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Keywords:

  • acetylcholine;
  • dopamine;
  • muscarinic;
  • Parkinson's disease;
  • tremulous jaw movements

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Experiments
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Deep brain stimulation (DBS) of the subthalamic nucleus is increasingly being employed as a treatment for parkinsonian symptoms, including tremor. The present studies used tremulous jaw movements, a pharmacological model of tremor in rodents, to investigate the tremorolytic effects of subthalamic DBS in rats. Subthalamic DBS reduced the tremulous jaw movements induced by the dopamine D2 family antagonist pimozide and the D1 family antagonist ecopipam, as well as the cholinomimetics pilocarpine and galantamine. The ability of DBS to suppress tremulous jaw movements was dependent on the neuroanatomical locus being stimulated (subthalamic nucleus vs. a striatal control site), as well as the frequency and intensity of stimulation used. Importantly, administration of the adenosine A2A receptor antagonist MSX-3 reduced the frequency and intensity parameters needed to attenuate tremulous jaw movements. These results have implications for the clinical use of DBS, and future studies should determine whether adenosine A2A antagonism could be used to enhance the tremorolytic efficacy of subthalamic DBS at low frequencies and intensities in human patients.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Experiments
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Resting tremor is a cardinal symptom of parkinsonism, presenting in > 70% of individuals with idiopathic Parkinson's disease (PD) (Deuschl et al., 2000; Hoehn & Yahr, 2001). Furthermore, tremor is also a feature of drug-induced parkinsonian symptoms that result from administration of dopamine (DA) antagonists that are used as antipsychotic drugs (Marsden et al., 1975; Sultana & McMonagle, 2000; Bergman & Deuschl, 2002; Rathbone & McMonagle, 2007; Drago et al., 2011). Although tremor causes significant distress in patients (Mansur et al., 2007), there is still considerable uncertainty about the neurochemical mechanisms that underlie the pathophysiology of parkinsonian tremor (Deuschl et al., 2000). Moreover, tremor has been shown to respond poorly to traditional antiparkinsonian medications, including levodopa (Clarimon et al., 2008). Thus, the development of alternative therapeutic strategies is critical. One such strategy is subthalamic nucleus (STN) deep brain stimulation (DBS). STN neurons show hyperactivity and alterations in firing pattern in primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Miller & DeLong, 1987). In PD patients, excessively synchronised, high-frequency (i.e. 15–30 Hz) oscillations that are correlated with tremor-related neuronal activity have been recorded from the STN (Levy et al., 2000). High-frequency stimulation of the STN has been shown to improve rigidity, akinesia, postural/gait instabilities and tremor in PD patients (Limousin et al., 1995; Ashkan et al., 2004; Deuschl et al., 2006; Moro et al., 2010). Moreover, levodopa can enhance the antiparkinsonian efficacy of STN stimulation (Bejjani et al., 2000).

Animal studies have shown positive results with STN DBS in models related to parkinsonism (Darbaky et al., 2003; Fang et al., 2010; Spieles-Engermann et al., 2010; Baunez, 2011; Brown et al., 2011), although there has been little specific focus on models of tremor. The tremulous jaw movement (TJM) model, an extensively validated rodent model of tremor (Salamone et al., 1998, 2005, 2008a,b; Collins-Praino et al., 2011), may be useful for studying the tremorolytic effects of DBS in rodents. TJMs in rodents are oral tremors in the 3–7-Hz frequency range that are induced by neurotoxic and pharmacological depletion of striatal DA, DA antagonism, and cholinomimetics that are known tremorogenic agents (Jicha & Salamone, 1991; Salamone et al., 1998, 2005, 2008a; Simola et al., 2004; Collins-Praino et al., 2011; Miwa et al., 2011); these conditions are all associated with the generation of parkinsonism in humans (Salamone et al., 1998; Collins et al., 2011; Collins-Praino et al., 2011). TJMs are attenuated by antiparkinsonian drugs, including levodopa, DA agonists, and muscarinic agonists (Cousins et al., 1997; Salamone et al., 2005; Betz et al., 2007, 2009), and meet a reasonable set of validation criteria for use as an animal model of parkinsonian tremor (Salamone et al., 1998, 2005, 2008b; Collins-Praino et al., 2011).

The present work was conducted to determine whether STN DBS could suppress drug-induced TJMs in rats, and to study the combined effects of DBS and adenosine A2A antagonism. In four experiments, we studied the ability of high-frequency unilateral stimulation of the STN to attenuate the TJMs induced by different pharmacological conditions (the DA D2 antagonist and antipsychotic drug pimozide, the DA D1 antagonist ecopipam, the muscarinic agonist pilocarpine, and the acetylcholinesterase inhibitor galantamine). Pimozide was selected because this drug has been reported to be more likely to induce parkinsonian tremor than other antipsychotics (Sultana & McMonagle, 2000; Rathbone & McMonagle, 2007). Galantamine (Reminyl) was investigated because this anticholinesterase has been shown to induce and exacerbate tremor in human patients (Aarsland et al. 2003; Litvinenko et al. 2008; Grace et al. 2009). Additional studies were conducted to determine whether the effects of DBS were either frequency-dependent or intensity-dependent. Furthermore, the adenosine A2A receptor antagonist MSX-3 was injected in combination with varying frequencies and intensities of STN DBS in order to determine whether adenosine A2A antagonism, which is a non-dopaminergic approach to treating parkinsonism (Ferré et al., 2004; Jenner, 2005; Schwarzschild et al., 2006; Morelli et al., 2007; Salamone et al., 2008b; Factor et al., 2010), could provide a synergistic effect when used in conjunction with stimulation. The adenosine A2A receptor subtype is expressed to a high degree in the neostriatum, particularly on the enkephalin-positive striatopallidal neurons that co-express DA D2 receptors (Fink et al., 1992; Rosin et al., 1998; Svenningsson et al., 1999; Ferré et al., 2001, 2004; Fuxe et al., 2007). Adenosine A2A antagonists have been shown to have modest antiparkinsonian effects in human clinical studies (Bara-Jimenez et al., 2003; Jenner, 2005; LeWitt et al., 2008; Stacy et al., 2008). Furthermore, research with animal models has demonstrated that antagonism of adenosine A2A receptors can produce motor effects that are consistent with antiparkinsonian actions (Morelli & Pinna 2002; Pinna et al., 2005), including suppression of TJMs (Correa et al., 2004; Simola et al., 2004; Tronci et al., 2007; Salamone et al., 2008a,b; Betz et al., 2009). It was hypothesised that STN DBS would suppress drug-induced TJMs, and that adenosine A2A antagonism would make rats more sensitive to the tremor-suppressant effects of low frequencies or intensities of STN DBS.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Experiments
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Animals

A total of 116 male Sprague Dawley rats (Harlan Sprague Dawley, Indianapolis, IN, USA) with no prior drug experience were used. They weighed 375–500 g during the course of the experiment, and had ad libitum access to laboratory chow and water. Rats were group-housed in a colony that was maintained at 23 °C (12-h light/dark cycle; lights on 07:00 h). These studies were conducted according to University of Connecticut Institutional Animal Care and Use Committee and NIH guidelines for animal research.

Behavioral procedure

Observations took place in an elevated 30 × 30 × 30-cm clear chamber with a wire mesh floor. TJMs were defined as rapid vertical deflections of the lower jaw that resembled chewing but were not directed at any particular stimulus (Salamone et al., 1998). Each individual deflection of the jaw was recorded by a trained observer, who was blind to the experimental condition of the rat being observed, and had > 90% inter-rater reliability with another observer. These methods have been described in detail elsewhere (Ishiwari et al., 2005; Salamone et al., 2005; Collins et al., 2010a).

Pharmacological agents

Repeated daily injections of the DA antagonists ecopipam and pimozide were used to induce TJMs, because previous research showed that this procedure gave the most robust response to DA antagonism (Ishiwari et al., 2005). Cholinomimetics produce very high levels of TJM activity with acute administration. All drug injections were intraperitoneal, and doses and observation times for pimozide, pilocarpine and galantamine were selected on the basis of previous research (Ishiwari et al., 2005; Salamone et al., 2005; Collins et al., 2010a,b) demonstrating that these conditions induced significant TJM activity relative to control conditions (ecopipam dose and observation time were from D. Galtieri, 2010, unpublished honors thesis, University of Connecticut).

D1 family antagonist

Ecopipam (SCH 39166; 0.5 mg/kg) was dissolved in 0.9% saline, and rats received priming injections for 7 days. On day 8, ecopipam was injected 20 min before behavioral and DBS testing sessions.

D2 family antagonist

Pimozide (1.0 mg/kg) was dissolved in 0.3% tartaric acid, and administered for 7 days before testing. On day 8, pimozide was administered 4 h before testing began.

Muscarinic agonist

Pilocarpine (0.5 mg/kg) was dissolved in 0.9% saline, and administered 10 min before testing.

Acetylcholinesterase inhibitor

Galantamine (3.0 mg/kg) was dissolved in 0.9% saline, and administered 30 min before testing.

Adenosine A2A antagonist

MSX-3 (5.0 mg/kg) was synthesised in the Müller laboratory at the Pharmazeutisches Institut (Universität Bonn; Bonn, Germany), and was dissolved in pH-adjusted 0.9% saline and administered 20 min before testing (Salamone et al., 2008a). MSX-3 is a pro-drug of the active adenosine A2A antagonist MSX-2 (Hockemeyer et al., 2004).

Surgical implantation

Rats were anesthetised with ketamine/xylazine (1.0 mg/kg, intraperitoneal) that contained ketamine (Bioniche Pharma, Lake Forest, IL, USA; 100 mg/mL) and xylazine (Phoenix Pharmaceuticals, St Joseph, MO, USA; 0.75 mL of a 20 mg/mL solution, added to 10.0 mL of ketamine solution), and implanted unilaterally with a stainless steel stimulating electrode (Plastics One, Roanoke, VA, USA) in either the STN or a striatal control site (STN site, electrode implanted at the following coordinates from bregma: AP, –3.6 mm, LM, ± 2.5 mm, and DV, –7.2 mm) (striatal control site: AP, +1.4 mm, LM, ± 4.0 mm, and DV, –3.5 mm) [coordinates modified from Paxinos & Watson (2006), to account for the age and weight of the rats], and anchored to the skull with acrylic and machine screws. Electrode placements were confirmed by histological analyses (Nissl stain) after the experiments. According to the histological criteria employed by Brown et al. (2011), only placements confirmed to be within 500 μm of the STN, but dorsal to the cerebral peduncles and internal capsule, were used for statistical analyses of STN stimulation effects. Figure 1 shows a representative electrode placement from the pilocarpine experiment. Also, Nissl-stained STN sections were examined for the possibility of electrolytic lesions at the electrode tip, but none were observed.

image

Figure 1. Left: photomicrograph showing a representative electrode placement, which was at the dorsal border of the STN. Consistent with the histological criteria employed by Brown et al. (2011), only placements that were within 500 μm of the STN, but dorsal to the cerebral peduncles and internal capsule, were used for statistical analyses of electrical stimulation effects. Right: schematic of a coronal section modified from Paxinos & Watson (2006), highlighting the position of the STN.

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Stimulation and testing procedures

After postsurgical recovery (1 week), behavioral observation/stimulation sessions were started. Following drug administration, TJMs were counted during three separate 10-min stimulation epochs, with each epoch consisting of 5 min without deep brain stimulation (i.e. OFF period) immediately followed by 5 min with stimulation (i.e. ON period), yielding a total of 30 min of observation per rat. During ON periods in experiments 1–4, rats received 5 min of continuous alternating current with biphasic symmetrical square impulses (pulse width, 60 μs; amplitude, 200 μA; frequency, 130 Hz). Rats were observed for TJMs during each ON and OFF period.

Experiments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Experiments
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

In experiments 1–4, we studied the ability of STN DBS to suppress the TJMs induced by DA antagonism (ecopipam and pimozide), or by cholinomimetics (pilocarpine and galantamine). In experiments 5 and 6, we investigated the frequency and intensity dependence of the effect of STN DBS on galantamine-induced TJMs, and determined whether the adenosine A2A antagonist MSX-3 could alter the frequency or intensity parameters needed to suppress galantamine-induced TJMs.

Data analyses

Tremulous jaw movement (TJM) data for experiments 1–4 were analysed with using factorial anova, with factors for stimulation (ON vs. OFF), and time period (epoch), in order to determine the effects of DBS. For experiments 5 and 6, TJM activity observed during DBS was expressed as the percentage of that in the immediately preceding OFF period, and factorial anovas (3 × 2) were conducted to characterise the effects of the three stimulation frequencies and intensities in control and MSX-3-treated groups. A combined control group consisting of untreated and saline-treated rats was used in experiments 5 and 6; the two control groups did not differ from each other, so their data were combined. The effects of DBS on TJMs were represented as percentage of OFF-stimulation levels of jaw movements in experiments 5 and 6, in order to normalise the data to the same scale under both control and MSX-3 conditions, and to simplify the graphs to highlight more clearly the main points of those experiments (i.e. to illustrate the intensity and frequency dependence of the stimulation, and to show the effect of adenosine A2A antagonism on the intensity and frequency dependence of the STN stimulation). A computerised statistical program (spss 12.0, IBM, Armonk, NY, USA; for Windows) was used for all analyses.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Experiments
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Experiments 1–4: STN DBS suppresses oral tremor induced by DA antagonism and cholinomimetics

In the first four experiments, we studied the effects of DBS on the TJMs induced by DA antagonism and by cholinomimetic drugs that are known to be tremorogenic agents (Figs 2 and 3). Separate two-way anovas were performed on the data from rats with STN electrodes and control site electrodes. STN DBS significantly reduced the TJMs induced by the DA D2 antagonist pimozide (Fig. 2A; F1,12 = 6.6, P < 0.05), the D1 antagonist ecopipam (Fig. 3A; F1,16 = 87.6, P < 0.05), the muscarinic agonist pilocarpine (Fig. 4A; F1,14 = 14.7, P < 0.05), and the acetylcholinesterase inhibitor galantamine (Fig. 5A; F1,18 = 24.3, P < 0.05). Although the overall effect of stimulation (i.e. ON vs. OFF) was statistically significant in each case, there were no significant stimulation × epoch interactions, indicating that the effects of STN stimulation were consistent across all three periods of stimulation. In contrast, stimulation of the control site was ineffective in reducing drug-induced TJMs (Figs 2B, 3B, 4B and 5B). These analyses provide strong evidence that high-frequency stimulation of the STN region suppresses drug-induced oral tremor, as measured by TJMs, across a broad range of conditions.

image

Figure 2. Subthalamic nucleus (STN) DBS suppresses TJMs induced by DA D2 antagonism. (A) Effect of STN DBS on TJMs induced by repeated administration of the DA D2 antagonist pimozide: number of jaw movements [mean ± standard error of the mean (SEM)] in 5 min when stimulation was either OFF or ON, across the three ON–OFF epochs. During ON periods, rats received 5 min of continuous alternating current with biphasic symmetrical square impulses (pulse width, 60 μs; amplitude, 200 μA) and a frequency of 130 Hz. *Significant difference from vehicle control (P < 0.05). (B) Effect of DBS of a striatal control site on TJMs induced by repeated administration of the DA D2 antagonist pimozide: number of jaw movements (mean ± SEM) in 5 min when stimulation was either OFF or ON. During ON periods, rats received 5 min of continuous alternating current with biphasic symmetrical square impulses (pulse width, 60 μs; amplitude, 200 μA) and a frequency of 130 Hz. High-frequency stimulation at this control site did not significantly attenuate TJMs during any observation epoch.

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image

Figure 3. Subthalamic nucleus (STN) DBS suppresses TJMs induced by DA D1 antagonism. (A) Effect of STN DBS on TJMs induced by repeated administration of the DA D1 antagonist ecopipam (SCH 39166): number of jaw movements [mean ± standard error of the mean (SEM)] in 5 min when stimulation was either OFF or ON. During ON periods, rats received 5 min of continuous alternating current with biphasic symmetrical square impulses (pulse width, 60 μs; amplitude, 200 μA) and a frequency of 130 Hz. *Significant difference from vehicle control (P < 0.05). (B) Effect of DBS of a striatal control site on TJMs induced by repeated administration of the DA D1 antagonist ecopipam. Number of jaw movements (mean ± SEM) in 5 min when stimulation was either OFF or ON. During ON periods, rats received 5 min of continuous alternating current with biphasic symmetrical square impulses (pulse width, 60 μs; amplitude, 200 μA) and a frequency of 130 Hz. High-frequency stimulation at this control site did not significantly attenuate TJMs during any observation epoch.

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image

Figure 4. Subthalamic nucleus (STN) DBS suppresses TJMs induced by the muscarinic agonist pilocarpine. (A) Effect of STN DBS on TJMs induced by acute administration of the muscarinic agonist pilocarpine. Number of jaw movements [mean ± standard error of the mean (SEM)] in 5 min when stimulation was either OFF or ON. During ON periods, rats received 5 min of continuous alternating current with biphasic symmetrical square impulses (pulse width, 60 μs; amplitude, 200 μA) and a frequency of 130 Hz. *Significant difference from vehicle control (P < 0.05). (B) Effect of DBS of a striatal control site on TJMs induced by pilocarpine. Number of jaw movements (mean ± SEM) in 5 min when stimulation was either OFF or ON. During ON periods, rats received 5 min of continuous alternating current with biphasic symmetrical square impulses (pulse width, 60 μs; amplitude, 200 μA) and a frequency of 130 Hz. High-frequency stimulation at this control site did not significantly attenuate TJMs during any observation epoch.

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image

Figure 5. Subthalamic nucleus (STN) DBS suppresses galantamine-induced TJMs. (A) Effect of STN DBS on TJMs induced by acute administration of the acetylcholinesterase inhibitor galantamine. Number of jaw movements [mean ± standard error of the mean (SEM)] in 5 min when stimulation was either OFF or ON. During ON periods, rats received 5 min of continuous alternating current with biphasic symmetrical square impulses (pulse width, 60 μs; amplitude, 200 μA) and a frequency of 130 Hz. *Significant difference from vehicle control (P < 0.05). (B) Effect of DBS of a striatal control site on galantamine-induced TJMs. Number of jaw movements (mean ± SEM) in 5 min when stimulation was either OFF or ON. During ON periods, rats received 5 min of continuous alternating current with biphasic symmetrical square impulses (pulse width, 60 μs; amplitude, 200 μA) and a frequency of 130 Hz. High-frequency stimulation at this control site did not significantly attenuate TJMs during any observation epoch.

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Experiments 5 and 6: the anti-tremor effects of STN DBS are frequency-dependent and intensity-dependent, and are enhanced by administration of an adenosine A2A receptor antagonist

Figure 6A shows the frequency dependence of the suppressive effect of STN DBS on galantamine-induced TJMs, and also demonstrates that administration of the adenosine A2A antagonist MSX-3 enhanced the tremorolytic effect of stimulation. Factorial anova was used to analyse the relative suppression of TJMs (i.e. the ON/OFF ratio expressed as a percentage) induced by different frequencies of DBS in the combined control group (untreated and saline-treated controls) and a group that received 5.0 mg/kg MSX-3. The overall effect of frequency level (e.g. 70, 100 or 130 Hz) was statistically significant (F2,54 = 45.8, P < 0.001), indicating that the DBS-induced suppression of TJMs was dependent on the frequency of stimulation. In addition, there was a significant overall difference between the control group and the MSX-3 group (F1,27 = 18.4, P < 0.001). Importantly, there was also a significant frequency × drug treatment interaction (F2,54 = 14.1, P < 0.001), indicating that MSX-3 treatment altered the frequency–response function. This conclusion was further supported by additional trend analysis showing that the linear trend in the control group significantly differed from that in the MSX-3 group (F1,27 = 22.9, P < 0.001). Rats treated with 5.0 mg/kg MSX-3 along with STN DBS showed significant attenuation of TJMs as compared with the immediately preceding baseline OFF period at all three stimulation frequencies (P < 0.05). Taken together, these results indicate that the suppressive effects of STN DBS were frequency-dependent, and that administration of the adenosine A2A antagonist MSX-3 altered this frequency dependence by enhancing sensitivity to the anti-tremor effects of STN DBS at low frequencies.

image

Figure 6. The ability of STN DBS to suppress galantamine-induced TJMs is both frequency-dependent and intensity-dependent: modulation by adenosine A2A antagonism. (A) Effect of co-administration of the adenosine A2A antagonist MSX-3 on the frequency dependence of the ability of STN DBS to reduce galantamine-induced TJMs. Data are expressed as percentage relative to the preceding OFF period [mean ± standard error of the mean (SEM)] for both the control group and the MSX-3 group. For rats in the control group, stimulation at 100 Hz (P < 0.01) and 130 Hz (P < 0.001) resulted in a significant decrease in TJMs when stimulation was ON. There was an overall effect of frequency, and a drug treatment × frequency interaction. (B) Effect of co-administration of the adenosine A2A antagonist MSX-3 on the intensity dependence of the ability of STN DBS to reduce galantamine-induced TJMs. As with frequency, the intensity data are expressed as percentage relative to the preceding OFF period (mean ± SEM). There was an overall effect of intensity, and a significant drug treatment × intensity interaction.

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As shown in Fig. 6B, the suppressive effect of STN DBS on galantamine-induced TJMs was also intensity-dependent, and the adenosine A2A antagonist MSX-3 enhanced the tremorolytic effect of lower-intensity stimulation. Factorial anova was used to analyse the relative suppression of TJMs (e.g. the ON/OFF ratio expressed as a percentage) induced by different intensities of DBS in the combined control group and the MSX-3 (5.0 mg/kg) group. The overall effect of intensity level (e.g. 50, 100 or 200 μA) was statistically significant (F2,38 = 6.93, P < 0.01), demonstrating that the DBS-induced suppression of TJMs was dependent on the intensity of stimulation. In addition, there was a significant overall difference between the control group and the MSX-3 group (F1,19 = 20.5, P < 0.001). As with frequency, there was also a significant intensity × drug treatment interaction (F2,38 = 3.64, P < 0.05); this shows that MSX-3 treatment altered the intensity–response function. Orthogonal analysis of trend also demonstrated that the linear trend in the control group significantly differed from that in the MSX-3 group (F1,19 = 8.8, P < 0.01). Rats treated with 5.0 mg/kg MSX-3 along with STN DBS showed significant attenuation of TJMs as compared with the immediately preceding baseline OFF period at all three intensity levels (P < 0.05). Thus, the suppressive effects of STN DBS were intensity-dependent, and injections of the adenosine A2A antagonist MSX-3 altered this intensity dependence by enhancing sensitivity to the anti-tremor effects of STN DBS at lower stimulation intensities.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Experiments
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

The present studies were conducted to determine whether high-frequency stimulation of the STN in rats would be capable of reducing the oral tremor induced by either DA antagonism or cholinomimetic stimulation. DBS of the STN, but not of a striatal control site, significantly reduced the number of TJMs induced by repeated 8-day administration of the DA D2 family antagonist pimozide and the D1 family antagonist ecopipam. Similar to the findings from the studies employing DA antagonists, high-frequency stimulation of the STN was also capable of significantly reducing the number of jaw movements induced by both the muscarinic agonist pilocarpine and the acetylcholinesterase inhibitor galantamine. Rats stimulated at the striatal control site did not show the same attenuation of jaw movement activity.

The short-duration (60 μs), high-frequency (130 Hz) stimulation parameters used for these studies have been widely adopted for use in preclinical rodent studies utilising STN DBS (Spieles-Engermann et al., 2010; Brown et al., 2011; Creed et al., 2011). Despite concerns raised by Spieles-Engermann et al. (2010) that stimulus amplitudes higher than 30–50 μA in rodents may result in involuntary dyskinetic movements that worsen as stimulation intensity increases, at the intensity used in the current studies (i.e. 200 μA) no dyskinetic movements, tonic twisting or involuntary rotational behavior were observed. This is consistent with previous studies with 200-μA stimulation for the treatment of motor deficits in hemiparkinsonian rats, which also failed to show any dyskinetic movements or electrolytic lesions of brain tissue (Akita et al., 2010).

The ability of STN DBS to significantly suppress TJMs was dependent on both the frequency and the intensity of stimulation used (Fig. 6). Rats stimulated with 130-Hz frequency and 200-μA intensity showed a maximal decrease in TJMs. These results are consistent with findings from both clinical patient populations and previous studies in animal models, which suggested that the parameters of STN DBS used in these studies are analogous to the stimulation parameters necessary for inducing clinical improvement in PD patients (Krack et al., 2003; Garcia et al., 2005). In PD patients undergoing STN stimulation, most stimulation parameters are 130–185 Hz for frequency, 60–210 μs for pulse duration, and 1–3.5 V for amplitude (i.e. intensity) (Krack et al., 2003). Therapeutic frequencies have been reported to be > 100 Hz, whereas frequencies <50 Hz are non-therapeutic (Garcia et al., 2005), and stimulation at 5–10 Hz actually worsens parkinsonism (Moro et al., 2002).

Importantly, the adenosine A2A receptor antagonist MSX-3 reduced both the frequency and intensity (Fig. 6) parameters necessary to achieve significant attenuation of TJMs with STN DBS. Whereas a stimulation frequency of 70 Hz and a stimulation intensity of 50 μA were unable to suppress TJMs in vehicle-treated control rats, both parameters were efficacious in reducing the number of jaw movements relative to the immediately preceding OFF period in rats treated with MSX-3. This is consistent with the findings of a previous study, which suggested that a synergistic effect may occur when high-frequency stimulation of the STN is used in conjunction with levodopa treatment (Bejjani et al., 2000). Given the numerous motor complications that can occur in response to levadopa treatment, adenosine A2A receptor antagonists may provide a reasonable alternative for co-administration with DBS. Adenosine A2A receptors are highly expressed in the neostriatum, and adenosine A2A antagonists exert motor effects in rodents and primates that are consistent with antiparkinsonian actions (Ferré et al., 2001, 2004, 2008; Schwarzschild et al., 2006; Morelli et al., 2007; Salamone et al., 2008b; Collins et al., 2010b). In studies using the jaw movement model, adenosine A2A antagonists have been shown to significantly reverse the TJMs induced by DA depletion, DA antagonism, and cholinomimetic administration (Correa et al., 2004; Simola et al., 2004; Salamone et al., 2008a; Collins et al., 2010a; Pinna et al., 2010). Human clinical reports have indicated that adenosine A2A antagonists significantly improve motor deficits, reduce OFF time and increase ON time in parkinsonian patients, suggesting that members of this drug class may be efficacious as antiparkinsonian agents (Jenner, 2005; LeWitt et al., 2008; Stacy et al., 2008; Pinna, 2009; Pinna et al., 2010; Salamone et al., 2010).

In addition to studies of motor function, there is growing evidence suggesting that adenosine A2A antagonists may also have utility in treating cognitive dysfunction (Shen & Chen, 2009; Wei et al., 2011), which could be important in view of the cognitive side effects that have been reported to occur with DBS in humans (Funkiewiez et al., 2004; Higginson et al., 2009; Daniels et al., 2010; ; Rinehardt et al., 2010; Baunez, 2011). Both administration of adenosine A2A antagonists and genetic deletion of adenosine A2A receptors have been shown to improve memory performance in a variety of behavioral tasks (Wang et al., 2006; Dall'igna et al., 2007; Cunha et al., 2008; Takahashi et al., 2008). Given the growing body of evidence suggesting that STN DBS may induce cognitive deficits, particularly in verbal fluency and executive functioning (Funkiewiez et al., 2004; Higginson et al., 2009; Daniels et al., 2010; Rinehardt et al., 2010), the findings of the present study may be particularly important clinically, as co-administration of an adenosine A2A receptor antagonist with with STN DBS may not only provide a refinement in the stimulation parameters used surgically for the treatment of tremor, but may also help to improve some of the cognitive impairments produced by DBS.

The mechanism of action through which STN DBS reduces any motor dysfunction, including tremor, is unknown. Several mechanisms of action have been proposed, including inhibition of STN neurons and generation of depolarisation block, activation of STN neurons, increased release of GABA in the substantia nigra pars reticulata, normalisation of pathological network oscillations, and restoration of cortical motor maps resulting from stimulation of the motor cortex (Beurrier et al., 2001; Windels et al., 2003; Perlmutter & Mink, 2006; Brown & Eusebio, 2008; Brown et al., 2011). Additional research with the TJM model could be useful for identifying the neural circuitry underlying the tremorolytic effects of STN area stimulation. Moreover, further investigations should focus on determining the mechanism through which adenosine A2A receptor antagonism acts to enhance the suppressive effects of STN DBS on tremor. In the striatum, adenosine A2A receptors are largely localised on the encephalin-containing medium spiny neurons that form the initial limb of the ‘indirect pathway’ of striatal output (Fink et al., 1992; Rosin et al., 1998; Svenningsson et al., 1999; Ferré et al., 2001, 2004; Fuxe et al., 2007). In view of studies indicating that these GABAergic neurons project to the globus pallidus (the lateral globus pallidus in primates), and that adenosine A2A antagonism suppresses the enhanced neural activity in these neurons that is associated with DA D2 antagonism (Betz et al., 2009; Farrar et al., 2010; Santerre et al., 2012), it is possible that A2A antagonism acts via the globus pallidus to modulate neural activity in the STN, the substantia nigra pars reticulata, or both (Betz et al., 2009). Additional studies also should determine whether the ability of adenosine A2A antagonists to enhance sensitivity to DBS is also present in human patients. If such a synergistic effect is found, it will have critical implications for patients, prolonging the battery life of the pulse generator, and significantly widening the therapeutic window of STN DBS.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Experiments
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

The authors wish to thank D. Satzer, M. McPherson, C. Rhodes, N. Hussain, and M. Huber for their technical assistance. This work was supported by grants from the University of Connecticut Health Center and the University of Connecticut Research Foundation. John Salamone received consultancy and speaker fees from Hoffman LaRoche. The other authors declare no competing financial interests.

Abbreviations
DA

dopamine

DBS

deep brain stimulation

PD

Parkinson's disease

STN

subthalamic nucleus

TJM

tremulous jaw movement

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Experiments
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
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