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The Journal of Neuroscience, September 27, 2006, 26(39):10043-10050; doi:10.1523/JNEUROSCI.1819-06.2006
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Behavioral/Systems/Cognitive
Bidirectional Dopaminergic Modulation of Excitatory Synaptic Transmission in Orexin Neurons
Christian O. Alberto, Robert B. Trask, Michelle E. Quinlan, andMichiru Hirasawa Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada A1B 3V6
Abstract
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Abstract
Introduction
Orexin neurons in the lateral hypothalamus (LH)/perifornical area (PFA) are known to promote food intake as well as provide excitatory influence on the dopaminergic reward pathway. Dopamine (DA), in turn, inhibits the reward pathway and food intake through its action in the LH/PFA. However, the cellular mechanism by which DA modulates orexin neurons remains largely unknown. Therefore, we examined the effect of DA on the excitatory neurotransmission to orexin neurons. Whole-cell patch-clamp recordings were performed using acute rat hypothalamic slices, and orexin neurons were identified by their electrophysiological and immunohistochemical characteristics. Pharmacologically isolated action potential-independent miniatures EPSCs (mEPSCs) were monitored. Bath application of DA induced a bidirectional effect on the excitatory synaptic transmission dose dependently. A low dose of DA (1 µM) increased mEPSC frequency, which was blocked by the D1-like receptor antagonist SCH 23390, and mimicked by the D1-like receptor agonist SKF 81297. In contrast, higher doses of DA (10–100 µM) decreased mEPSC frequency, which could be blocked with the D2-like receptor antagonist, sulpiride. Quinpirole, the D2-like receptor agonist, also reduced mEPSC frequency. None of these compounds affected the mEPSCs amplitude, suggesting the locus of action was presynaptic. Furthermore, DA (1 µM) induced an increase in the action potential firing, whereas DA (100 µM) hyperpolarized and ceased the firing of orexin neurons, indicating the effect of DA on excitatory synaptic transmission may influence the activity of the postsynaptic cell. In conclusion, our results suggest that D1- and D2-like receptors have opposing effects on the excitatory presynaptic terminals impinging onto orexin neurons.
Key words: orexin neuron; dopamine; miniature EPSC; food intake; obesity; patch clamp
Introduction
Why do we eat beyond our energy demand? This question remains conspicuous as the obesity-related health problems continue to mount around the world. A part of the answer might be that food is a natural reward. There is a growing notion that drug addiction and overeating result from similar reinforcing properties of drugs and food that activate the common brain reward circuitry (Kelley and Berridge, 2002; Cota et al., 2005
The lateral hypothalamus (LH) has long been viewed as one of the brain areas involved in reward and feeding (Margules and Olds, 1962
Dopamine (DA) is another critical player in food reinforcement: genotypes that alter DA reuptake or receptors have a strong influence on food reinforcement and weight gain (Epstein and Leddy, 2006
DA also has an inhibitory influence on food intake through its action in the LH/PFA. DA receptor activation inhibits feeding (Leibowitz and Rossakis, 1979
Modulation of excitatory synaptic inputs is one mechanism by which the firing activity of the postsynaptic orexin neuron can be altered (Li et al., 2002
Materials and Methods
All experiments were performed in accordance with the guidelines established by the Canadian Council on Animal Care and were approved by the Memorial University Internal Animal Care Committee. Attention was paid to use only the number of animals necessary to produce reliable results.Slice preparation. Male Sprague Dawley rats (60–100 g) were decapitated under deep halothane anesthesia. The brain was removed and 250-µm-thick coronal slices containing the hypothalamus were generated at 0–2°C in buffer solution composed of the following (in mM): 87 NaCl, 2.5 KCl, 1.25 NaH2PO4, 7 MgCl2, 0.5 CaCl2, 25 NaHCO3, 25 glucose, 30 sucrose, 3 pyruvic acid, 1 ascorbic acid. Slices were incubated at 33–34°C for 45 min and then at room temperature until the recording in artificial CSF (ACSF) composed of the following (in mM): 126 NaCl, 2.5 KCl, 1.2 NaH2PO4, 1.2 MgCl2, 2 CaCl2, 25 NaHCO3, 10 glucose, 1 ascorbic acid. Both solutions were continuously bubbled with a mixture of O2 (95%) and CO2 (5%).
Electrophysiological recording. A hemisected slice was transferred into a recording chamber and perfused at 1.5–2 ml/s with ACSF at 33–34°C. Whole-cell patch-clamp recording was performed using a Multiclamp 700B amplifier and pClamp 9.2 software (Molecular Devices, Sunnyvale, CA). The tip resistance of the recording electrode was 3–7 M
when filled with the internal recording solution containing the following (in mM): 123 K-gluconate, 2 MgCl2, 8 KCl, 0.2 EGTA, 10 HEPES, 4 Na2-ATP, 0.3 Na-GTP, pH 7.3. With the visual guidance of infrared-differential interference contrast microscope (DM LFSA; Leica Microsystems), neurons adjacent to the fornix with diameter of 10–20 µm were selected. To characterize the electrophysiological features of recorded cells, the cells were injected with a series of hyperpolarizing and depolarizing 300 ms step pulses in current-clamp mode. The remaining experiments were performed in voltage-clamp mode at a holding potential of –80 mV in the presence of picrotoxin (50 µM) and tetrodotoxin (1 µM) to record miniature EPSCs (mEPSCs), or in current-clamp mode to record spontaneous firing activity in the presence of picrotoxin (50 µM). mEPSCs are non-NMDA receptor mediated because they are sensitive to CNQX (data not shown). After completion of electrophysiological recordings, some brain slices were saved for immunohistochemical studies. Membrane currents were filtered at 1 kHz, digitized at 5 kHz and stored for off-line analysis. A 20 mV hyperpolarizing pulse lasting for 100 ms was applied every 20–60 s throughout each experiment, and the steady-state current and decay rate of the capacitance transient were monitored as measures of input resistance and series/access resistance, respectively. Cells that showed significant change in these parameters were excluded from additional analysis.
Miniature EPSCs were detected by using Mini Analysis 6.0 software (Synaptosoft, Decatur, GA). The data are expressed as mean ± SE. Statistical comparisons were performed by using appropriate tests (i.e., Kolmogorov–Smirnov test for testing individual cells, and unpaired or paired Student's t tests for group comparison as appropriate). A value of p < 0.05 was considered significant.
Immunohistochemistry. For immunohistochemical identification of the recorded cell, biocytin (1–1.5 mg/ml) was included in the internal solution. Immediately after the recording, slices were placed in 4% paraformaldehyde in 0.1 M PBS overnight at 4°C, then washed and stored in PBS before the addition of primary antibodies. Slices were incubated with anti-orexin A goat polyclonal IgG (1:3000 dilution; Santa Cruz Biotechnology, Santa Cruz, CA) and anti-melanin-concentrating hormone (MCH) rabbit polyclonal IgG (1:2000 dilution; Phoenix Pharmaceuticals, Belmont, CA) for 3 d at 4°C. Slices were then washed and treated for 3 h with a combination of Cy3-conjugated donkey anti-goat antibody, Cy2-conjugated donkey anti-rabbit antibody, and streptavidin-conjugated aminomethylcoumarin acetate (AMCA), all at 1:500 dilution at room temperature. Antibodies were diluted with PBS with 0.05% Triton X. Slices were then washed, mounted, and examined under a fluorescence microscope for detection of orexin A (Cy3), MCH (Cy2) immunoreactivity, and biocytin (AMCA).
Chemical compounds. All drugs were bath perfused at final concentrations as indicated, by diluting aliquots of 1000x stock in the ACSF immediately before use. DA stock and the solutions included ascorbic acid (1 mM) and were light protected during the recordings to minimize oxidation. The final concentration of DMSO used as a vehicle was 0.1%. SKF 81297, quinpirole, SCH 23390 and sulpiride were purchased from Tocris Bioscience (Ellisville, MO), dopamine, biocytin, picrotoxin from Sigma-Aldrich (St. Louis, MO), and tetrodotoxin from Alomone Labs (Jerusalem, Israel).
Results
In all of the cells that were identified to be orexin A immunopositive (n = 47), we observed a depolarizing sag (Ih current) in response to hyperpolarizing pulses from the resting membrane potential and a rebound depolarization at the current offset (Fig. 1A). In some cells, the rebound was large enough to evoke a spike. In addition, the majority of these cells displayed minimal spike adaptation (76.6%, 36 of 47) and spontaneous firing at rest (89.4%, 42 of 47) (Fig. 1A). The average resting membrane potential for orexin A-immunopositive neurons was –48.6 ± 0.8 mV. In contrast, as shown in Fig. 1C, MCH-immunopositive neurons showed no Ih current (100%, nine of nine) nor rebound depolarization (100%, nine of nine). The average resting membrane potential for MCH neurons was –58.8 ± 1.9 mV, and a majority of them did not fire spontaneously (88.9%, eight of nine). Furthermore, eight of nine cells showed a clear spike adaptation (88.9%). Thus, our result is consistent with that of the previous studies (Eggermann et al., 2003
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Figure 1. Identification of orexin neurons. A, Electrophysiological characteristics of an orexin neuron. In a typical orexin neuron, hyperpolarization induced a sag characteristic of an Ih current (arrow head) and rebound depolarization at the current offset (arrow). B, Immunohistochemical identification of recorded orexin neurons. Left, An example of a cell filled with biocytin during recording. Middle, Orexin A immunoreactivity is shown in red. Right, Overlay showing the biocytin labeled cell is orexin A-immunopositive. C, Electrophysiological characteristic of an MCH neuron. A typical MCH neuron displays neither Ih current nor rebound depolarization, but shows a strong spike adaptation. D, Immunohistochemical identification of recorded MCH cell. Left, An example of a cell filled with biocytin during recording. Middle, MCH immunoreactivity is shown in green. Right, Overlay showing the biocytin labeled cell is MCH-immunopositive. Calibration: A, C, 50 ms, 25 mV (same bar applies to A and C). Scale bars: B, D, 20 µm.
DA application induced a reversible change in the frequency of spontaneous excitatory transmission in orexin neurons (Fig. 2). The direction of the effect was dose dependent: 1 µM induced a significant increase (n = 9; p < 0.05) (Fig. 2A1–A3,C), whereas 10 or 100 µM elicited a decrease in mEPSC frequency (10 µM, n = 5, p < 0.05; 100 µM, n = 9, p < 0.01) (Fig. 2B1–B3,C). A concentration of 0.1 µM had no significant effect in four cells tested (p > 0.05) (Fig. 2C). In contrast, there was no significant change in the amplitude of mEPSCs even when there was a change in the frequency, indicating that the locus of DA action is presynaptic [1 µM, n = 5, p > 0.05 (Fig. 2A4); 10–100 µM, n = 6, p > 0.05 (Fig. 2B4)].
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Figure 2. Dopamine induces a bidirectional change in the spontaneous excitatory transmission. A1, Sample traces showing mEPSCs in control condition, in the presence of DA (1 µM) and after wash as indicated. A2, Time-effect plot of the frequency of mEPSCs from a representative cell in the presence of DA (1 µM). A3, A4, Cumulative plot of interevent interval (A3) or amplitude (A4) of mEPSCs from the same cell as A2. B1, Sample traces showing mEPSCs in control condition, in the presence of DA (100 µM) and after wash as indicated. B2, A representative time-effect plot of the effect of DA (100 µM) on the frequency of mEPSCs. B3, B4, Cumulative plot of interevent interval (B3) or amplitude (B4) of mEPSCs recorded from the same cell as shown in B2. C, Summary of the effect of DA on mEPSC frequency at different concentrations. Calibration: A1, B1, 100 ms, 50 pA. *p < 0.05; ***p < 0.005. Error bars indicate SE.
It is possible that the bidirectional effect of DA on mEPSCs results from activation of different subtypes of DA receptors. There are two classes of DA receptors, namely D1-like (D1/D5) and D2-like receptors (D2/D3/D4). To test whether these two classes of DA receptors mediate differential effects, DA receptor subtype specific agonists were examined. SKF 81297 (10 µM), the D1-like receptor agonist, significantly increased the frequency of mEPSCs (n = 9, p < 0.05) (Fig. 3A,B1,B2,D) without affecting the amplitude (p > 0.05) (Fig. 3B3). Because 1 µM DA induced an increase in mEPSCs, this effect may be caused by activation of D1-like receptors. In support of this idea, the D1-like receptor antagonist SCH 23390 (10 µM) not only blocked 1 µM DA-induced facilitation of mEPSCs, but also inhibited mEPSCs (n = 5, p < 0.05) (Fig. 3C,D). In addition, the effects of 1 µM DA and SKF 81297 were not significantly different (p > 0.05). In contrast, quinpirole (10–50 µM), the D2-like agonist, reduced the frequency of mEPSC (n = 6, p < 0.05) (Fig. 4A,B1,B2,D) but not the amplitude (p > 0.05) (Fig. 4B3). This inhibitory effect was similar to that of high dose DA, therefore, we tested the effect of the D2-like receptor antagonist on 100 µM DA-induced modulation. In the presence of sulpiride (10 µM), 100 µM DA had no effect on the frequency of mEPSCs (n = 4, p > 0.05) (Fig. 4C,D). Furthermore, the effect of DA 100 µM was not significantly different from that of quinpirole (p > 0.05). Thus, inhibitory effect of high concentration of DA seems to be mediated by D2-like receptors.
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Figure 3. D1-like receptor activation increases the frequency of mEPSCs. A, Sample traces showing basal mEPSCs (control), in the presence of SKF 81297 (10 µM) and after wash as indicated. Calibration: 200 ms, 20 pA. B1, A representative time-effect plot showing the frequency of mEPSCs in presence of SKF 81297 (10 µM). B2, B3, Cumulative plot of interevent interval (B2) or amplitude (B3) of mEPSCs from the same cell as shown in B1. C, Time-effect plot of the frequency of mEPSCs depicting the response to DA (1 µM) in a cell pretreated with SCH 23390 (10 µM). D, Summary of the effect of DA 1 µM, SCH 23390 plus DA 1 µM, and SKF 81297 on mEPSC frequency. *p < 0.05; **p < 0.01. Error bars indicate SE.
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Figure 4. D2-like receptor activation decreases the frequency of mEPSCs. A, Sample traces showing basal mEPSCs (control), in the presence of quinpirole (10 µM) and after wash as indicated. Calibration: 200 ms, 20 pA. B1, Time-effect plot of a representative cell showing the effect of quinpirole (10 µM) on the frequency of mEPSCs. B2, B3, Cumulative plot of interevent interval (B2) or amplitude (B3) of mEPSCs from the same cell as shown in B1. C, Time-effect plot depicting the response of the frequency of mEPSCs to DA (100 µM) in a cell pretreated with sulpiride (10 µM). D, Summary of the effect of 100 µM DA, sulpiride plus 100 µM DA, and quinpirole (10–50 µM) on mEPSC frequency. *p < 0.05; ***p < 0.005. Error bars indicate SE.
Next, we asked the question whether the effects of DA on excitatory transmission could alter the firing activity of orexin neurons. In current-clamp mode, spontaneous action potentials were monitored in the presence of picrotoxin to block the influence of inhibitory synaptic inputs. In this condition, 1 µM DA significantly increased the frequency of action potential firing in all the cells tested (n = 4, p < 0.05) (Fig. 5A1–A3). In contrast, 100 µM DA hyperpolarized and ceased the firing activity of orexin neurons (n = 3, p < 0.05) (Fig. 5B1–B3).
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Figure 5. Bidirectional modulation of the firing activity by low and high dose of dopamine. A, DA (1 µM) increases the rate of action potentials in orexin neurons. A1, Sample recording showing the effect of 1 µM DA. A2, Expanded traces from another cell recorded before, during, and after DA application. A3, Time-effect plot of the same experiment as shown in A2. B, DA (100 µM) hyperpolarizes and diminishes the firing activity. B1, Typical recording depicting the effect of 100 µM DA. B2, Traces from another orexin neuron recorded before, during, and after DA application, shown at an expanded time scale. B3, Time-effect plot of the same experiment as in B2. Calibration: A1, B1, 50 s, 20 mV; A2, B2, 5 s, 20 mV.
In some of the orexin neurons examined, multiple experiments were performed by sequentially applying compounds having opposite effects (agonists or different doses of DA). Figure 6 depicts examples of these cells. Every cell tested was able to respond in both directions: D1 receptor activation resulted in increase in mEPSC or action potential frequency, whereas D2 receptor activation caused reduction in mEPSC or action potentials. Therefore, both D1 and D2 receptors can modulate the excitatory synapses that impinge on a single orexin neuron.
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Figure 6. D1- and D2-like receptors modulate synaptic inputs to the same neuron. A, A time-effect plot of a representative cell showing the frequency of mEPSCs in response to sequential applications of DA (100 µM) and SKF 81297 (10 µM). B, An example of the frequency of mEPSCs modulated in opposite direction by consecutive applications of quinpirole (10 µM) and SKF 81297 (10 µM). C, A typical cell showing the rate of action potential firing being bidirectionally modulated by low and high dose of DA.
Discussion
The present study demonstrates that DA modulates excitatory synaptic transmission in a dose-dependent and reversible manner in orexin neurons. The direction of modulation depends on distinct types of receptors. D1-like receptors mediate the effect of low dose DA (1 µM) that induces facilitation whereas D2-like receptors mediate the effect of higher doses (10–100 µM) that diminish the frequency of spontaneous excitatory transmission. These changes occurred in the absence of any alteration in the amplitude of mEPSCs, indicating that DA affects the transmitter release probability at the presynaptic terminal, but does not change the postsynaptic sensitivity. Furthermore, low and high doses of DA application results in an increase and decrease in action potential firing of orexin neurons, respectively. These seemingly opposite effects of DA can be observed in the same postsynaptic neuron. Thus, our results suggest that D1- and D2-like receptors can exert opposite effects on synapses converging onto the same neuron.The hyperpolarizing effect of DA on orexin neurons is in agreement with the previous reports that used high doses (30–300 µM) (Li and van Den Pol, 2005; Yamanaka et al., 2006
Bidirectional effect
The dose-dependent bidirectional effect of DA is somewhat similar to that seen in the inhibitory transmission and NMDA receptor modulation in the prefrontal cortex (PFC). In the PFC slice, DA has been shown to induce a biphasic effect on the amplitude of evoked IPSCs: D2-like mediated inhibition was followed by a long-lasting D1-like receptor-mediated increase, with the D1-mediated effect apparent at lower a dose (Seamans et al., 2001The mechanisms underlying the dopaminergic modulation in the PFC and orexin neuron are likely to be different. In the PFC, presynaptic D1 receptors cause a long-lasting increase in GABA release, and postsynaptic D2 receptors modulate the phosphorylation state of postsynaptic GABAA receptors (Trantham-Davidson et al., 2004
Physiological implication
There is a functional and anatomical reciprocal communication between the LH/PFA and the mesolimbic DA system. A bulk of the DA input to the LH/PFA originate from the midbrain A8, A9, and A10 cell groups (Leibowitz and Brown, 1980Based on the current study, in addition to previous reports demonstrating orexin neurons modulating the mesoaccumbens DA projection, we propose a dose-dependent dual feedback mechanism between the two systems. A low/moderate level of DA in the LH/PFA may excite orexin neurons through D1 receptor-mediated facilitation of excitatory input, which in turn provides excitatory influence on VTA neurons, thus creating a positive feedback mechanism. When dopaminergic activity elevates and higher concentration of DA is achieved in the hypothalamus, this will work to activate D2 receptors and inhibit orexin neurons. This will lead to decreased excitatory input to the VTA, acting as a negative feedback mechanism. This idea is supported by neurochemical and behavioral studies demonstrating that injection of sulpiride, the D2-like antagonist, into the LH/PFA induces DA efflux in the NAcc leading to locomotion and feeding (Parada et al., 1995
In conclusion, the DA effect on excitatory transmission onto orexin neurons shown in this study may be one of the mechanisms by which DA intrinsic to the LH/PFA influences feeding, reward, and locomotion. It has been shown that D1 and D2 receptor agonists normalize hyperphagia as well as rectify metabolic and endocrine abnormalities independent of food intake, resulting in a improvement of obese-diabetic syndrome in leptin deficient ob/ob mice (Scislowski et al., 1999
Footnotes
Received April 28, 2006; revised Aug. 3, 2006; accepted Aug. 25, 2006.This work was supported by the Canadian Institutes of Health Research (CIHR) and Natural Sciences and Engineering Research Council of Canada. M.H. is a CIHR New Investigator.
Correspondence should be addressed to Dr. Michiru Hirasawa, Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's Campus, Newfoundland, Canada A1B 3V6. Email: michiru{at}mun.ca
Copyright © 2006 Society for Neuroscience 0270-6474/06/2610043-08$15.00/0
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