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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Neurosci. Author manuscript; available in PMC Jan 14, 2013.
Published in final edited form as:
PMCID: PMC3544522

Tonic dopamine induces persistent changes in the transient potassium current through translational regulation


Neuromodulatory effects can vary with their mode of transmission. Phasic release produces local and transient increases in dopamine (DA) up to micromolar concentrations. Additionally, since DA is released from open synapses and reuptake mechanisms are not nearby, tonic nanomolar DA exists in the extracellular space. Do phasic and tonic transmissions similarly regulate voltage dependent ionic conductances in a given neuron? It was previously shown that DA could immediately alter the transient potassium current (IA) of identified neurons in the stomatogastric ganglion (STG) of the spiny lobster, Panulirus interruptus. Here we show that DA can also persistently alter IA, and that DA’s immediate and persistent effects oppose one another. The lateral pyloric neuron (LP) exclusively expresses type 1 DA receptors (D1Rs). Micromolar DA produces immediate depolarizing shifts in the voltage dependence of LP IA, whereas tonic nanomolar DA produces a persistent increase in LP IA maximal conductance (Gmax) through a translation dependent mechanism involving target of rapamycin (TOR). The pyloric dilator neuron (PD) exclusively expresses type 2 DA receptors (D2Rs). Micromolar DA produces an immediate hyperpolarizing shift in PD IA voltage dependence of activation, whereas tonic DA persistently decreases PD IA Gmax through a translation dependent mechanism not involving TOR. The persistent effects on IA Gmax do not depend on LP or PD activity. These data suggest a role for tonic modulators in the regulation of voltage gated ion channel number; and furthermore, that dopaminergic systems may be organized to limit the amount of change they can impose on a circuit.

Keywords: Dopamine, stomatogastric, metaplasticity, translation dependent, homeostatic plasticity, compensation, pyloric network


By and large, neurons communicate using wired or volume transmission (Zoli et al., 1998; Fuxe et al., 2007). Wired corresponds to classical fast synaptic transmission, whereas volume transmission is characterized by paracrine release and modulator diffusion. Dopaminergic neurons use volume transmission and fire tonically with intermittent bursts (Dreyer et al., 2010; Ford et al., 2010). This results in nanomolar concentrations of DA in the extracellular space that can locally and transiently increase to micromolar levels during neuronal bursts (Zoli et al., 1998). Phasically released DA produces transient, temporally relevant alterations in neuronal circuits, whereas tonic DA has a permissive function. Deficits caused by lesions to the dopaminergic system can be rescued through tonic administration of DA agonists (Schultz, 2007). The molecular mechanisms underpinning the actions of tonic DA are not well studied.

DA acts through two basic types of G protein-coupled receptors (GPCRs), D1Rs and D2Rs (Yao et al., 2008), to rapidly and transiently alter the biophysical properties of ion channels (Harris-Warrick et al., 1998; Surmeier et al., 2007). Many GPCRs, including DA receptors, can also persistently modulate ionic conductances through translation using target of rapamycin (TOR) and/or mitogen activated kinase (MAPK) pathways (Smith et al., 2005; Hoeffer and Klann, 2010; Musnier et al., 2010; O’Dell et al., 2010; Sossin and Lacaille, 2010; White and Sharrocks, 2010). We speculated that the persistent effects of tonic nanomolar DA might be mediated through translation.

The stomatogastric nervous system (STNS, Figure 1), is a well-characterized model for studying neuromodulation (Marder and Bucher, 2007). It comprises multiple central pattern generators (CPGs), including the 14-neuron pyloric network. We previously showed that dopaminergic systems in the STNS and mammalian CNS are similar: both use volume transmission (Schultz, 2007; Oginsky et al., 2010) and the same transduction pathways (Clark and Baro, 2006, 2007; Clark et al., 2008; Oginsky et al., 2010). In both systems DARs are concentrated on/near synaptic structures involved in wired transmission (Shetreat et al., 1996; Wong et al., 1999; Yao et al., 2008; Oginsky et al., 2010; Zhang et al., 2010). Mammalian DARs may segregate to specific synapses (Goto and Grace, 2005, 2008), and D2Rs are localized to only 40% of all synaptic structures on an identified STNS neuron (Oginsky et al., 2010).

Figure 1
Experimental preparation and protocol

IA is transiently regulated by DA in a variety of cells and systems (Harris-Warrick et al., 1998; Hoffman and Johnston, 1999; Perez et al., 2006). IA is encoded by shal (Kv4) channels, operates at sub-threshold membrane potentials and plays an important role in neuronal function by regulating excitability, spike timing and frequency, dendritic integration and plasticity, and the phasing of neurons in rhythmically active networks (Harris-Warrick et al., 1998; Hoffman and Johnston, 1999; Perez et al., 2006). The immediate effects of micromolar DA on IA have been well characterized for all pyloric neurons (Harris-Warrick et al., 1995b; Harris-Warrick et al., 1995a; Kloppenburg et al., 1999; Peck et al., 2001). Here we studied two pyloric neurons to examine whether or not DA could persistently modulate IA through translation.

Materials and Methods


California spiny lobsters, Panulirus interruptus, were purchased from Don Tomlinson Commercial Fishing (San Diego, CA), Catalina Offshore Products (San Diego, CA) and Marinus Scientific (Long Beach, CA) and housed in saltwater aquaria at Georgia State University (Atlanta, GA). Animals were a mix of both male and females.


All drugs were purchased from Sigma-Aldrich, unless otherwise noted. All drugs were administered to the STG via superfusion by peristaltic pump. DA was administered for 1 hour in all cases. To minimize oxidation, DA was made fresh and exchanged after 30 min. Antagonists, translational, and transcriptional inhibitors were administered 10 min prior to DA for all experiments. Dosages for translational (30μM anisomycin, 10 μM cycloheximide, and 100nM Rapamycin) and transcriptional inhibitors (50μM actinomycin D (ACD), 100μM 5,6-dichloro-1-ß-D-ribobenzimidazole (DRB)) were chosen to be greater than or equal to previously demonstrated effective dosages in several invertebrate species. The DAR receptor antagonists were initially applied according to previously determined dosages and increased as necessary (Zhang et al., 2010).

STNS Dissection, Pyloric cell identification

Lobsters were anaesthetized on ice for at least 30 min, followed by an STNS dissection, as previously described (Selverston et al., 1976). The STNS was pinned in a Sylgard-lined dish. The STG was desheathed, and during this process a portion of the juxtaposed stn was also desheathed. A Vaseline well was constructed around the STG and the juxtaposed stn and dvn. The well was continuously superfused for the remainder of the experiment (Figure 1A). Using a Dynamax peristaltic pump (Rainin), the STG was superfused with Panulirus (P.) saline (in mM: 479 NaCl, 12.8 KCl, 13.7 CaCl2, 39 Na2SO4, 10 MgSO4, 2 Glucose, 4.99 HEPES, 5 TES; pH 7.4). For overnight experiments the STNS was placed in a culture media (Panchin et al., 1993) consisting of (final concentration): 1X P. saline, 0.5X L15 Leibovitz medium, 200U/L Penicillin/ Streptomycin (ATCC), and 0.1mg/L Neomycin. This results in slightly hypertonic medium, which does not cause any deleterious effects on the preparation.

The entire experiment was performed at room temperature. Temperature was continuously monitored with a miniature probe in the bath. The temperature changed by less than 1°C throughout the course of the day (the change ranged from 0.1 to 0.9°C on any given day), and by only 3°C across all experiments (19-22°C).

Cells were identified using previously described standard intracellular and extracellular recording techniques. Intracellular somatic recordings were obtained using 20–40 MΩ glass microelectrodes filled with 3 M KCl and Axoclamp 2B or 900A amplifiers (Molecular Devices, Foster City, CA). Extracellular recordings of identified motor neurons were obtained using a differential AC amplifier (A-M Systems, Everett, WA) and stainless steel pin electrodes. PD and LP neurons were identified by their distinct waveforms, the timing of their voltage oscillations, and correlation of spikes on the extracellular and intracellular recordings (Figure 1B).

Two-electrode voltage clamp

A portion of the stomatogastric nerve was desheathed and isolated in a Vaseline well. Descending inputs were removed with a sucrose block applied into the well for 1 hour. At this point, the STG was superfused continuously with blocking saline, which consisted of P. saline containing picrotoxin (10−6M) to block glutamatergic synaptic inputs and voltage-dependent ion channel blockers: tetrodotoxin (TTX, 100nM, INa), tetraethylammonium (TEA, 20mM, IK(V) and IK(Ca)), cadmium chloride (CdCl2, 200μM, ICa) and cesium chloride (5mM, Ih). LP and PD cells were penetrated with two low resistance microelectrodes (5-9 MΩ) filled with 3M KCl. The holding potential was −50mV. IA activation was measured using 12 sweeps in which a 200ms −90mV prepulse was followed by a series of depolarizing steps (500ms) ranging from −40 to +60mV in 10mV increments. IA was further isolated by digitally subtracting the leak current, which was determined using the same activation protocol without the −90mV prepulse. After subtraction, the peak current was converted to conductance (G= Ipeak/(Vm-Ek) and fit using a 1st order Boltzmann equation to determine the voltage of half activation and maximal conductance. Steady state inactivation was measured by a series of sweeps that varied the range of the 200ms prepulse from −110 to −20mv in 10mV increments followed by a constant step to 20mV (500ms). Again to further isolate IA a digital subtraction of the leak current was performed. In this case leak current was determined by subtracting a depolarizing prepulse to −20mV, followed by a test pulse to 20mV. Peak current was again converted to conductance and fit with a 1st order boltzmann equation to derive voltage of half inactivation.

Experimental Design

The STNS was dissected and the STG was continuously superfused with P. saline (Figure 1A). The spontaneous motor output of the pyloric network was monitored throughout the experiment with extracellular electrodes on the lateral ventricular nerve (lvn) and the pyloric dilator nerve (pdn) (Figure 1A). PD & LP neurons were identified. To examine the persistent effects of DA we then applied either 5nM or 5μM DA to the STG for 1 hour (Figure 1B). Control preparations received saline during this time. In both DA treated and control conditions, this was followed by 3 hours of saline wash, unless otherwise indicated. After the wash, the ganglion was prepared for TEVC by applying a sucrose block to the stn and perfusing the ganglion with blocking saline for 1hour. The sucrose block and blocking solution disrupted descending input to LP and PD neurons, prevented the spontaneous oscillations in membrane potential and spiking activity normally observed in LP and PD, and prevented spike evoked and graded glutamatergic transmission within the STG. IA in LP and PD neurons was subsequently measured with TEVC. The limitation of this approach is that it does not allow for the comparisons of IA before and after treatment within an individual preparation. However, this limitation is offset by the fact that in order to obtain a measurement at t=0, spontaneous rhythmic activity would need to be disrupted before DA application. This could trigger homeostatic and/or compensatory mechanisms that might confound interpretation of results. Quantitative real-time PCR. Electrophysiologically identified LP and PD somata were physically removed from the STG as previously described (Oginsky et al., 2010). The ganglion was incubated with 1.2 mg/ml of collagenase type IA (Sigma-Aldrich, St. Louis, MO) until the cells were amenable to extraction with a fire-polished micropipette. Cells were immediately placed on dry ice and stored at −80°C until reverse transcription. LP and PD cells were processed for RT-PCR by using a modification of the cells-to-cDNA kit (Ambion). First, 9 μl of lysis buffer was added to the cell and incubated at 75°C for 10 minutes. Next, 0.2 μl of DNase1 was added to lysis buffer and incubated for 15 minutes at 37°C, and then again at 95°C for an additional 5 minutes for inactivation. RNA was then reverse transcribed as per the manufacturer’s instructions. After reverse transcription, the cDNA was precipitated using the following protocol (Liss, 2002): 1μg glycogen, 250ng polyC RNA, 250ng polyC DNA, 1/10 volume 2M sodium acetate, and 3.5 volumes EtOH was added to the cDNA, incubated overnight at −20°C, centrifuged at maximum for 60 min, washed with 70% EtOH, centrifuged again for 15min. The pellet was then dried and re-suspended in 13μl of sterile water, and incubated for 60min at 45°C prior to qPCR.

Specific taqman primers for Panulirus shal were designed using primer express 3 (Applied Biosystems), forward: 5′-ACGTTAGGATACGGCGACATG, reverse 5′-CACACGCCACCCACAATCT, and VIC labeled probe 5′-TCCCCACACGCCCACGGG. FAM labeled Eukaryotic 18S rRNA probes were used as the endogenous control (Applied Biosystems). All reactions were run in triplicate, with 2μl cDNA in each reaction. Assays were run with Jumpstart Taqready mastermix (Sigma-Aldrich), on an ABI Fast 7500 Real-Time PCR machine, using the following parameters: 2:00 95°C for one cycle, 0:15 95°C, 1:00 60°C for 50 cycles. Assay efficiencies were determined by serial dilution. Data were analyzed via t-test of RQ (2−ΔΔCt).

Statistical Analysis

Data were checked for normal distribution and analyzed using parametric statistical tests with Prism software package (Graphpad, La Jolla, California, USA). Significance was set at p<0.05 in all cases. Means are followed by standard deviations unless otherwise indicated. Individual samples that were more than 2 standard deviations from the mean were excluded from the analysis. There are two electrically coupled PD neurons in each ganglion, and they have been shown to have highly correlated IA transcript levels (Schulz et al., 2006). As such, only one cell per preparation could be used for analysis, owing to these cells not being independent samples. In the cases where two cells were subjected to TEVC, we simply included the lower Gmax value of the two.


The immediate and persistent effects of DA on LP IA are opposed

LP expresses D1Rs, but not D2Rs (Zhang et al., 2010). 5-100 μM DA produced an immediate decrease in the peak LP IA through a PKA-dependent mechanism (Harris-Warrick et al., 1995a; Zhang et al., 2010). The persistent effects of DA on LP IA have never been examined. We designed an experiment to determine if nanomolar or micromolar concentrations of DA persistently altered LP IA (see Materials and Methods, Experimental Design and Figure 1). A 1-hour 5nM or 5μM DA administration followed by a 3-hour wash significantly increased the peak LP IA relative to controls (Figure 2A). This persistent increase was not due to a shift in the voltage dependencies of activation or inactivation, as there were no significant differences between control, 5nM or 5μM treatment groups (ANOVAs, p>0.05, Figure 2B, Table 1). On the other hand, LP IA in both DA treated groups showed a significant ~25% increase in average maximal conductance (Gmax) compared to controls, (ANOVA F2,23=7.09, p=0.004; Tukey’s post hoc, p<0.01 for 5nM vs. control, p<0.05 for 5μM DA vs. control, Figure 2C). The DA induced increase in LP IA Gmax could be blocked by 25-40μM flupenthixol which was previously shown to be an effective antagonist for pyloric D1Rs and D2Rs (t-test, DA vs Flu+DA; t11=2.122, p=0.029) (Zhang et al., 2010). It should be noted that higher concentrations of the antagonist were required to block the persistent vs. immediate effects of DA.

Figure 2
A 1hr administration of 5nM or 5μM DA produces the same persistent increase in LP IA Gmax
Table 1
IA Voltage Dependencies

DA administration produced a significant, persistent elevation in LP IA Gmax relative to controls, but IA Gmax was only measured at the end of the experiment. Without knowledge of the initial values for IA Gmax, we could not assess which group changed relative to time 0. Did IA Gmax increase in the DA-treated groups and/or decrease in the control group over the course of our experiments? To examine this issue, we compared LP IA Gmax measurements obtained from the 4hr experiments described here to those obtained from a previous study (Zhang et al., 2010) where LP IA was measured with TEVC immediately after cell identification (termed acute group in Figure 2C, n=41). Consistent with previous reports (Schulz et al., 2006), acute measurements showed a wide range of values for IA Gmax. Both DA treatments restricted IA Gmax to the upper range of the acute distribution. Both DA treatment groups were significantly different from the acute population (ANOVA, F3,61= 8.235, p=0.0001, Tukey’s post hoc p<0.01 for both 5μM and 5nM vs. acute). If we assume that at t=0 the DA treatment groups demonstrated the same range as the acute group, then DA either increased or maintained IA Gmax, depending upon its initial value. Control 4hr preparations were not significantly different than the acute group (Tukey’s post hoc, p>0.05), suggesting control values for IA Gmax did not change in a consistent fashion over the course of our experiments.

In summary, 5nM and 5μM DA persistently increased IA Gmax by ~25%. This persistent effect opposes the immediate action of DA on LP IA, which is to shift the voltage dependence of activation and inactivation in the depolarizing direction, thereby decreasing the peak IA activated across the physiological range of depolarizing potentials (Harris-Warrick et al., 1995a; Zhang et al., 2010). The threshold concentration for the immediate effect was ~1μM in our hands (Zhang et al., 2010), which was at least three orders of magnitude higher than the saturating concentration for the persistent effect (note the 5nM and 5μM DA effects were similar in magnitude).

The immediate and persistent effects of DA on PD IA are opposed

PD neurons express D2Rs, but not D1Rs (Oginsky et al., 2010). Acute application of high concentrations of DA increases IA within seconds (Kloppenburg et al., 1999). The persistent effects of DA on PD IA were unknown. We therefore performed the same experimental paradigm: 1hour 5nM or 5μM DA bath application (P. saline for controls) followed by a 3hr wash, a 1hr block and finally TEVC to measure PD IA (Figure 1). DA produced a persistent decrease in the peak PD IA (Fig 3A & C). As was the case in LP, the DA induced change in the peak IA was not due to significant alterations in PD IA voltage dependencies (ANOVAs, p>0.05, Table 1, Figure 3B). Instead IA Gmax was significantly decreased in 5μM DA (~20%), but not 5nM DA treated preparations. (ANOVA F2,26= 5.064, p=0.014; Tukey’s p<0.05 for 5μM, Fig 3C). This DA induced decrease in IA Gmax was blocked by the application of 100μM metoclopramide (t-test, DA vs Met+DA, t18=1.92, p=0.035), which was previously shown to be a specific antagonist for pyloric D2Rs (Zhang et al., 2010). Again, higher concentrations of the antagonist were required to block the persistent vs. immediate effects of DA.

Figure 3
A 1hr administration of DA produces a persistent decrease in PD I A Gmax

In sum, the immediate and persistent effects of DA on PD IA were opposed, as was the case for LP. 100μM DA produced an immediate increase in PD IA, whereas 5nM and 5μM DA persistently reduced the peak PD IA relative to control by decreasing PD IA Gmax, but only the 5μM effect was statistically significant. Notably, both the persistent and immediate effects of DA were opposed for D1Rs vs. D2Rs.

The 5μM, but not 5nM DA induced changes in IA persist for 24 hours

We next asked if the DA induced changes in IA Gmax persisted beyond 4 hrs and up to 24 hrs. We followed a similar experimental procedure, except that the 1-hour DA application was followed by a 1-hour wash and then the preparation was placed in culture media overnight, and IA Gmax was measured the following day (18-24 hours after DA administration, Figure 4A). The persistent effect of 5μM DA on LP IA Gmax was maintained over this extended time course (38% increase), but 5nM DA was not significantly different (ANOVA, F2,16= 4.652, p=0.028, Tukey’s p<0.05 for 5μM compared to control, Figure 4B). At 24hrs, PD IA Gmax was still significantly reduced by 23% in 5μM DA preparations relative to controls (t9=2.602, p=0.029, Figure 4C).

Figure 4
DA effects on IA persisted for 24 hours in both cell types

DA-induced changes in IA do not depend on LP or PD activity

In our experimental conditions the pyloric circuit is spontaneously active and produces a rhythmic motor output until blocking saline and the stn block were applied prior to TEVC (Figure 1C). DA can cause immediate alterations in LP and PD activity, and the threshold for this effect is ~10−6M at 12-14°C (Flamm and Harris-Warrick, 1986). Since the immediate and persistent effects of DA are opposed, it is possible that the persistent changes in IA Gmax represent a homeostatic/compensatory response to the immediate DA induced changes in target neuron activity. To determine if this was the case, we performed the same experimental paradigm but included 100nM TTX from t=-10min-1hr to block neuronal activity during 5μM DA administration (Figure 5A). TTX prevented action potentials and oscillations in membrane potential (Figure 5B), and at TTX resting membrane potentials (average LP, −59+5mV, n=10; average PD, −52+4mV, n=10) graded transmission will be negligible (Johnson and Harris-Warrick, 1990; Johnson et al., 1995). Under these conditions, DA still produced a significant increase in LP IA Gmax (ANOVA F3,25= 4.072, p=0.018, Dunnett’s, DA and TTX+DA p<0.05 compared to saline control, Fig 5C) and a significant decrease in PD IA Gmax (ANOVA, F3,33= 5.353, p=0.0041, Dunnett’s p<0.05 for DA and TTX+DA compared to saline control, Figure 5D). In neither PD nor LP were IA Gmax values after TTX alone significantly different than saline control. These data suggest that DA induced changes in IA Gmax do not represent a homeostatic/compensatory response to DA-induced changes in target neuron activity, but may represent direct dopaminergic regulation of ion channel density. This is consistent with the fact that 5nM DA elicits a persistent change in IA Gmax, but does not change LP or PD activity (Flamm and Harris-Warrick, 1986).

Figure 5
Blocking activity does not alter the persistent effects of DA on IA

DA-induced changes in IA are translation dependent

The duration of the DA effect (18+ hours) points towards a long-lasting mechanism that may be protein synthesis dependent. To test this, we performed the 4hr experimental paradigm in the presence of the protein synthesis inhibitors anisomycin (Anis) or cycloheximide (CHX)(Figure 6A). 30μM Anis, applied throughout the experiment, was sufficient to block the DA induced changes in LP IA Gmax (ANOVA, F3,24=4.36, p=0.014, Tukey’s, p<0.05, Ctrl vs DA, DA vs Anis+DA, Figure 6B). Application of 10μM CHX, again given for the duration of the 4hr experiment (Figure 6A), produced similar results in LP (ANOVA, F3,25=3.57, p= 0.028, Tukey’s, p<0.05, Ctrl vs DA, DA vs CHX+DA, Figure 6D). Neither Anis nor CHX alone significantly altered LP IA Gmax (p>0.05 Tukey’s Ctrl vs Anis, Ctrl vs CHX).

Figure 6
Translational inhibitors block or occlude persistent DA induced changes in IA

Application of Anis or CHX to the STG appeared to occlude the effects of DA on PD IA Gmax. Application of Anis, or Anis+DA non-significantly lowered IA Gmax (Figure 6C) to an intermediate point between control and DA treated (ANOVA F3,31=3.540, p=0.026, Tukey’s, p<0.05 ctrl vs DA, p>0.05 all other comparisons). CHX and CHX+DA both significantly decreased IA Gmax relative to controls (ANOVA F3,31=7.27, p=0.0008, Tukey’s, p<0.05, for all groups compared to saline control). CHX alone was not significantly different than CHX+DA, indicating that CHX occludes the DA induced effect on IA (p>0.05). This suggests that the DA induced effect on PD IA Gmax is also translation dependent. Taken together, these data demonstrate that the DA induced changes in IA Gmax depend on translation in both cell types.

Tonic DA does not regulate transcription of shal

In pyloric neurons, IA is mediated by ion channels in which the pore forming subunits are encoded by the shal gene (Baro et al., 1997; Baro et al., 2000). To test whether persistent DA-induced changes in IA were underpinned by changes in shal transcript numbers, we used a taqman based quantitative real-time PCR assay to compare shal expression in single LP and PD neurons from control and 5μM DA treated preparations (4hr protocol, Figure 1). There were no significant differences in shal transcript number between control and 5μM DA treated LP neurons (t-test, p>0.05). No measurable differences in shal expression were detected between control and 5μM DA treated PD neurons (t-test, p>0.05).

We further asked if the DA-induced changes in LP and PD IA Gmax depended upon transcription of other proteins or small noncoding RNAs, by repeating the experiments while applying general transcription inhibitors (ACD or DRB) from t=-10min to 1hr (Data not shown). The results were equivocal. In our hands the transcription inhibitors inconsistently altered control preparations and significantly increased variability, rendering the data uninterpretable. In sum, while DA does not persistently alter IA Gmax at 4hrs by altering shal transcript number, we cannot determine if it acts by modifying the transcription/stability of non-shal transcripts.

D1R induced increases in IA are TOR dependant

Target of rapamycin (TOR) is a serine/threonine kinase that regulates translation initiation (Hoeffer and Klann, 2010). Translation of dendritic Kv1.1 channel transcripts can be regulated by mTOR (Raab-Graham et al., 2006), and mTOR can be regulated by DARs (Hoeffer and Klann, 2010). We tested whether TOR was involved in the DA-induced changes in LP and PD IA Gmax by applying DA with the specific TOR inhibitor, rapamycin (Figure 7A). Rapamycin alone had no effect on LP IA, but it blocked the DA induced increase in LP IA Gmax (ANOVA, F3,25= 5.259, p=0.006, Dunnett’s, p>0.05 for rapamycin alone and Rapamycin+DA compared to saline control, Figure 7B). These data provide additional support to the hypothesis that DA persistently increases LP IA by regulating translation. In contrast, DA still decreased PD IA Gmax in the presence of rapamycin (ANOVA, F3,34=5.371, p=0.0039, Dunnett’s post hoc, p<0.05, DA & rapamycin +DA compared to saline control, Figure 7C). Taken together, these data indicate that D1Rs increased IA Gmax through a TOR dependant mechanism, while D2Rs used an alternate translation dependent pathway to decrease IA Gmax.

Figure 7
The persistent increase in LP IA, but not the persistent decrease in PD IA depends upon TOR

Tonic DA-induced changes in LP IA Gmax do not produce the predicted alterations in pyloric motor output

We expected the significant changes in LP and PD IA to have functional consequences. In this system, IA influences cycle frequency, phase constancy, inter-spike interval (ISI) and post-inhibitory rebound (PIR) (Tierney and Harris-Warrick, 1992; Hooper, 1997). We examined LP PIR in the three treatment groups. LP is rhythmically inhibited by the pacemaker kernel, which comprises the electrically coupled PD and Anterior Burster neurons. Upon release from inhibition, the LP neuron rebounds and fires a series of spike on a depolarized plateau (Figure 1B&5B). LP-on delay is measured as the time between the last PD spike and the first LP spike, and it reflects the rate of PIR. IA helps determine LP-on delay (Tierney and Harris-Warrick, 1992), and in acutely isolated preparations LP shal transcript number linearly correlates with LP-on delay (Goaillard et al., 2009). A tonic DA-induced increase in LP IA Gmax should reduce the rate of LP repolarization and increase LP-on delay. We measured LP-on delay in the experiments illustrated in Figure 1 at t=0 and t=4hr for all three treatment groups (Figure 8A). In contrast to the predicted increase in LP-on delay in the DA treatment groups, we found that LP-on delay had significantly decreased in control and 5nM treatment groups (Figure 8B; Student t-Test comparing LP-on delay at t=0 to t=4hr for both treatment groups), and that there was no significant change in the 5μM DA treatment group (Student t-test, p>0.05). These data suggested that tonic DA application may alter multiple conductances and that motor output was changing under control conditions, despite the presence of descending modulatory inputs.

Figure 8
Increase in LP IA Gmax does not effect LP-on delay in the predicted manner


We have shown that DA can persistently alter voltage-gated ionic conductances through translation dependent mechanisms in a manner that is independent of target neuron activity. A tonic 1hr D1R activation produced a persistent ~25% increase in LP IA Gmax that was mediated by TOR. A tonic 1hr D2R activation persistently decreased PD IA Gmax by ~20% through an unknown translation-dependent mechanism. In both cases, the persistent and immediate effects of DA on IA were opposed. We speculate that steady-state DA could limit the effects of phasic DA on IA and/or bias for or against specific synapses.

Translational regulation of ion current densities

Translational regulation of ion channel genes constitutes a critical mechanism for regulating plasticity and excitability (Weston and Baines, 2007). The complexity of translation provides several avenues for regulation including: phosphorylation of proteins involved in translation initiation and elongation via TOR (Kelleher et al., 2004; Proud, 2007), microRNA translational suppression (Fabian et al., 2010), and regulating the availability of mRNA with RNA binding proteins such as the fragile X mental retardation protein (FMRP) (Weston and Baines, 2007; Richter, 2010) or the PUF family (Quenault et al., 2011).

D1Rs can regulate TOR activity (Schicknick et al., 2008; Santini et al., 2009), and alter the phosphorylation state of FMRP in the prefrontal cortex (Wang et al., 2010). To the best of our knowledge, this is the first study to demonstrate that tonic nanomolar DA can persistently regulate voltage gated ion current densities through translation dependent mechanisms. These findings are consistent with previous work showing that neuromodulators regulate ionic conductances over the long term in the STNS (Thoby-Brisson and Simmers, 2000; Mizrahi et al., 2001; Khorkova and Golowasch, 2007; Zhang et al., 2009; Zhao et al., 2010).

Contrasts between immediate and persistent DA effects

DA differentially modulates IA, and there are at least four important distinctions between its immediate and persistent effects: First, the immediate and persistent effects are opposed. Second, DA targets two different biophysical properties to bring about these effects: immediate changes rely largely on alterations in IA voltage dependencies (Harris-Warrick et al., 1995a; Kloppenburg et al., 1999; Zhang et al., 2010), whereas persistent changes rely exclusively on alterations in IA Gmax. Third, the dose dependencies for the two effects differ by ~ 3 orders of magnitude for LP D1Rs. Fourth, immediate but not persistent effects were reversible under experimental conditions (Kloppenburg et al., 1999; Zhang et al., 2010).

The magnitude and duration of the persistent effect

We measured LP IA acutely, after a 4hr wash (control), and after a 1hr DA treatment followed by a 3hr wash. Acute measures of LP IA Gmax ranged from 0.86-3.67μS (n=41), consistent with different combinations of synaptic and ionic conductances generating similar activity patterns (Marder and Taylor, 2011). Control measures (1.58-3.03μS, n=12) were not significantly different from acute, but LP IA Gmax values in the 5nM DA treatment group were skewed toward the upper limit of the physiological range (2.4-3.5μS, n=7). This TOR-dependent increase in IA Gmax persisted for more than 3hrs but less than 24hr after DA removal. It is not clear if mechanisms to oppose the persistent actions of DA exist in vivo (e.g., other tonic modulators), and if so, whether they were present under our experimental conditions.

The time- and concentration-dependencies for both the duration and amplitude of DA’s persistent effects have not yet been determined. Duration varies with DA concentration: The effect of 1hr 5μM DA persisted longer than 1hr 5nM DA. It is not clear if amplitude varies with concentration as both 5nM and 5μM DA produced the same persistent effect. It is not clear how the length of the DA application affects the duration or amplitude of the persistent response, as we did not vary length of application. However, a 15min exposure to D1/D5 agonist SKF-38393 (100μM) produced an increase in local protein synthesis (Smith et al., 2005).

A 1hr, 5μM DA application acted at both D1Rs and D2Rs to produce significant changes in IA Gmax that persisted for more than 24hr after DA removal. This application is not physiologically relevant, but was used to gain insight into the consequences of psychotropic drug consumption, which results in prolonged, elevated levels of DA (Frank et al., 2008). Long lasting changes in neuronal excitability are a hallmark of drug addiction (Wolf, 2010). Since dopaminergic systems have been highly conserved across species, from modes of transmission through signaling cascades and even effects on final targets (Clark and Baro, 2006, 2007; Clark et al., 2008; Oginsky et al., 2010), our findings might suggest that persistent DA-induced changes in voltage-gated ion channel number may represent an initial step in the dynamic process leading to addiction.

Do distinct DARs generate persistent vs. immediate effects?

High and low affinity D1Rs mediate persistent and immediate changes in LP IA, respectively. As in mammals, there are two crustacean D1Rs. D1αPan receptors preferentially couple with Gs and Gq, while D1βPan receptors couple only with Gs (Clark et al., 2008). The immediate D1R induced decrease in LP IA is mediated through an increase in cAMP and PKA activity, which act to produce depolarizing shifts in the voltage dependence of activation and inactivation (Zhang et al., 2010). On the other hand, TOR mediates the persistent translation-dependent increase in LP IA Gmax. Both Gs and Gq coupled receptors have been shown to modulate TOR (Hoeffer and Klann, 2010). Thus, either or both D1Rs could mediate DA’s immediate and/or persistent effects on LP IA. When expressed in human embryonic kidney (HEK) cells, the DA EC50s were ~10−8 and 10−6 for D1αPan and D1βPan, respectively (Clark and Baro, 2006); however these were based on cAMP assays and may not be accurate for D1Rs involved in the persistent response.

There is a single D2-like receptor in invertebrates, whose transcript is alternately spliced to create distinct isoforms with DA EC50s ranging from ~ 10−6 to 10−8 when expressed in HEK cells (Hearn et al., 2002; Clark and Baro, 2007). D2Rs couple with Gi (Clark et al., 2008), but the cascade(s) mediating the immediate and persistent changes in PD IA have not been determined. Since a given receptor can couple with multiple signaling cascades, and those cascades can change over time during continuous agonist application (Beaulieu and Gainetdinov, 2011), it is not clear if the immediate and persistent responses are generated by the same or distinct receptor proteins.

Localization of Dopaminergic action

Does DA act locally or globally to persistently regulate IA? In the STNS, both D1Rs and D2Rs are localized exclusively to terminals and/or synaptic structures on fine dendrites (Clark et al., 2008; Oginsky et al., 2010; Zhang et al., 2010). Calcium imaging studies have shown that the DA induced immediate increases (LP) or decreases (PD) in calcium are highly localized (Kloppenburg et al., 2000, 2007). It is not clear if the changes in IA we observe are similarly localized, however previous work in other systems has shown that IA density can be locally regulated (Losonczy et al., 2008; Makara et al., 2009), and that TOR can regulate translation of dendritic K+ channels (Raab-Graham et al., 2006; Jimenez-Diaz et al., 2008). Further, neuromodulators have been demonstrated to locally regulate translation at specific synapses (Wang et al., 2009; Wang et al., 2010). These data raise the possibility that the persistent effects of DA are highly localized. Alternatively, high concentrations of DA (100μM) have been shown to increase somatic cAMP within minutes (Hempel et al., 1996). Thus, global regulation cannot be ruled out.


What is the purpose of tonic and phasic modulation of IA in a single cell? Theoretically, DARs involved in tonic vs. phasic modulation could be differentially localized and act on different subsets of ion channels. Alternatively, these two components could act together to generate metaplasticity (Abraham, 2008). Grace first proposed that exposing a cell to tonic DA could modulate that cell’s response to phasic DA (Grace, 1991), and this idea has been borne out experimentally (Matsuda et al., 2006; Kolomiets et al., 2009; Kroener et al., 2009). The opposing actions of tonic and phasic DA may suggest that steady-state DA limits the effect of phasic DA. Due to volume transmission, as the activity of bursting dopaminergic neurons increases, local steady-state DA may also increase, thereby dampening further effects of phasic modulation. If true, this could represent a novel activity-dependent homeostatic mechanism to preserve target neuron activity within limits. This mechanism would compensate for changes in activity of the modulatory, not the target, neurons.

Additionally, or alternatively, tonic DA may serve in synapse selection. Tonic nanomolar peptide applications can weaken sensory modulation of a motor circuit (DeLong and Nusbaum, 2010). Similarly, tonic DA might bias for or against specific synapses, and phasic DA could transiently remove/reverse that bias. PD D2Rs are found only at 40% of synaptic structures (Oginsky et al., 2010), suggesting DARs may be localized to specific inputs/outputs, consistent with findings for nucleus accumbens neurons (Goto and Grace, 2005, 2008). This could provide a substrate for branch/synapse specific changes in IA. Our working model is that tonic DA simultaneously weakens extrinsic excitatory inputs to branches/terminals containing D1Rs by increasing IA to locally shunt synaptic currents, and strengthens inputs to D2R containing branches/terminals by locally decreasing IA. Phasic DA would momentarily remove/reverse this bias. Since each synaptic structure in the STNS contains input and output elements (King, 1976), and pyloric neurons use graded synaptic transmission, tonic DA could also increase (D2Rs) and decrease (D1Rs) graded release at specific branches/terminals. Ultimately, the dopaminergic system could provide a mechanism for selecting specific inputs/outputs.


The authors would like to thank Timothy Dever and Kimilia Kent for excellent technical assistance. This work was supported by DA024039 to DJB.


There are no conflicts of interest for this work.


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