Dialysate Dopamine Concentrations Research Articles

Risperidone and escitalopram co-administration: A potential treatment of schizophrenia symptoms with less side effects.

Schizophrenia is a psychiatric disorder characterized by positive and negative symptoms often accompanied by depression and cognitive deficits. Positive symptoms, like delusions and hallucinations are caused by an excess of dopamine (DA) signaling and are treated with the second generation antipsychotic drugs. Negative symptoms of schizophrenia are represented by social withdrawal, apathy and blunted emotional response. It was demonstrated that co-administration of risperidone and selective serotonin reuptake inhibitors alleviated depressive symptoms and cognitive dysfunction in animal models of schizophrenia. Moreover, combination of fluoxetine or mirtazapine with risperidone increased DA and 5-hydroxytryptamine (5-HT) release in the rat frontal cortex more potently than either drug given separately. The present study aimed to investigate whether combination of risperidone and escitalopram is effective in increasing DA and 5-HT release. The extracellular level of neurotransmitters in the rat frontal cortex and nucleus accumbens was examined using microdialysis in freely moving animals. The dialysate concentration of DA and 5-HT was assayed by HPLC. It was found that risperidone (0.2 and 1mg/kg) and escitalopram (5 and 10mg/kg) given together significantly increased cortical DA and 5-HT levels and were more efficient in enhancing neurotransmitter concentrations than any single-drug treatment. A similar effect on DA and 5-HT release was observed in the nucleus accumbens after administration of risperidone (1mg/kg) and escitalopram (5mg/kg). The present study demonstrates that co-administration of risperidone and escitalopram may be used to treat positive and negative symptoms of schizophrenia and will allow to minimize the drugs' side effects.

Hypofunction of prefrontal cortex NMDA receptors does not change stress-induced release of dopamine and noradrenaline in amygdala but disrupts aversive memory

A dysfunction of prefrontal cortex has been associated with the exacerbated response to stress observed in schizophrenic patients and high-risk individuals to develop psychosis. The hypofunction of NMDA glutamatergic receptors induced by NMDA antagonists produces cortico-limbic hyperactivity, and this is used as an experimental model to resemble behavioural abnormalities observed in schizophrenia. The aim of the present study was to investigate whether injections of NMDA antagonists into the medial prefrontal cortex of the rat change (1) the increases of dopamine, noradrenaline and corticosterone concentrations produced by acute stress in amygdala, and (2) the acquisition of aversive memory related to a stressful event. Male Wistar rats were implanted with guide cannulae to perform microdialysis and bilateral microinjections (0.5 μl/side) of the NMDA antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phophonic acid (CPP) (25 and 100 ng). Prefrontal injections were performed 60 min before restraint stress in microdialysis experiments, or training (footshock; 0.6 mA, 2 s) in inhibitory avoidance test. Retention latency was evaluated 24 h after training as an index of aversive memory. Acute stress increased amygdala dialysate concentrations of dopamine (160% of baseline), noradrenaline (145% of baseline) and corticosterone (170% of baseline). Prefrontal injections of CPP did not change the increases of dopamine, noradrenaline or corticosterone produced by stress. In contrast, CPP significantly reduced the retention latency in the inhibitory avoidance test. These results suggest that the hypofunction of prefrontal NMDA receptors does not change the sensitivity to acute stress of dopamine and noradrenaline projections to amygdala but impairs the acquisition of aversive memory.

Reverse microdialysis of a 5-HT2A receptor antagonist alters extracellular glutamate levels in the striatum of the MPTP mouse model of Parkinson’s disease

Clinical observations have suggested that antagonism of 5-HT2A receptors may benefit patients with parkinsonian symptomatology. The mechanism of the antiparkinsonian effects of 5-HT2A receptor antagonists has not been fully elucidated. We have shown that the selective 5-HT2A receptor antagonist M100907 [R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenethyl)]-4-piperidinemethanol] improved motor impairments in mice treated with the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In Parkinson’s disease (PD) patients and animal models of parkinsonism dopamine denervation is associated with increased cortico-striatal glutamatergic transmission. We hypothesized that 5-HT2A receptor antagonists may exert their antiparkinsonian effects by decreasing striatal glutamate. Here, using in vivo microdialysis, we have shown an increased basal level of extracellular striatal glutamate when measured 3weeks after MPTP administration. The local administration of M100907 to the striatum significantly decreased striatal extracellular glutamate levels in MPTP-treated and saline treated mice. Basal extracellular serotonin (5-HT) levels were also elevated, whereas dopamine (DA) levels were significantly reduced in the striatum of MPTP-treated mice. Infusion of M100907 into the striatum produced no effect on dopamine or 5-HT levels. Local application of tetrodotoxin suppressed glutamate, 5-HT and DA concentrations in striatal dialysates in the presence or absence of M100907. The striatal expression of the glutamate transporter GLT1 was unchanged. However, there was an upregulation of the expression of 5-HT2A receptors in the striatum of MPTP-treated animals. Our data provide further evidence of enhanced glutamatergic neurotransmission in parkinsonism and demonstrate that blocking 5-HT2A receptors in the striatum will normalize glutamatergic neurotransmission.

Relationship of 5-hydroxy indole acetic acid, melatonin and dopamine in rat model of Parkinson’s disease induced by 6-hydroxydopamine

Objective To investigate dynamic changes in extracellular striatal 5-hydroxy indole acetic acid (5-HIAA) and melatonin (MLT) concentrations in the 6-hydroxydopamine (6-OHDA)-induced Parkinson’s disease (PD) rat models. Methods A hemiparkinsonium rat model was established by a unilateral injection of 6-OHDA into the right substantia nigra pars compacta (SNc) and the right medial forebrain bundle (MFB). Dialysate samples were collected at 10: 00 in the lesioned striatum by microdialysis at 1, 2, 3 and 4 weeks post-lesion, respectively. The levels of dopamine (DA) and 5-HIAA, as well as MLT in dialysate samples were measured by high performance liquid chromotorgraphy (HPLC). Results One week after surgery, the level of DA in PD group was (1.19±0.22) ng/ml, which was distinctly lower than those in the vehicle group ((8.62±0.73) ng/ml) and the sham group ((8.73±0.78) ng/ml) (P<0.01). The levels of 5-HIAA in PD group had a downward trend, but there were no significant differences. The level of MLT in PD group was (43.31±11.37)pg/ml at 4 weeks post-lesion, and significantly higher than those in the vehicle group ((19.13±5.38)pg/ml) and the sham group ((19.80±6.96)pg/ml) (P<0.05). The striatal dialysate DA and 5-HIAA concentrations had a good positive correlation in the PD group (r=0.867, P<0.01). Conclusion Decreased DA level concomitantly with changes of 5-HIAA and MLT in the ipsilateral striatum of 6-OHDA-induced PD rats, and these changes may be related to PD progression. Key words: Parkinson’s disease; Dopamine; 5-hydroxy indole acetic acid; Melatonin

Imaging dopamine transmission in the frontal cortex: a simultaneous microdialysis and [11C]FLB 457 PET study

In a recent human PET study we demonstrated the ability to detect amphetamine-induced dopamine release in the prefrontal cortex as a reduction in the binding of the dopamine D2/3 radioligand [11C]FLB 457. A key requirement for validating this paradigm for use in clinical studies is demonstrating that the changes in [11C]FLB 457 binding observed with PET following amphetamine are related to changes in dialysate dopamine concentration as measured with microdialysis. Microdialysis and PET experiments were performed to compare, in five rhesus monkeys, amphetamine-induced dopamine release and [11C]FLB 457 displacement in the frontal cortex after three doses of amphetamine (0.3 mg/kg, 0.5 mg/kg, and 1 mg/kg). Amphetamine led to a significant dose-dependent increase in dialysate dopamine (DA, 0.3 mg/kg: 999 ± 287%; 0.5 mg/kg: 1320 ± 432%; 1.0 mg/kg: 2355 ± 1026%) as measured with microdiaysis and decrease in [11C]FLB 457 binding potential (BPND, 0.3 mg/kg: −6 ± 6%; 0.5 mg/kg: −16 ± 4%; 1.0 mg/kg: −24 ± 2%) as measured with PET. The relationship between amphetamine-induced peak ΔDA and Δ[11C]FLB 457 BPND in the frontal cortex was linear. The results of this study clearly demonstrate that the magnitude of dialysate dopamine release is correlated with the magnitude of the reduction in [11C]FLB 457 BPND in the frontal cortex. The use of the [11C]FLB 457-amphetamine imaging paradigm in humans should allow for characterization of prefrontal cortical dopamine release in neuropsychiatric disorders such as schizophrenia and addiction.

Dynamic changes in dopamine tone during self-stimulation of the ventral tegmental area in rats

In a prior study, phasic release of dopamine (DA) in the nucleus accumbens (NAc) was only transiently and rarely detected by means of fast-scan cyclic voltammetry (FCSV) in rats already trained to work for electrical stimulation of the ventral tegmental area (VTA) on a continuous reinforcement schedule. However, in rats receiving rewarding electrical stimulation via lateral hypothalamic (LH) electrodes, elevated DA tone in the NAc terminal field was detected via microdialysis for up to 2 h, even when short (1.5 s) inter-train intervals were employed. To better characterize the similarities and differences between the FSCV and microdialysis measurements, we trained rats to self-administer VTA stimulation under conditions similar to those employed in the initial FSCV study. The results resemble those obtained by means of microdialysis in rats receiving LH stimulation but differed from the prior FSCV data. Although the concentration of DA in dialysate obtained from NAc probes did fall after having peaked at the 30 min mark, this decline set in much later than in the FSCV studies, and elevated DA tone could still be detected after 110 min of self-stimulation. The stimulation-induced peak in DA tone could be restored by a 30 min rest period, a manipulation that was ineffective previously in restoring the FSCV measure of phasic release. These findings are discussed in terms of the differential sensitivity of the FSCV and microdialysis methods to phasic and tonic signaling by DA neurons and to different transitions between their activity states.

Predictable and unpredictable rewards produce similar changes in dopamine tone.

Unpredicted rewards trigger more vigorous phasic responses in midbrain dopamine (DA) neurons than predicted rewards. However, recent evidence suggests that reward predictability may fail to influence DA signaling over longer scales: In rats passively receiving rewarding electrical brain stimulation, the concentration of DA in dialysate obtained from nucleus accumbens probes was similar regardless of whether reward onset was predictable (G. Hernandez et al., 2006). The present experiment followed up on these findings by requiring the rats to work for the rewarding stimulation, thus confirming whether they indeed learned the timing and predictability of reward delivery. Performance under fixed-interval and variable-interval schedules was compared, and DA levels in the nucleus accumbens were measured by means of in vivo microdialysis. The observed patterns of operant responding indicate that the rats working under the fixed-interval schedule learned to predict the time of reward availability, whereas the rats working under the variable-interval schedule did not. Nonetheless, indistinguishable changes in DA concentration were observed in the 2 groups. Thus, reward predictability had no discernable effect on a measure believed to track the slower components of DA signaling.

Partial depletion of dopamine in substantia nigra impairs motor performance without altering striatal dopamine neurotransmission

Previous data indicate that the release of somatodendritic dopamine in substantia nigra influences motor activity and coordination, but the relative importance of somatodendritic dopamine release vs. terminal striatal dopamine release remains to be determined. We utilized simultaneous measurement of dopamine neurotransmission by microdialysis and motor performance assessment by rotarod test to investigate the effects of local dopamine depletion in rats. The vesicular monoamine transporter inhibitor tetrabenazine (100 microm) was administered locally in substantia nigra as well as in striatum. Nigral tetrabenazine administration decreased nigral dopamine dialysate concentrations to 7% of baseline and whole-tissue dopamine content by 60%. Nigral dopamine depletion was associated with a reduction in motor performance to 73 +/- 6% of pretreatment value, but did not alter dialysate dopamine concentrations in the ipsilateral striatum. Striatal tetrabenazine administration decreased striatal dopamine dialysate concentrations to 5% of baseline and doubled the somatodendritic dopamine response to motor activity, but it was not associated with changes in motor performance or dopamine content in striatal tissue. Simultaneous treatment of substantia nigra and striatum reduced motor performance to 58 +/- 5% of the pretreatment value. The results of this study indicate that partial depletion of nigral dopamine stores can significantly impair motor functions, and that increased nigral dopamine release can counteract minor impairments of striatal dopamine transmission.

Reduced basal and ethanol stimulation of striatal extracellular dopamine concentrations in dopamine D2 receptor knockout mice

The present study was undertaken to examine the role of the dopamine (DA) D2 receptor in the ethanol-evoked DA response in the ventral striatum. We performed microdialysis experiments using the D2 null mutant and wild-type controls and measured the effect of an intraperitoneal (i.p.) injection of either saline or ethanol (2 g/kg) on dialysate DA concentrations in the ventral striatum. Dialysate ethanol concentrations were also determined in the samples from the ventral striatum. In addition, the effects of quinpirole, a D2/D3 agonist, were examined in both the ventral and dorsal striatum. Basal dialysate concentrations of DA were significantly reduced in both the ventral and dorsal striatum of the D2 knockouts compared with wild-type controls. Ethanol administration significantly enhanced ventral striatal DA in both groups, but the increase in dialysate DA concentration was 3.5-fold higher in the wild-type controls. The time course of dialysate ethanol concentrations was similar in the two groups. Saline injection did not alter DA concentrations in either the ventral or dorsal striatum. However, quinpirole (0.3 mg/kg) administration significantly depressed striatal dialysate DA concentrations in the wild-type mice, but not in the D2 knockouts. The results suggest that the D2 receptor is necessary for normal development and regulation of striatal extracellular DA concentrations, but the mechanism for this alteration is unclear. In addition, the blunted ethanol-evoked DA response in the D2 knockouts may contribute, in part, to some of the behavioral deficits previously observed in response to ethanol.

Modulation of dopamine release by striatal 5‐HT2C receptors

Previous work has demonstrated that dopamine (DA) transmission is regulated by serotonin-2C (5-HT2C) receptors but the site(s) in the brain where these receptors are localized is not known. The present work utilized in vivo microdialysis to investigate the modulation of DA release by 5-HT2C receptors localized in the nerve terminal regions of the mesocortical and nigrostriatal DA pathways. Microdialysis probes implanted in the striatum or the prefrontal cortex (PFC) measured dialysate DA concentrations, while the selective 5-HT2B/2C inverse agonist SB 206553 was given locally by reverse dialysis into these terminal regions. Additionally, the effects of the 5-HT2C agonist mCPP on striatal DA were measured. Local administration of SB 206553 (0.1-100 microM) into the striatum increased DA efflux in a concentration-dependent manner. Systemic administration of mCPP (1.0 mg/kg i.p.) decreased striatal DA and attenuated the SB 206553-induced increase. In contrast, infusion of SB 206553 (0.1-500 microM) by reverse dialysis into the PFC had no significant effect on basal DA efflux in this region. Additionally, high concentrations of SB 206553 had no effect on high potassium (K(+))-stimulated DA release in the PFC. These data contribute to a body of evidence indicating that 5-HT2C receptors inhibit nigrostriatal dopaminergic transmission. In addition, the results suggest that the nigrostriatal system is regulated by 5-HT2C receptors localized in the dorsal striatum. Elucidating the mechanisms by which serotonin (5-HT) modulates striatal and prefrontocortical DA concentrations may lead to improvements in the treatment of diverse syndromes such as schizophrenia, Parkinson's disease, anxiety, drug abuse, and/or depression.

Catecholamine release in human skin—a microdialysis study

Dermal microdialysis might be a promising tool to investigate properties of sympathetic neurons in the skin as investigation of peripheral noradrenergic neurons in humans usually relies on highly variable vasoconstrictor reflexes or on indirect measurements like skin temperature recordings. To evaluate this technique, 21 experiments were performed in 15 healthy subjects with four intracutaneous microdialysis fibers (diameter, 200 μm; cutoff, 5 kDa) at hands or feet. After 60 min, saline perfusion tyramine at concentrations of 0.195 to 200 μg/ml was applied for 15 min followed by a 15-min saline perfusion again. Catecholamine concentrations were detected through high-performance liquid chromatography with electrochemical detection. Control experiments were performed in human skin homogenates with and without tyramine incubation. In vivo, norepinephrine (NE) concentration increased from 36.3 ± 10.2 pg/ml to 84.4 ± 18.4 pg/ml ( P < 0.001) during stimulation with tyramine, dialysate dopamine (DA) concentration increased from 105.2 ± 36.5 pg/ml to 7162.4 ± 3972.4 pg/ml ( P < 0.001). Both tyramine-induced NE and DA release were dose-dependent (NE: r = 0.438, P < 0.05; DA: r = 0.894, P < 0.001). In skin homogenates, tyramine incubation led to a significant increase of DA concentrations (387.0 ± 34.8 pg/ml, controls: 13.2 ± 2.4 pg/ml; P < 0.05), while NE and epinephrine levels remained unchanged. In conclusion, our experiments show that dermal microdialysis is capable of locally measuring catecholamines in human skin. This offers the opportunity to investigate the function of the peripheral sympathetic nervous system. Additional to non-enzymatic oxidation, DA increase probably reflects metabolic degradation of tyramine by non-neuronal pathways and therefore does not reflect local sympathetic innervation.

Effect of amphetamine, cocaine and depolarization by high potassium on extracellular dopamine in the nucleus accumbens shell of SHR rats. An in vivo microdyalisis study

Spontaneously hypertensive rats (SHR) exhibit behavioural abnormalities (hyperactivity and hyper reactivity to stress) that resemble the behavioural abnormalities of human attention-deficit with hyperactivity disorder (ADHD). Because dopamine has been implicated in ADHD we studied by in vivo microdialysis the dopamine output in the nucleus accumbens (NAc) shell of 6 week-old (pre-hypertensive stage) SHR rats and in their normotensive age matched Wistar Kyoto controls (WKY). We observed that SHR rats had significant higher basal dialysate dopamine concentrations (about 20%) than WKY. Systemic administration of amphetamine (0.25 and 0.5 mg/kg s.c.), and methylphenidate (1 and 2 mg/kg i.p.) produced an higher increase in dialysate dopamine in the NAc shell of SHR rats as compared with WKY rats, although only after the administration of the lowest dose of amphetamine and methylphenidate this difference was found to be significant. In contrast when the microdialysis fiber was perfused by 30 or 60 mM K +, a lower increase of dialysate dopamine was observed in SHR rats as compared with WKY rats. These apparently contradictory results can be explained by postulating that SHR rats have a higher tone of NAc shell dopamine transmission and synthesis associated with a lower storage capacity of vesicles in dopamine terminals of the same area.

Role of the nitric oxide/cyclic GMP pathway and extracellular environment in the nitric oxide donor-induced increase in dopamine secretion from PC12 cells: a microdialysis in vitro study.

In vitro microdialysis was used to investigate the mechanism of nitric oxide (NO) donor-induced changes in dopamine (DA) secretion from PC12 cells. Infusion of the NO-donor S-nitroso-N-acetylpenicillamine (SNAP, 1.0 mm) induced a long-lasting increase in DA and 3-methoxytyramine (3-MT) dialysate concentrations. SNAP-induced increases were inhibited either by pre-infusion of the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4] oxadiazolo[4,3]quinoxalin-1-one (ODQ, 0.1 mm) or by Ca2+ omission. Ca2+ re-introduction restored SNAP effects. SNAP-induced increases in DA + 3-MT were unaffected by co-infusion of the l-type Ca2+ channel inhibitor nifedipine. The NO-donor (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR-3, 1.0 mm) induced a short-lasting decrease in dialysate DA + 3-MT. Ascorbic acid (0.2 mm) co-infusion allowed NOR-3 to increase dialysate DA + 3-MT. ODQ pre-infusion inhibited NOR-3 + ascorbic acid-induced DA + 3-MT increases. Infusion of high K+ (75 mm) induced a 2.5-fold increase in dialysate DA + 3-MT. The increase was abolished by NOR-3 co-infusion. Conversely, co-infusion of ascorbic acid (0.2 mm) with NOR-3 + high K+ restored high K+ effects. Co-infusion of nifedipine inhibited high K+-induced DA + 3-MT increases. These results suggest that activation of the NO/sGC/cyclic GMP pathway may be the underlying mechanism of extracellular Ca2+-dependent effects of exogenous NO on DA secretion from PC12 cells. Extracellular Ca2+ entry may occur through nifedipine-insensitive channels. NO effects and DA concentrations in dialysates largely depend on both the timing of NO generation and the extracellular environment in which NO is generated.

Influence of r-type (Ca v2.3) and t-type (Ca v3.1–3.3) antagonists on nigral somatodendritic dopamine release measured by microdialysis

The release of dopamine from soma and dendrites of dopaminergic neurons in substantia nigra has been reported to be calcium-dependent, but it remains to be determined which calcium channels mediate this effect. We have used in vivo microdialysis in rat substantia nigra and striatum to investigate the effect of Ca v3.1–3.3 (T-type) and Ca v2.3 (R-type) calcium channel antagonists on somatodendritic and terminal dopamine release. Local reverse dialysis administration of 0.1–10 μM of the Ca v2.3 inhibitor SNX-482, or 100 μM of mibefradil, decreased the concentrations of dopamine and its metabolites in dialysate from substantia nigra, whereas 1 μM mibefradil or 40–80 μM nickel(II) induced an increase in nigral dialysate dopamine concentrations. Dopamine concentrations in striatal dialysates were decreased only by 10 μM of SNX-482 or 100 μM of mibefradil. Nickel(II) induced an increase in striatal dialysate dopamine concentration similar to that in substantia nigra. The results indicate a role for Ca v2.3 (R-type) voltage sensitive calcium channels in the calcium dependency of somatodendritic dopamine release, but argue against a calcium dependency mediated substantially by Ca v3.1–3.3 (T-type) channels.

Effects of sufentanil on the release and metabolism of dopamine and ascorbic acid and glutamate release in the striatum of freely moving rats

The effects of either intraperitoneally (i.p.) or intrastriatally administered sufentanil on the release and metabolism of dopamine (DA) in the rat striatum were evaluated using in vivo microdialysis. Dialysate concentrations of DA and its acidic metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased following i.p. administration of either clinical anesthetic (20 μg/kg) or clinical analgesic (1 μg/kg) sufentanil doses. In addition, sufentanil also increased uric acid concentrations. In contrast, dialysate ascorbic acid and glutamate concentrations were unaffected. Intrastriatal infusion of sufentanil (250 nM) induced only a short lasting decrease in dialysate DA. Subcutaneous naloxone (1.0 mg/kg) abolished sufentanil-induced increases in dialysate DA, DOPAC+HVA and uric acid; however, naloxone (0.1 mM) failed to affect these increases when infused intrastriatally. These results demonstrate that sufentanil, at clinical doses, increases striatal DA release and oxidative metabolism of both DA and xanthine acting at extrastriatal sites with a μ-receptor-mediated mechanism.

In vivo formation of salsolinol induced by high acetaldehyde concentration in rat striatum employing microdialysis.

The in vivo formation of salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquionoline), an endogeneous condensation product of dopamine (DA) with acetaldehyde (AcH), was examined following the administration of cyanamide (CY) plus ethanol (EtOH) using microdialysis-high-performance liquid chromatography with electrochemical detection. After the insertion of a microdialysis probe into the striatum, rats were treated with CY (a potent inhibitor of aldehyde dehydrogenase, 50 mg/kg), 4-methylpyrazole (4-MP, a strong inhibitor of alcohol dehydrogenase, 82 mg/kg), and CY + 4-MP, followed 1 h later by EtOH (1 g/kg), CY and 4-MP only by intraperitoneal administration. In the CY + EtOH group, salsolinol was detected in striatal dialysates and high AcH concentrations were found in the blood. The time course of changes in salsolinol concentrations correlated with blood AcH concentrations. In the other experimental groups, salsolinol in the dialysates and high AcH concentrations in the blood were not detected. These observations indicate that: (1) high AcH concentrations induce the formation of salsolinol in the rat striatum; (2) there is no effect of EtOH or AcH on striatal dialysate concentrations of DA and 5-hydroxytryptamine.

Polychlorinated biphenyls alter extraneuronal but not tissue dopamine concentrations in adult rat striatum: an in vivo microdialysis study.

Polychlorinated biphenyls (PCBs) reduce tissue dopamine (DA) concentrations and increase media DA concentrations in both in vitro preparations of bovine adrenal chromaffin cells and adult rat striatal tissue. To determine whether these changes also occur in the intact animal, we used in vivo microdialysis to determine changes in concentrations of DA in striatal dialysates from freely moving adult male rats after exposure to 25 mg/kg/day Aroclor 1254 for varying periods of time. We also determined DA concentrations in striatal tissue obtained postmortem from similarly treated animals. The effects of PCBs on dialysate DA concentrations depended on the length of exposure; DA concentrations were significantly elevated after 3 days of exposure and were significantly reduced after exposure for periods of 1 week or longer. On the other hand, striatal tissue concentrations of DA, determined postmortem in rats exposed to PCBs for the same periods of time, were not significantly altered. We suggest that these time-dependent alterations in dialysate DA concentrations a) reflect PCB-induced alterations of both plasma membrane and vesicular DA transporter function; b) provide a more sensitive index of altered central DA function after exposure to PCBs than does measurement of postmortem tissue DA concentrations; and c) play an important role in mediating some PCB-mediated changes in behavior.

A study on the role of nitric oxide and iron in 3-morpholino-sydnonimine-induced increases in dopamine release in the striatum of freely moving rats.

1. We showed previously that interaction between NO and iron (II), both released following the decomposition of sodium nitroprusside (SNP), accounted for the late SNP-induced dopamine (DA) increase in dialysates from the striatum of freely moving rats; in addition, we showed that co-infusion of iron (II) with the NO-donor S-nitroso-N-acetylpenicillamine mimicked SNP effects on striatal DA release. 2. In the present study, intrastriatal co-infusion of iron (II) (given as FeSO(4), 1 mM for 40 min) with the NO-donor and potential peroxynitrite generator 3-morpholinosydnonimine (SIN-1) (0.2, 0.5, 1.0 or 5.0 mM for 180 min), potentiated the SIN-1-induced increase in DA concentration in dialysates from the striatum of freely moving rats. Neither alone nor associated with iron (II) did SIN-1 induce changes in dialysate ascorbic acid or uric acid concentrations. 3. Neither co-infusion of a superoxide dismutase mimetic nor uric acid affected SIN-1-induced increases in dialysate DA concentration. 4. Infusion of the iron chelator deferoxamine (0.2 mM for 180 min) decreased dialysate DA and attenuated SIN-1-induced increases in dialysate DA concentrations. 5. These results suggest that iron plays a key role in SIN-1-induced release of striatal DA and do not support any role for either peroxynitrite or superoxide anion in SIN-1-induced release of striatal DA.

Selective D3 receptor agonist effects of (+)-PD 128907 on dialysate dopamine at low doses

An involvement of the D3 dopamine receptor in the modulation of extracellular dopamine concentrations is suggested by pharmacological studies. However, recent studies using D3 receptor knock out mice indicated that several functions previously attributed to the D3 receptor are mediated by other receptor types. In the present study, we used the no-net flux microdialysis technique to characterize: (i) basal dopamine dynamics in the ventral striatum of D3 knock out and wild type mice and (ii) the effects of the putative D3-receptor selective agonist (+)-PD 128907. Neither the extracellular dopamine concentration nor the in vivo extraction fraction, an indirect measure of basal dopamine uptake, differed between D3 knock out and wild type mice. Moreover, no differences in potassium (60 mM) or cocaine (5 or 20 mg/kg i.p.) evoked dopamine concentrations were detected between the two genotypes. However, intra-striatal or systemic administration of doses of (+)-PD 128907 that failed to modify dopamine concentrations in knock out mice significantly decreased dialysate dopamine concentrations in the wild type. Comparison of the concentration–response curve for (+)-PD 128907 revealed IC 25 values of 61 and 1327 nM in wild type and knock out mice, respectively, after intra-striatal infusions. Similar differences were obtained after systemic administration of the D3 preferring agonist (IC 25 0.05 and 0.44 mg/kg i.p. in wild type and knock out mice, respectively). We conclude that the activation of the D3 receptor decreases extracellular dopamine levels and that, at sufficiently low doses, the effects of (+)-PD 128907 on extracellular dopamine are selectively mediated by the D3 receptor.

κ-Opioid Receptor Activation Modifies Dopamine Uptake in the Nucleus Accumbens and Opposes the Effects of Cocaine

Coadministration of kappa-opioid receptor agonists (kappa-agonists) with cocaine prevents alterations in dialysate dopamine (DA) concentration in the nucleus accumbens (Acb) that occur during abstinence from repeated cocaine treatment. Quantitative microdialysis was used to determine the mechanism producing these effects. Rats were injected with cocaine (20 mg/kg, i.p.), or saline, and the selective kappa-agonist U-69593 (0.32 mg/kg, s.c.), or vehicle, once daily for 5 d. Extracellular DA concentration (DA(ext)) and extraction fraction (E(d)), an indirect measure of DA uptake, were determined 3 d later. Repeated cocaine treatment increased E(d), whereas repeated U-69593 treatment decreased E(d), relative to controls. Coadministration of both drugs yielded intermediate E(d) values not different from controls. In vitro DA uptake assays confirmed that repeated U-69593 treatment produces a dose-related, region-specific decrease in DA uptake and showed that acute U-69593 administration increases DA uptake in a nor-binaltorphimine reversible manner. Repeated U-69593 also led to a decrease in [(125)I]RTI-55 binding to the DA transporter (DAT), but did not decrease total DAT protein. These results demonstrate that kappa-opioid receptor activation modulates DA uptake in the Acb in a manner opposite to that of cocaine: repeated U-69593 administration decreases the basal rate of DA uptake, and acute U-69593 administration transiently increases DA uptake. kappa-agonist treatment also alters DAT function. The action of kappa-agonists on DA uptake or DAT binding, or both, may be the mechanism(s) mediating the previously reported "cocaine-antagonist" effect of kappa-opioid receptor agonists.