The brain microdialysis technique has been used to examine the in vivo effects of the neurotoxin domoic acid (an ionotropic glutamate receptor agonist) on ...
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Neurochemical Research, Vol. 28, No. 10, October 2003 (© 2003), pp. 1487–1493
Mechanisms Underlying Domoic Acid–Induced Dopamine Release from Striatum: An in Vivo Microdialysis Study* M. Alfonso,1, 3 R. Durán,1 F. Campos,1 D. Perez-Vences,1 L. R. F. Faro,2 and B. Arias1 (Accepted March 28, 2003)
The brain microdialysis technique has been used to examine the in vivo effects of the neurotoxin domoic acid (an ionotropic glutamate receptor agonist) on dopamine (DA) release in the striatum of conscious and freely moving rats. Local application of domoic acid (500 M) through the microdialysis probe produced an increase in striatal DA content (597 96% with respect to basal levels). The release of DA induced by domoic acid was not attenuated in a Ca2-free medium (469 59%) or after pretreatment with 10 mg/kg reserpine (533 79%). Intrastriatal infusion of 1 M tetrodotoxin (TTX) partially reduced the domoic acid–evoked DA release (278 34%). Moreover, domoic acid perfusion had no effect on K-evoked DA release. The results suggest that domoic acid increases the striatal DA release according to a reserpine-independent, calcium-independent and partially TTX-insensitive mechanism, suggesting that these effects probably involve a nonexocytotic process. On the other hand, the inhibitor of DA uptake nomifensine (10 M) reduced the domoic acid–evoked DA release (356 59%), suggesting that a carrier-dependent mechanism could be involved in the effect of domoic acid on the striatal DA levels.
KEY WORDS: Domoic acid; dopamine; striatum, microdialysis; rats.
INTRODUCTION
acid is a potential seafood contaminant with excitotoxic properties and it is considered as an AMPA/KA receptor agonist (2). Considerable experimental evidence has shown a close interaction between the nigrostriatal dopaminergic system and cortical glutamatergic neurons. Since initial studies by Nieoullon et al. (3), who reported that glutamate evokes the release of tritiated dopamine (DA) from cat striatum, several in vitro (4–6) and in vivo studies (7–9) have reported that glutamate agonists induce release of radiolabeled or endogenous DA. The relationship between the cortical afferent glutamate pathway to striatum and the local DA release is of primary interest and has been extensively studied (10). Thus, increased extracellular levels of glutamate in the striatum lead to increased DA. There is some uncertainty regarding the mechanism(s) by which glutamate agonists act to induce the DA release in striatum and other brain regions. In general, two mechanisms may account for
Domoic acid is a phytoplanckton-derived neurotoxin related to the neurotransmitter glutamate, the main excitatory amino acid (EAA) in the central nervous system. In late November 1987, domoic acid was identified as the causative agent of toxicity in a number of individuals who acutely developed gastrointestinal symptoms, confusion, memory loss, and motor symptoms following the consumption of contaminated mussels (1). Domoic * Special issue dedicated to Dr. Arsélio Pato de Carvalho. 1 Departamento de Biología Funcional y Ciencias de la Salud, Facultad de Ciencias, Universidad de Vigo, 36200 Vigo, Spain. 2 Departamento de Fisiologia, Centro de Ciências Biológicas, UFPA, Belem, PA, Brasil. 3 Address reprint requests to: Departmento de Biología Funcional y Ciencias de la Salud, Universidad de Vigo, 36200 Vigo, Spain. Tel: (34) (986) 81 23 91; Fax: (34) (986) 81 25 56; E-mail: pallares@ uvigo.es
1487 0364-3190/03/1000–1487/0 © 2003 Plenum Publishing Corporation
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1488 glutamate agonist-induced activation of DA release, such as a direct presynaptic regulation (presumably mediated by glutamate receptors on DA terminals) and multisynaptic mechanisms in which glutamate agonists increase the firing rate of local circuit neurons or activate feedback loops that indirectly stimulate the release of DA. On the other hand, the mechanism by which glutamate increased the intrastriatal DA levels could be by stimulation of DA synthesis and/or release (11) or by inhibition of the DA uptake (12). In previous studies we used brain microdialysis to assess the in vivo effects of domoic acid on striatal DA release. We observed that intrastriatal perfusion of domoic acid increased the extracelular DA concentration in striatum associated with decreases in intrastriatal metabolite levels (13). The effect of domoic acid on striatal DA levels was mediated by AMPA/KA glutamate receptors (14). The present study was carried out to elucidate the mechanisms underlying the actions of domoic acid on in vivo striatal DA release using brain microdialysis technique in freely moving rats. For this purpose we used several pharmacological agents or different experimental approaches: reserpine (a vesicular DA depletor agent), tetrodotoxin (a voltage-sensitive Na channel blocker), Ca2-free medium, medium with high K concentration, nomifensine (DA uptake inhibitor), and amphetamine (which induces carrier-mediated DA release).
EXPERIMENTAL PROCEDURE Chloral hydrate, reserpine, tetrodotoxin (TTX), nomifesine, amphetamine, reagents for high-performance liquid chromatography (HPLC), and components of perfusion fluid for microdialysis were obtained from Sigma Chemical Co. (St. Louis, MO, USA). Domoic acid was obtained from Tocris (Bristol, UK). For experiments using medium with high K concentration and Ca2-free medium, the ionic strength of the perfusion solution was maintained by changing Na concentration. All reagents were of analytical grade. Male Sprague-Dawley rats weighing 250–300 g were used in all experiments. Animals were housed at 22 2°C in a room under a 12-h light/dark cycle, with food and water available ad libitum. All experimental procedures were performed in accordance with the guidelines of the European Union Council (86/69/UE) for use of laboratory animals. Dialysis probes were implanted into striatum of chloral hydrate– anesthetized animals (500 mg/kg, IP). Rats were placed in a sterotaxic frame (Narishige SR-6), and a small incision was made in the skin over the skull. A CMA 11 microdialysis guide cannula (CMA/Microdialysis, Stockholm, Sweden) was implanted stereotaxically into the striatum. The striatum coordinates, in millimeters, with respect to Bregma, according to the rat brain atlas (15) were AP 2.0, L 3.0, V 6.0. The guide cannula was fixed to the skull with acrylic cement. The wound was sutured and the animals left to recover for at least 24 h in individual cages with free access to food and water.
Alfonso, Durán, Campos, Perez-Vences, Faro, and Arias All the experiments were carried out in conscious and freely moving rats. A CMA/12 microdialysis probe (0.5 mm diameter, 3 mm membrane length) (CMA/ Microdialysis, Stockholm, Sweden) was implanted, through the guide cannula, into the striatum of the unrestrained rats 24 h postsurgery. The inlet of the probe was connected to a 1-ml microsyringe (Exmire, Fuji, Japan) mounted on a CMA/102 perfusion pump (CMA/Microdialysis, Stockholm, Sweden). The probes were perfused continuously with a Ringer’s solution (147 mM NaCl, 3.4 mM CaCl2, 4 mM KCl; pH 7.4) at a flow rate of 2 l/min. After a period of 30 min (washout period), dialysates were collected every 15 min (30 l). After collection of four basal samples, domoic acid (500 M) was perfused for 30 min. Nomifensine (10 M), amphetamine (50 M), or a high K solution (100 mM) was perfused through the dialysis probe alone or together with domoic acid for 30 min. Reserpine (10 mg/kg) was injected intraperitoneally 120 min before the domoic acid administration. TTX (1 M) was perfused for 30 min before its coinfusion with domoic acid. After all treatments, the medium was switched back to the unmodified Ringer’s solution, and sampling was continued for an additional period of 120 min. Ca2-free medium was perfused 60 min before the administration of a domoic acid solution in Ca2-free medium, and sampling was continued during 120 min in Ca2-free medium conditions. Samples were collected using a CMA/142 microsampler (CMA/Microdialysis, Stockholm, Sweden), and 20 l of every dialysate was immediately injected into an HPLC system with electrochemical detection, using a Rheodyne 7125 injection valve. The isocratic separation of DA, and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) was achieved using Spherisorb ODS-1 reversed-phase columns (10-m particle size), according to Duran et al. (16). The eluent consisted of 70 mM KH2PO4, 1 mM EDTA, 1 mM octanesulfonic acid, and 5% methanol (pH 4.0). The elution was carried out at a flow rate of 2.0 ml/min using a Jasco PU1580 pump. Detection of substances was achieved using an ESA Coulochem 5100A electrochemical detector (MA, USA) at a potential of 400 mV. The detection limit for DA under these conditions was approximately 10 pM per 20 l of sample injected. DA, DOPAC, and HVA content in dialysate samples was expressed as a percentage of the basal value (100%), measured as the mean of three samples before domoic acid administration that differed by less than 10% from each other (considered as a stable baseline). In vitro recoveries for dialysis probes, at a flow rate of 2 l/min, were: 15%, 23%, and 24% for DA, DOPAC, and HVA, respectively. At the end of the experiments rats were sacrificed under deep chloral hydrate anesthesia, and the position of the dialysis probe was verified macroscopically in every case. The statistical analysis of results was performed by one-way ANOVA followed by Student–Newman-Keuls multiple range test, considering the following significant differences: *P .01 and **P .001.
RESULTS The day after surgery, levels of DA and its metabolites were stable in control rats throughout the experiment. Basal striatal levels of DA and metabolites were as follows (mean SEM, n 12): DA 0.22 0.05, DOPAC 8.51 0.46 and HVA 6.24 0.39 (pM/20 l).
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Mechanism of Domoic Acid–Induced Alterations in Dopamine Release The perfusion of domoic acid (500 M) through the dialysis probe increased DA content in striatal dialysate up to 597 96%, with respect to basal levels (Fig. 1A). This increase was achieved 15 min after the onset of perfusion. Moreover, the intrastriatal application of domoic acid decreased DOPAC and HVA extracellular levels to 47 4% and 34 4%, respectively, 30 min after the onset of perfusion (Fig 1B, 1C). To test the dependence of vesicular DA stores on domoic acid–induced striatal DA release, rats were pretreated with reserpine (10 mg/kg, ip) 120 min before domoic acid administration. Reserpine treatment induced a sharp decrease in striatal dialysate DA concentration. The lowest concentration of DA (47 6% of basal values) was observed 120 min after reserpine administration. In contrast, DOPAC and HVA levels increased up to 302 49% and 235 38%, respectively. These results were considered basal values for the measurement of the effect of domoic acid in reserpinized animals. Fig. 1A shows that perfusion of 500 M domoic acid in reserpine-preteated animals increased striatal DA levels up to 533 79%, but this DA increase induced by domoic acid in reserpinized animals was not significantly different from that observed in nonreserpinized animals. In reserpinized animals, perfusion of 500 M domoic acid decreased DOPAC and HVA extracellular levels to 40 3% and 33 3, respectively (Fig 1B, 1C). Thus reserpine pretreatment did not alter striatal DA efflux evoked by domoic acid. The involvement of extracellular calcium in domoic acid–induced striatal DA release was assessed by perfusing Ca2-free Ringer’s solution through the dialysis probe. Perfusion of Ca2-free medium decreased significantly DA striatal levels (147 9%). When domoic acid was perfused in Ca2-free Ringer’s solution, striatal DA levels increased to 469 59%, with respect to Ca2-free basal values (Fig. 2A). This effect was no significantly different compared with the administration of domoic acid in normal Ringer’s solution. The perfusion of domoic acid in Ca2-free Ringer’s solution decreased the extracellular DOPAC and HVA contents to 40 12% and 17 2%, respectively (Fig. 2B, 2C). To assess whether the increase of striatal DA levels induced by domoic acid was dependent on voltage-sensitive sodium channels, 1 M TTX was infused through the dialysis probe. Intrastriatal infusion of TTX produced an expected decrease in basal striatal DA levels that dropped to 35 4%, with respect to basal values 90 min after TTX administration (Fig. 3A). When domoic acid was perfused (30 min) in TTXtreated animals, striatal DA levels increased up to
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Fig. 1. Effects of the infusion of 500 M domoic acid on the extracellular levels of DA (A), DOPAC (B), and HVA (C) in striatum of reserpine-pretreated rats. Animals received an IP reserpine injection (10 mg/kg) 120 min before domoic acid administration. The time of domoic acid infusion is indicated by arrows. The results are expressed as the mean SEM of five independent experiments, using a percentage of basal levels (100%). Basal levels were considered as the mean of substance concentrations in the three samples before domoic acid administration. Significant differences for the domoic acid treatment: * P .01 and ** P .001, with respect to basal.
278 34%, with respect to basal levels in TTX-treated animals (Fig. 3A). This increase was attenuated compared with that elicited by domoic acid in non–TTX-treated animals. TTX infusion had no effect on DOPAC and HVA levels. Domoic acid infusion in TTX-treated animals decreased DOPAC and HVA extracellular levels to 20 5% and 21 2%, respectively (Fig. 3B, 3C). Taken together, the results indicate that domoic acid–induced DA release is partially dependent on voltage-sensitive sodium channels. To further assess the effect of domoic acid on high K-stimulated DA release in striatum we perfused through the dialysis probe a Ringer’s solution with a
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Fig. 2. Effect of infusion of 500 M domoic acid in a Ca2-free Ringer’s solution on the extracellular levels of DA (A), DOPAC (B), and HVA (C) in striatum of rats. The time of domoic acid infusion is indicated by arrows. The results are expressed as the mean SEM of five independent experiments, using a percentage of basal levels (100%). Basal levels were considered as the mean of substance concentrations in the three samples under Ca2-free conditions before domoic acid administration. Significant differences for the domoic acid treatment: * P .01 and ** P .001, with respect to basal.
high concentration of KCl (100 mM). The perfusion of a medium with high K concentration for 30 min increased striatal DA release to 2221 604%, with respect to the basal values (Fig. 4A), whereas DOPAC and HVA levels decreased to 75 3% and 51 7%, respectively (Fig. 4B, 4C). When domoic acid was coadministered with a medium with high K concentration, striatal DA levels increased to 2046 560%, with respect to basal levels. Thus, domoic acid had apparently no effect on K-stimulated DA release. To determine whether DA uptake carrier might be involved in domoic acid–induced DA release, we investigated the effects of nomifensine (an inhibitor of high-affinity DA transporter) and amphetamine (which produces the release of DA from presynaptic terminals through DA transporter). Nomifensine treatment (10 M
Alfonso, Durán, Campos, Perez-Vences, Faro, and Arias
Fig. 3. Effect of infusion of 500 M domoic acid on the extracellular levels of DA (A), DOPAC (B), and HVA (C) in striatum of in TTX-treated (1 M) rats. The time of TTX or domoic acid infusion are indicated by arrows. The results are expressed as the mean SEM of five independent experiments, using a percentage of basal levels (100%). Basal levels were considered as the mean of substance concentrations in the three samples under TTX treatment before domoic acid administration. Significant differences for the domoic acid treatment: * P .01 and ** P .001, with respect to basal.
for 30 min) increased striatal DA levels to 580 69%, with respect to basal levels (Fig. 5). When domoic acid was coadministered with nomifensine, striatal DA levels increased to 356 59%, with respect to basal levels. This increase was lower than that elicited by domoic acid or nomifensine alone. Thus, nomifensine partially reduced the domoic acid–evoked DA release. Intrastriatal perfusion of amphetamine (50 M for 30 min) induced a substantial increase in DA efflux (786 182%, with respect to basal levels). On the other hand, DOPAC and HVA striatal levels declined following amphetamine treatment (57 14% and 75 4%, respectively). Finally, the perfusion of domoic acid did not affect significantly amphetamine-induced DA release (Fig. 6).
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Mechanism of Domoic Acid–Induced Alterations in Dopamine Release DISCUSSION
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Previously, we reported that the perfusion of domoic acid produced a dose-dependent increase in striatal DA levels and induced a decrease in the interstitial levels of DOPAC and HVA (13). Moreover, domoic acid-evoked DA efflux was demonstrated to be mediated by the activation of AMPA/kainate glutamate receptors (14). However, the underlying mechanism(s) involved in the release of DA induced by the neurotoxin has not been well established. Although glutamate exerts its stimulatory effects on DA release mainly by the activation of glutamate
receptors, the underlying mechanism is poorly understood. Several studies (17–20) have demonstrated that DA may be released by two distinct mechanisms: (i) a vesicular, calcium-sensitive, and carrier-independent process and (ii) a calcium-insensitive, and carrierdependent mechanism. Therefore the effects of vesicular DA depletion on domoic acid response was assessed in the present study. Vesicular DA stores were disrupted by pretreatment for 120 min with reserpine. When domoic acid was administered in reserpinized animals, the increase in extracellular DA levels was not statistically different compared with that produced by domoic acid alone. These results could
Fig. 4. Effect of infusion of 100 mM KCl on the extracellular levels of DA (A), DOPAC (B), and HVA (C) in striatum in the absence or presence of 500 M domoic acid. The time of high K concentration and/or domoic acid is indicated by arrow. The results are expressed as the mean SEM of five independent experiments, using a percentage of basal levels (100%). Basal levels were considered as the mean of substance concentrations in the three samples before drug administration. Significant differences: * P .01 and ** P .001 with respect to basal.
Fig. 5. Effect of infusion of 10 M nomifensine on the extracellular levels of DA (A), DOPAC (B), and HVA (C) in striatum in the absence or presence of 500 M domoic acid. The time of drug infusion is indicated by arrow. The results are expressed as the mean SEM of five independent experiments, using a percentage of basal levels (100%). Basal levels were considered as the mean of substance concentrations in the three samples before drug administration. Significant differences: * P .01 and ** P .001 with respect to basal, a P .01 with respect to nomifensine or domoic acid perfusion group.
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1492 indicate that domoic acid induced a nonvesicular increase in DA extracellular levels. Because extracellular Ca2 is of crucial importance for the exocytotic vesiculardependent release of neurotransmitters, we have also investigated to what extent the absence of Ca2 in the perfusion medium can influence the DA release induced by domoic acid. The synaptic activity in neuronal terminals is accompanied by an increased influx of Ca2 from extracellular fluid, through membrane voltage-dependent Ca2 channels. These Ca2 ions then interact with specific citoplasmatic proteins and trigger the exocytotic release of the neurotransmitter (21). The spontaneous release of DA is Ca2 dependent because the reduction of external Ca2 significantly decrease extracellular DA levels. However,
Fig. 6. Effect of infusion of 50 M amphetamine on the extracellular levels of DA (A), DOPAC (B), and HVA (C) in striatum in the absence or presence of 500 M domoic acid. The time of drug infusion is indicated by arrow. The results are expressed as the mean SEM of five independent experiments, using a percentage of basal levels (100%). Basal levels were considered as the mean of substance concentrations in the three samples before drug administration. Significant differences: * P .01 and ** P .001 with respect to basal.
Alfonso, Durán, Campos, Perez-Vences, Faro, and Arias the reduction of external Ca2 had no effect on domoicinduced DA release because domoic acid administered in Ca2-free Ringer’s solution increased the extracellular DA levels in a way similar to that produced by domoic acid administered in normal Ringer’s solution, indicating that the increases in extracellular DA levels induced by domoic acid appear to be Ca2 independent. Several studies have demonstrated that DA release induced by different agents is partially or totally independent of calcium (17,22,23). Moreover, Lonart and Zigmond (18) observed that glutamate is able to induce DA release in a Ca2-free medium. Previously, using cultured chick retina cells, we observed that domoic acid induced GABA release by a Ca2-independent mechanism (24). In another set of experiments, we observed that TTX treatment decreased basal levels of DA in striatum and reduced the effect of domoic acid on DA release. Because TTX is a voltage-sensitive blocker of sodium channels, our results seem to indicate that release of DA induced by domoic acid is partially insensitive to the depolarization mediated by voltage-dependent sodium channels. Several studies have indicated that TTX may exert differential effects on DA release induced by glutamatergic agonists such as NMDA and kainic acid (25,26). Thus Westerink et al. (19) observed that DA release induced by NMDA or kainic acid was partially or totally (according to the concentration of the agonist) insensitive to TTX. We also assessed the effects of a medium with a high K concentration on domoic acid–induced DA release. The perfusion of domoic acid in a medium with a high K concentration did not produce changes in extracellular DA levels compared with the effects of medium with high K alone. Thus domoic acid appears to induce an increase in spontaneous release of DA, without altering KCl-evoked release of DA. These results suggest that domoic acid increases striatal DA release through a reserpine-independent, calcium-independent, and partially TTX-insensitive mechanism. This process probably involves a nonexocytotic mechanism insensitive to depolarization induced by K concentration. In some cases, Ca2-independent efflux of neurotransmitters is mediated by high-affinity neurotransmitter uptake systems often present in presynaptic terminal membranes (27). To test the role of the DA uptake carrier in the domoic acid–induced DA release, nomifensine (a DA uptake inhibitor) or amphetamine (which stimulates the release of DA by a carrier-dependent mechanism) were infused together with domoic acid. Amphetamine did not affect significantly the increase of DA induced by domoic acid whereas nomifensine reduced the domoic
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Mechanism of Domoic Acid–Induced Alterations in Dopamine Release acid–evoked DA release. Therefore a carrier-dependent release mechanism appears to mediate the effects of domoic acid on striatal DA levels. Thus Arbuthnott et al. (28) defined that the nonexocytotic (carrier-dependent) release of DA was “efflux which persists in reduced Ca2 and which is blocked by nomifensine.” Taken together the results observed in the present study after treatment with reserpine, Ca2-free Ringer’s solution, TTX, medium with high K concentration, nomifensine, and amphetamine, suggest that domoic acid may induce the release of striatal DA by a nonexocytotic mechanism probably mediated by presynaptic DA transporter.
ACKNOWLEDGMENTS This research was supported by grants from University of Vigo and Xunta de Galicia (Spain). The authors wish to thank Dr. J. L. Soengas for his help in the preparation of manuscript.
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