form of hereditary primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the protein torsinA. This form of dystonia is referred to as DYT1. We have used a transgenic mouse model of DYT1 dystonia [human mutant-type (hMT)1 mice] to examine the effect of the mutant human torsinA protein on striatal dopaminergic function. Analysis of striatal tissue dopamine (DA) and metabolites using HPLC revealed no difference between hMT1 mice and their non-transgenic littermates. Pre-synaptic DA transporters were studied using in vitro autoradiography with [(3)H]mazindol, a ligand for the membrane DA transporter, and [(3)H]dihydrotetrabenazine, a ligand for the vesicular monoamine transporter. No difference in the density of striatal DA transporter or vesicular monoamine transporter binding sites was observed. Post-synaptic receptors were studied using [(3)H]SCH-23390, a ligand for D(1) class receptors, [(3)H]YM-09151-2 and a ligand for D(2) class receptors. There were again no differences in the density of striatal binding sites for these ligands. Using in vivo microdialysis in awake animals, we studied basal as well as amphetamine-stimulated striatal extracellular DA levels. Basal extracellular DA levels were similar, but the response to amphetamine was markedly attenuated in the hMT1 mice compared with their non-transgenic littermates (253 +/- 71% vs. 561 +/- 132%, p < 0.05, two-way anova). These observations suggest that the mutation in the torsinA protein responsible for DYT1 dystonia may interfere with transport or release of DA, but does not alter pre-synaptic transporters or post-synaptic DA receptors. The defect in DA release as observed may contribute to the abnormalities in motor learning as previously documented in this transgenic mouse model, and may contribute to the clinical symptoms of the human disorder.

Stress-induced changes in extracellular dopamine and serotonin in the medial prefrontal cortex and dorsal hippocampus of prenatally malnourished rats

Prenatal protein malnutrition continues to be a significant problem in the world today. Exposure to prenatal protein malnutrition increases the risk of a number of neuropsychiatric disorders in adulthood including depression, schizophrenia and attentional deficit disorder. In the present experiment, we have examined the effects of stress on extracellular serotonin (5-HT) and dopamine in the medial prefrontal cortex and dorsal hippocampus of rats exposed in utero to protein malnutrition. The medial prefrontal cortex and dorsal hippocampus were chosen as two limbic forebrain regions involved in learning and memory, attention and the stress response. Extracellular 5-HT and dopamine were determined in the medial prefrontal cortex and dorsal hippocampus of adult male Sprague–Dawley rats using dual probe in vivo microdialysis. Basal extracellular 5-HT did not differ between malnourished and well-nourished controls in either the medial prefrontal cortex or the dorsal hippocampus. Basal extracellular dopamine was significantly decreased in the medial prefrontal cortex of malnourished animals. Restraint stress (20 m) produced a significant rise in extracellular dopamine in the medial prefrontal cortex of well-nourished rats but did not alter release in malnourished rats. In malnourished rats, stress produced an increase in 5-HT in the hippocampus, whereas stress produced a decrease in 5-HT in the hippocampus of well-nourished rats. These data demonstrate that prenatal protein malnutrition alters dopaminergic neurotransmission in the medial prefrontal cortex as well as alters the dopaminergic and serotonergic response to stress. These changes may provide part of the bases for alterations in malnourished animals' response to stress.

Activation of serotonin-3 receptors increases dopamine release within the ventral tegmental area of Wistar and alcohol-preferring (P) rats

The objectives of the present study were to (a) examine the effects of activating serotonin-3 (5-HT 3) receptors on dopamine (DA) release in the anterior and posterior ventral tegmental area (VTA) of Wistar rats and (b) determine if there are differences in 5-HT 3–stimulated DA release in the VTA between alcohol-preferring (P) and Wistar rats. Local perfusion with the 5-HT 3 agonist 1-( m-chlorophenyl)-biguanide (CPBG) in the anterior and posterior VTA stimulated DA release in both the regions. The CPBG-stimulated increase in extracellular DA levels was significantly higher in the posterior than anterior VTA of Wistar rats. The basal extracellular DA levels were not significantly different between the anterior and posterior VTA of Wistar rats. However, the basal extracellular DA levels were significantly higher in the posterior VTA of Wistar rats than P rats. Local perfusion of CPBG into the posterior VTA stimulated somatodendritic DA release significantly more in the P than Wistar rat. Overall, the results indicate that there may be a heterogeneous distribution of functional 5-HT 3 receptors within the VTA, with higher numbers in the posterior than anterior VTA, and that, compared to 5-HT 3 receptors in Wistar rats, 5-HT 3 receptors in the posterior VTA of P rats may be more responsive to stimulation.

Kynurenic acid leads, dopamine follows: A new case of volume transmission in the brain?

Intrastriatal infusion of nanomolar concentrations of kynurenic acid (KYNA), an astrocyte-derived neuroinhibitory tryptophan metabolite, reduces basal extracellular dopamine (DA) levels in the rat striatum. This effect is initiated by the inhibition of alpha7 nicotinic acetylcholine receptors (alpha7nAChRs) on glutamatergic afferents. The present study was designed to further investigate this functional link between KYNA and DA using striatal microdialysis in awake animals. In rats, increases in KYNA, caused by intrastriatal infusions of KYNA itself (100 nM) or of KYNA's bioprecursor L-kynurenine (2 microM), were associated with substantial reductions in DA. Co-infusion of KYNA with the alpha7nAChR agonist galantamine (5 microM), but not with the NMDA receptor agonist D-serine (100 nM), prevented this effect. Moreover, KYNA also reduced DA levels in the NMDA-lesioned striatum. Conversely, extracellular DA levels were enhanced when KYNA formation was compromised, either by astrocyte poisoning with fluorocitrate or by perfusion with aminooxyacetic acid (AOAA; 5 mM), a non-specific inhibitor of KYNA synthesis. Notably, this effect of AOAA was prevented by co-perfusion with 100 nM KYNA. In the striatum of 21 day-old mice with a targeted deletion of kynurenine aminotransferase II, extracellular KYNA levels were reduced by 67 +/- 6%, while extracellular DA levels were simultaneously increased by 170 +/- 14%. Taken together, a picture emerges where fluctuations in the astrocytic production of KYNA, possibly through volume transmission, inversely regulate dopaminergic tone. This newly uncovered mechanism may profoundly influence DA function under physiological and pathological conditions.

Blockade of tachykinin NK1 receptors attenuates stress‐induced rise of extracellular noradrenaline and dopamine in the rat and gerbil medial prefrontal cortex

Substance P receptor antagonists cause antidepressant- and anxiolytic-like effects in rodents that are thought to involve brain monoamines. In the present study, we examined the effects of the NK1 receptor antagonist GR-205,171 on basal and stress-induced rise of extracellular noradrenaline (NA) and dopamine (DA) in the medial prefrontal cortex (mPFC) of conscious rats and gerbils with the in vivo microdialysis technique. GR-205,171 given intraperitoneally to rats (10 and 30 mg/kg) and gerbils (0.3 and 1 mg/kg) did not affect extracellular NA in either species and increased extracellular DA in rats. Forty minutes of immobilization increased extracellular NA and DA by, respectively, 179% and 188% of baseline values in rats and 222% and 316% of baseline values in gerbils. At 10 mg/kg, GR-205,171 attenuated the stress-induced increase of extracellular NA in the rat. At 30 mg/kg, GR-205,171 suppressed the effect of stress on extracellular DA but had no effect on NA. A lower dose (1 mg/kg) attenuated the stress-induced rise of extracellular NA and DA in the mPFC of gerbils. The results show that blockade of NK1 receptors marginally increased basal extracellular DA in rats but had no effect in gerbils, whereas the stress-induced rise of extracellular NA and DA was markedly attenuated in both species. It is suggested that catecholamines may contribute to the functional effects of GR-205,171.

In vivo brain microdialysis studies on the striatal dopamine and serotonin release in zitter mutant rats

In the present study, using in vivo brain microdialysis, we investigated the basal extracellular dopamine (DA) and serotonin (5-HT) release in the caudal striatum (cSTR) of young (4–6 months old) and aged (10–12 months old) zitter mutant rats. The basal extracellular levels of DA release in both young and aged zitter rats were significantly lower than that of age-matched Sprague-Dawley (SD) rats, whereas only aged zitter rats showed a significant difference in the basal 5-HT release. Dopaminergic neurons were more vulnerable than serotonergic neurons in the cSTR of zitter mutant rats during aging. Perfusion of 60 mM potassium (K +) enhanced the extracellular levels of cSTR DA in the young zitter rats and the extracellular levels of both DA and 5-HT in the cSTR of the aged zitter rats. The firing rate of K +-stimulated monoamine release in the cSTR was significantly higher in the zitter rats than in the age-matched SD rats. These findings suggest that there are innate quantitative differences in the releasable pool and the availability of monoamines in the cSTR of zitter mutant rats.