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REPORT
1Graduate School Neurosciences Amsterdam; 2Department of Anatomy, Vrije Universiteit Medical Center, Amsterdam; and 3Department of Animal Physiology and Cognitive Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, The Netherlands
Submitted 2 July 2004; accepted in final form 23 September 2004
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ABSTRACT |
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INTRODUCTION |
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; Taverna et al. 2004; Tunstall et al. 2002). 
-Aminobutyric acid-A (GABAA)–receptor mediated lateral inhibition between MSNs is prominent and is thought to have a strong impact on distributed network activity in the Nac, possibly by reinforcing the selection of competing neuronal ensembles, which may affect behavior by winner-take-all mechanisms (Plenz 2003; Redgrave et al. 1999a; Taverna et al. 2004). Because MSNs receive extensive dopaminergic inputs from mesencephalic areas (Nauta et al. 1978), dopamine may have an important modulatory function on lateral inhibition. To test whether this modulation indeed exists, we performed dual-cell patch-clamp recordings from MSNs recorded simultaneously in acutely prepared slices of rat Nac. |
METHODS |
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). The composition of artificial cerebrospinal fluid (ACSF) was as follows (in mM): 124 NaCl, 3.5 KCl, 1 NaH2PO4, 2.5 CaCl2, 26 NaHCO3, 1.3 MgSO4, and 10 D-glucose, saturated with 95% O2–5% O2 (pH 7.3). The 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)–receptor blocker NBQX (5 µM) was added to ACSF at the beginning of experiments. Patch-clamp glass pipettes (5–7 M
) contained the following solution (in mM): 60 K-gluconate, 58 KCl, 10 HEPES, 0.5 EGTA, 1 MgCl2, 2 Na2-ATP, 0.3 Na3-GTP, 20 Na2-phosphocreatine, 0.1 leupeptin, and 26 biocytin (pH 7.2, adjusted with KOH). Recordings were made at 31–33°C.
Medium-sized spiny neurons were characterized by relatively negative resting membrane potentials (–70 to –80 mV), inward rectification, high-input resistance (about 200 M), a slow depolarizing ramp at potential levels just below firing threshold, regular firing of action potentials when stimulated over threshold, and prominent spike afterhyperpolarizations (AHPs). Cells stained with biocytin were characterized by the presence of numerous dendritic spines and a thin, varicose axon, usually showing several collaterals.
Presynaptic MSNs were stimulated with suprathreshold current injections. Depolarizing postsynaptic potentials (dPSPs) were recorded at resting membrane potential (–70 to –80 mV) in current-clamp mode. Dopamine was prepared as a 50 mM stock solution in water and 50 mM sodium-metabisulfite (SMB) was added to prevent oxidation. Before experiments, dopamine and SMB were added to control ACSF to their final concentration (100 µM). SKF 38393 was dissolved in ACSF before experiments at a final concentration of 20 or 50 µM from a 10 mM stock solution in water. Control dPSP trains were recorded for 2–4 min in control ACSF at an interval of 15 s. SCH 23390 was prepared as a 1,000x stock solution in water and added to SKF 38393-containing ACSF to a final concentration of 25 µM. Although these concentrations are high relative to affinity constants reported in receptor binding studies, they are in the same range as used in previous electrophysiological studies (Nicola and Malenka 1997; Pennartz et al. 1992; Thomas et al. 2000). Drugs were washed out in control ACSF. Each experiment with SKF 38393 and dopamine was carried out on different individual slices to avoid interaction effects between sequentially applied drugs.
Data were statistically evaluated using the Mann–Whitney U (MWU) test for within-cell-pair comparisons and Wilcoxon's matched-pairs signed-rank (WMPSR) test for across-pair comparisons. The response area was calculated by integrating the trace representing a 1-s lasting synaptic response to presynaptic firing, with respect to baseline.
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RESULTS |
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). Presynaptic action potentials induced by current injection elicited fast dPSPs mediated by GABAA-receptors (Czubayko and Plenz 2002; Taverna et al. 2004; Tunstall et al. 2002). Electrophysiological properties of pre- and postsynaptic MSNs evoked unitary inhibitory postsynaptic currents and dPSPs, and trains of dPSPs lasting 1–2 s were similar to those reported before (Taverna et al. 2004). Morphological analysis based on biocytin staining confirmed that the recorded cells were MSNs (Fig. 1).
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Similar results were obtained with the dopamine D1-receptor–selective agonist SKF 38393 (20–50 µM, Fig. 2). Compared with control conditions, the relative response area and first dPSP after SKF 38393 perfusion were 59 ± 3 and 51 ± 5%, respectively (n = 7 pairs, P < 0.002, WMPSR test). In 2 pairs, partial recovery of inhibition was achieved by adding the D1-receptor antagonist SCH 23390 (25 µM) to the ACSF + SKF 38393 medium (75 ± 1% of control area, P > 0.05 WMPSR test). In these 2 pairs, SKF 38393 attenuated the response area to 55 ± 9% of control. In those pairs where SCH 23390 could not be applied, the decline in dPSP amplitude was likely attributable to the pharmacological effect of SKF 38393 rather than to the stability of baseline responses.
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DISCUSSION |
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, 1998; Pennartz et al. 1992) and dorsal striatum (Flores-Hernandez et al. 2000; Guzman et al. 2003). Yet, in all of these studies GABAergic synaptic responses were induced by extracellular stimulation or exogenous application of GABA, leaving open the question where the GABAergic inputs exactly originated (i.e., MSNs, GABAergic interneurons, or extrinsic fibers terminating on MSNs). Because the recorded cells in the current study were identified as MSNs by electrophysiological and morphological criteria, contributions by interneurons or extrinsic GABAergic inputs can be ruled out.
The present data do not exclude that dopamine receptors of the D2 class may play an additional role in modulating lateral inhibition (Harsing and Zigmond 1997). In fact, pre- and postsynaptic localization of both D1 and D2 receptors have been reported in the striatum (Delle Donne et al. 1997; Wong et al. 1999). Further work is needed to understand the spectrum of dopamine interactions with lateral inhibition in more detail. For instance, dose–response relationships for agonists and antagonists will need to be established, as well as possible dopamine receptor effects on baseline inhibitory postsynaptic potentials (IPSPs) to assess whether endogenous dopamine exerts a basal modulatory effect. Insights into the mechanism of modulation can be obtained, for instance, by detailed studies of effects on IPSP failures.
It should be noted that we used a relatively high dopamine concentration (100 µM) with respect to basal values reported for nucleus accumbens in vivo (order of about 10 nM; Tang et al. 2003). However, such basal values are considerably lower than those achieved in the extracellular space surrounding a microdialysis probe under conditions of intense activity of mesencephalic dopamine neurons (Garris et al. 1994; Wu et al. 2001). According to models of dopamine diffusion in and around the synaptic cleft (Cragg and Rice 2004), dopamine concentrations close to release sites may well reach into the micromolar range. In the present study, a 100-µM dose was chosen to aim for receptor saturation and to obtain appropriate drug penetration into the slice in the face of potent dopamine transporter mechanisms (Cragg and Rice 2004). By way of comparison, electrically evoked excitatory PSPs in the Nac were previously shown to be strongly attenuated by 100 µM dopamine but less so by 30 µM, without demonstrable side involvement of noradrenaline receptors (Pennartz et al. 1992; cf. Nicola and Malenka 1998). Similarly, 60–100 µM dopamine was used by Nicola et al. (1997), who observed an attenuation of electrically evoked IPSPs in Nac, an effect that appeared to be mediated by D1-like receptors. Although a similar affinity is likely to hold for dopaminergic modulation of lateral inhibition between MSNs, and a D1-receptor–mediated mechanism is indicated by the mimicking effect of SKF 38393 and antagonism by SCH 23390, possible side involvement of related receptors and a dose–response curve for dopamine should be addressed in future studies.
In conclusion, we report that dopamine and the D1-receptor agonist SKF 38393 attenuate GABAergic lateral inhibition between principal cells in rat Nac. GABAergic lateral inhibition may represent an important functional substrate for the filtering and selecting function that has been attributed to the striatum (Beiser et al. 1997; Groves 1983; Pennartz et al. 1994) because it may enable certain configurations of MSN population activity to become or remain dominant at the expense of competing ensembles. Thus dopaminergic attenuation of this inhibition may represent a mechanism for shifting input selection from one cell or ensemble to another, contributing to the initiation of new behaviors or the switching between different behavioral programs and cognitive resources such as attention (Christakou et al. 2004; Pennartz et al. 1994; Redgrave et al. 1999b).
In a similar vein, dopamine may amplify the gain at which behaviorally relevant stimuli affect neuronal populations in Nac controlling motor behavior (Cardinal et al. 2002; Robbins and Everitt 1996; Taylor and Robbins 1984). These findings may also help in understanding the role of dopamine in several neuropsychiatric disorders including drug addiction; schizophrenia, for instance, has been interpreted as involving a malfunctioning of ventral striatal systems for output selection and conversion of sensory input into motivated behavior (Swerdlow and Koob 1987).
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GRANTS |
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Present address of S. Taverna and B. Canciani: Northwestern University, Dept. of Physiology, 303 East Chicago Avenue, Chicago, IL 60611.
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FOOTNOTES |
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Address for reprint requests and other correspondence: C.M.A. Pennartz, University of Amsterdam, Swammerdam Institute for Life Sciences, Department of Animal Physiology and Cognitive Neuroscience, Kruislaan 320, 1090 GB Amsterdam, The Netherlands (E-mail: pennartz{at}science.uva.nl)
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REFERENCES |
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