Dopamine agonists suppress cholinomimetic-induced tremulous jaw movements in an animal model of Parkinsonism: tremorolytic effects of pergolide, ropinirole and CY 208–243

Behavioural Brain Research 156 (2005) 173–179

Research report

Dopamine agonists suppress cholinomimetic-induced tremulous jaw movements in an animal model of Parkinsonism: tremorolytic effects of pergolide, ropinirole and CY 208–243 John D. Salamone∗ , Brian B. Carlson1 , Clifford Rios2 , Elizabeth Lentini, Merce Correa3 , Ania Wisniecki, Adrienne Betz Department of Psychology, University of Connecticut, Storrs, CT 06269-1020, USA Received 21 November 2003; received in revised form 15 May 2004; accepted 17 May 2004 Available online 4 July 2004

Abstract Considerable evidence indicates that cholinomimetic-induced tremulous jaw movements in rats share many characteristics with human Parkinsonian tremor, and several antiparkinsonian drugs suppress cholinomimetic-induced tremulous jaw movements. The present study investigated three different types of dopamine agonists, which have known antiparkinsonian characteristics, for their ability to suppress the tremulous jaw movements induced by tacrine (5.0 mg/kg). The non-selective dopamine agonist pergolide, a widely used antiparkinsonian drug, was highly potent at suppressing tacrine-induced jaw movements (e.g. 0.125–1.0 mg/kg). The selective D2 agonist ropinirole, which also is used clinically as an antiparkinsonian drug, suppressed jaw movements in the dose range of 2.5–20.0 mg/kg. The D1 agonist CY 208–243, which has been reported to suppress tremor, also reduced jaw movement activity (4.0 mg/kg). Across several studies, the rank order of potency for suppressing cholinomimetic-induced jaw movements in rats is related to the potency for producing antiparkinsonian effects in humans. Together with previous studies, the present results suggest that cholinomimetic-induced jaw movements in rats can be used to characterize dopaminergic antiparkinsonian agents and to investigate the basal ganglia circuits involved in the generation of tremulous movements. © 2004 Elsevier B.V. All rights reserved. Keywords: Tremor; Parkinsonism; Extrapyramidal; Motor; Basal ganglia

1. Introduction Parkinsonism is a family of movement disorders, with symptoms that include rigidity, bradykinesia, akinesia, and tremor. Idiopathic Parkinson’s disease results from the degeneration of nigrostriatal dopamine (DA) neurons [6,45]. In addition, Parkinsonian symptoms can be produced or exacerbated by various drugs, including DA antagonists ∗

Corresponding author. Tel.: +1 860 486 4302; fax: +1 860 486 2760. E-mail address: [email protected] (J.D. Salamone). 1 Present address: Department of Neurology, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA. 2 Present address: School of Medicine, University of Connecticut Health Center, Farmington Avenue, Farmington, CT 06030, USA. 3 Present address: Area de Psicobiologia, Universitat Jaume I, 12071 Castello, Spain. 0166-4328/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2004.05.019

[45] and cholinomimetics [2,24,54]. Idiopathic and druginduced Parkinsonism typically is treated by drugs that stimulate DA tone or block muscarinic acetylcholine (ACh) receptors [2,49,53,62]. Current models of basal ganglia function suggest that Parkinsonian symptoms are produced by a cascade of neurochemical and physiological events involving several transmitters in various parts of basal ganglia circuitry [22,28,32,52,78]. Considerable research in this area has focused upon the pharmacological and neurochemical interactions between ACh and DA [2,21,62,65]. Although resting tremor is one of the cardinal symptoms of Parkinsonism, much of the clinical pharmacology research in this area has focused upon akinesia, or general indices of Parkinsonism, and relatively few clinical pharmacology studies have specifically emphasized tremor [66]. As noted in several recent articles [6,23,76,77] there still is considerable

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uncertainty about the central mechanisms through which Parkinsonian tremor is generated. For these reasons, it is important to focus additional research on the pharmacology and neurochemistry of tremor, and studies employing animal models are an important part of this research [76]. In general, there have been few reports of Parkinsonian tremor in rodents [15,76]. Nevertheless, one of the rodent behavioral procedures that has emerged within the last few years as a potential model of Parkinsonian resting tremor is drug-induced tremulous jaw movements [58,65]. Tremulous jaw movements are defined as rapid and repetitive vertical deflections of the lower jaw that are not directed at any particular stimulus [65]. These movements can be induced by a number of conditions that parallel the neurochemistry of the pathology of Parkinsonism, including DA depletions in the ventrolateral neostriatum [27,35], acute or sub-chronic injections of DA antagonists [68,69], and reserpine [4,61,69]. Tremulous jaw movements also are induced by muscarinic agonists such as arecoline and pilocarpine [5,59,60,63,64,70] and anticholinesterases such as physostigmine or tacrine [9,14,19,20,37,46]. Considerable evidence indicates that tremulous jaw movements observed in rats could be related to Parkinsonian tremor [65]. Analysis of electromyographic data and slow-motion videotapes has demonstrated that the 3–7 Hz frequency of the jaw movements induced by reserpine, DA depletions, pilocarpine and tacrine resembles the frequency of resting tremor in Parkinsonism [18,27,46,61,65]. Tremulous jaw movements can be reduced by antiparkinsonian drugs with various pharmacological profiles, including apomorphine, L-DOPA, bromocriptine, amantadine, benztropine [19], and diphenhydramine [13]. In addition, the atypical antipsychotic drug clozapine, which is known to be antitremorogenic in Parkinsonian patients, has been shown to suppress tacrine-induced jaw movements in rats [16,72,73]. In view of the general importance of DA agonists for the treatment of Parkinsonism, and the recent development of additional DA agonists with varied pharmacological characteristics [11,44,55,66], the present study was undertaken to investigate the effects of three DA agonists with various receptor binding profiles and pharmacological characteristics for their effects on tremulous jaw movements in rats. In the present work, the anticholinesterase tacrine was used to generate tremulous jaw movements. Several clinical reports indicate that cholinomimetics can induce or exacerbate Parkinsonian symptoms [3,7,12,24,33,36,38,50,67], and tacrine (Cognex) is an anticholinesterase that has been shown to induce Parkinsonian symptoms, including tremor, in humans [54]. Moreover, tacrine-induced jaw movements in rats have been used in previous research to assess the effects of various drugs with antiparkinsonian characteristics [19]. In previous research, the antiparkinsonian DA agonists apomorphine and bromocriptine have been investigated for their ability to suppress cholinomimetic-induced tremulous jaw movements [19]. Apomorphine is non-selective for distinct DA receptor families, while bromocriptine has modest

D2 family selectivity. The three DA agonists assessed in the present study were pergolide, ropinirole, and CY 208–243. Pergolide is an ergot derivative that is not highly selective for different DA receptor subfamilies [42]. Pergolide has been used widely as an antiparkinsonian agent for many years in research and clinical practice [41], and this drug was reported to be effective at suppressing Parkinsonian tremor in humans [51,75]. Ropinirole is a non-ergoline DA agonist that is highly selective for the D2 family of DA receptors [25,57,74]. Ropinirole was introduced clinically within the last few years, and several studies have demonstrated that this drug has antiparkinsonian effects in humans [11,40,56]. Moreover, a recent study indicates that ropinirole can suppress resting tremor in patients with Parkinson’s disease [66]. CY 208–243 is a DA agonist with partial selectivity for D1 receptors, which has been shown to be effective in improving motor function in MPTP-treated primates, either alone or in combination with other antiparkinsonian agents [8,30,31]. Although CY 208–243 has been observed to produce only a mild antiparkinsonian effect in humans, tremor was reported to be the symptom that most reliably responded to this drug [26]. Because pergolide, ropinirole and CY 208–243 have been reported to suppress Parkinsonian tremor in humans, it was hypothesized that all three drugs would reduce tacrineinduced tremulous jaw movements in rats. In addition, based upon data from human patients and MPTP primates, it was hypothesized that pergolide would be much more potent than CY 208–243 and ropinirole. 2. Materials and methods 2.1. Animals Male Harlan–Sprague–Dawley rats (Harlan Sprague Dawley, Indianapolis, IN, USA; total n = 25) with no prior drug experience were used in these experiments. Animals weighed between 270 and 340 g at the beginning of the experiment, and had ad libitum access to water and lab chow during the course of the experiment. Animals were group housed in a colony maintained at approximately 23 ◦ C with a 12-h light/dark cycle with lights on at 07:00 h. The Institutional Animal Care and Use Committee approved the animal research protocols used, and all procedures were in agreement with the Guide for the Care and Use of Animals. 2.2. Drugs Tacrine and pergolide were obtained from Sigma Chemical Co., St. Louis, MO. Ropinirole (Requip) was generously donated by SmithKline Beecham, and CY 208–243 was obtained from Research Biochemicals International, Natick, MA. All drugs were dissolved in 0.9% saline, which was used as the control. The drug doses used were selected based upon extensive pilot work, and by an examination of the literature [1,57]. 2.3. Observation of tremulous jaw movements Observations of tremulous jaw movements were made in a clear Plexiglas chamber (27 cm × 17.5 cm × 17 cm) with a wire mesh

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2.4. Experiment 1: effect of pergolide on tremulous jaw movement activity A group of rats (n = 7) was used to assess the effect of pergolide treatment on tacrine-induced tremulous jaw movements. Animals were tested once per week for five weeks. On test days animals were injected with one of the following treatments: 1.0 ml/kg vehicle, or 0.125, 0.25, 0.5 or 1.0 mg/kg pergolide IP. After injection, animals were returned to their home cage for 30 min. After the 30-min period, all animals received an injection of 5.0 mg/kg tacrine IP to induce tremulous jaw movements, and were immediately placed in the test chamber to habituate for 10 min before the 5 min testing period began. Each animal received all doses in a randomly varied order, with one injection per week over the 5-week period. 2.5. Experiment 2: effect of ropinirole on tremulous jaw movement activity A second group of rats (n = 8) was used to assess the effect of ropinirole treatment on tacrine-induced tremulous jaw movements. Animals were tested once per week for five weeks. On test days animals were injected with one of the following treatments: 1.0 ml/kg vehicle, or 2.5, 5.0, 10.0 or 20.0 mg/kg ropinirole IP. After injection, animals were returned to their home cage for 30 min. After the 30min period, all animals received an injection of 5.0 mg/kg tacrine IP to induce tremulous jaw movements, and were immediately placed in the test chamber to habituate for 10 min before the 5 min testing period began. Each animal received all doses in a randomly varied order, with one injection per week over the 5-week period. 2.6. Experiment 3: effect of CY 208–243 on tremulous jaw movement activity An additional group of rats (n = 10) was used to assess the effect of CY 208–243 treatment on tacrine-induced tremulous jaw movements. Animals were tested once per week for 5 weeks. On test days animals were injected with one of the following treatments: 1.0 ml/kg vehicle, or 0.5, 1.0, 2.0, 4.0 mg/kg CY 208–243 IP. After injection, animals were returned to their home cage for 30 min. After the 30-min period, all animals received an injection of 5.0 mg/kg tacrine IP to induce tremulous jaw movements, and were immediately placed in the test chamber to habituate for 10 min before the 5 min testing period began. Each animal received all doses in a ran-

domly varied order, with one injection per week over the 5-week period. 2.7. Data analysis For all experiments, tremulous jaw movement data were analyzed using a repeated-measures analysis of variance (ANOVA), with dose as the repeated measure. Planned comparisons using the overall error term were used to assess the differences between each drug condition and the vehicle control condition, keeping the total number of comparisons to the number of conditions minus one [39].

3. Results In Experiment 1, pergolide produced a significant reduction of tacrine-induced tremulous jaw movements [F(4,24) = 6.07, P < 0.002; see Fig. 1]. Planned comparisons revealed that pergoline plus tacrine differed from tacrine alone at all doses (0.125 mg/kg, F(1,24) = 11.7, P < 0.01; 0.25 mg/kg, F(1,24) = 6.8, P < 0.01; 0.5 mg/kg, F(1,24) = 15.6, P < 0.01; and 1.0 mg/kg, F(1,24) = 19.4, P < 0.001). Experiment 2 demonstrated that ropinirole produced a significant reduction of tacrine-induced tremulous jaw movements [F(4,28) = 8.745, P < 0.001; see Fig. 2]. Planned comparisons revealed that all doses of ropinirole plus 5.0 mg/kg tacrine had significantly lower mean tremulous jaw movements compared to the effect of tacrine alone (2.5 mg/kg, F(1,28) = 5.1, P < 0.05; 5.0 mg/kg, F(1,28) = 13.4, P < 0.01; 10.0 mg/kg, F(1,28) = 16.7, P < 0.001; 20.0 mg/kg, F(1,28) = 30.42, P < 0.01). In Experiment 3, it also was shown that CY 208–243 significantly reduced tacrine-induced tremulous jaw movements [F(4,36) = 4.9, P < 0.01; see Fig. 3]. Planned comparisons revealed that only the 4.0 mg/kg dose of CY 208–243 plus 5.0 mg/kg tacrine had significantly lower mean tremulous jaw Tremulous Jaw Movements

floor. The chamber was elevated 42 cm above the tabletop to allow viewing of the animal from several angles. Tremulous jaw movements were defined as rapid vertical deflections of the lower jaw that resembled chewing but were not directed at any particular stimulus. Each individual deflection of the jaw was recorded using a mechanical hand counter. All observations were made by an observer who was blind to the experimental condition. Separate studies parallel to the present work, which used these methods with two independent observers, demonstrated an interrater reliability of r = 0.92 (P < 0.05). To induce tremulous jaw movements each animal received an intraperitoneal (IP) injection of 5.0 mg/kg of tacrine 10 min before testing. Rats were placed in the observation chamber immediately after tacrine injection to allow for habituation to the observation chamber. Animals were observed for tremulous jaw movements for a 5-min period after the 10-min habituation (i.e., the period of time 10–15 min after tacrine injections).

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Dose Pergolide (mg/kg) Fig. 1. Mean (±S.E.M.) number of individual jaw movements (per 5 min observation period) after injection of 5.0 mg/kg tacrine, or tacrine plus various doses of pergolide. ∗ P < 0.05, significantly different from tacrine alone, planned comparison.

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Dose Ropinirole (mg/kg) Fig. 2. Mean (±S.E.M.) number of individual jaw movements (per 5 min observation period) after injection of 5.0 mg/kg tacrine, or tacrine plus various doses of ropinirole. ∗ P < 0.05, significantly different from tacrine alone, planned comparison.

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Dose CY 208-243 (mg/kg) Fig. 3. Mean (±S.E.M.) number of individual jaw movements (per 5 min observation period) after injection of 5.0 mg/kg tacrine, or tacrine plus various doses of CY 208–243. ∗ P < 0.05, significantly different from tacrine alone, planned comparison.

movements compared to the effect of tacrine alone (F(1,36) = 12.8, P < 0.01). Although locomotion was not specifically measured in the present experiments, the observers noted that animals treated with tacrine alone showed extremely low levels of motor activity, and that co-administration of DA agonists tended to restore locomotion in tacrine-treated animals.

4. Discussion The present experiments demonstrated that the three DA agonists, pergolide, ropinirole, and CY 208–243, all significantly suppressed tacrine-induced tremulous jaw

movements. Pergolide was the most potent drug, with significant effects even at the lowest dose tested (i.e., as low as 0.125 mg/kg). Pergolide was studied in the present experiment to provide additional validation of the jaw movement model by investigating the effects of a welldocumented antiparkinsonian agent. Thus, the present data showing suppressive effects of pergolide in the jaw movement model are consistent with the extensive clinical data showing antiparkinsonian effects of pergolide on various symptoms, including tremor [41,75]. Previous research has demonstrated that apomorphine suppresses the tremulous jaw movements induced by the anticholinesterase tacrine [19], as well as the muscarinic agonist pilocarpine [70]. Thus, these previous studies, together with the present data, demonstrate that non-selective DA agonists such as pergolide and apomorphine, which are useful as antiparkinsonian drugs, can suppress tremulous jaw movement activity in rats. The non-ergoline DA D2-family agonist, ropinirole, suppressed tremulous jaw movement activity in rats in a dose range of 2.5–10.0 mg/kg. The present results are the first report of antitremorogenic activity of ropinirole in rodents, and these data are consistent with reports of tremorolytic activity of this drug in human patients with Parkinson’s disease [66]. Ropinirole has a higher degree of D2-family selectivity relative to bromocriptine, yet both drugs have been shown to suppress cholinomimetic-induced tremulous jaw movements in rats (Experiment 2; see also [19]). These data suggest that selective stimulation of D2-family receptors is sufficient to suppress cholinomimetic-induced tremulous jaw movements, although it is possible that stimulation of D1-family receptors also contributes to the suppressive effects of bromocriptine. In a previous study, it was reported that ropinirole and bromocriptine failed to suppress oxotremorineinduced body tremor in mice [29]. However, it has been noted that oxotremorine-induced body tremor in mice does not appear to be a valid model of Parkinsonian resting tremor [6,65,76]. In general, oxotremorine-induced body tremor in mice is not a focal tremor generated at rest, and the tremor frequency generated by oxotremorine in mice is typically greater than 8 Hz, which is higher than the 3–7 Hz frequency that is characteristic of Parkinsonian tremor [6,65,76]. In contrast, tremulous jaw movements in rats are typically generated at rest, with a peak frequency in the 3–7 Hz range [65]. It has been suggested that oxotremorine-induced body tremor in rodents could be more related to Parkinsonian postural tremor or action tremor [6,65,76]. In this regard, it is interesting to note that both ropinirole and bromocriptine suppress tremulous jaw movements in rats, because both of these drugs suppress resting Parkinsonian tremor in humans [66], yet neither drug was reported to suppress postural or action tremor in Parkinson’s disease patients [66]. Thus, studies of tremulous jaw movements in rats have generated a pattern of results with D2-family agonists that is similar to the pattern of data generated in studies of resting tremor in humans. CY 208–243 suppressed tacrine-induced tremulous jaw movements in rats when administered at a dose of 4.0 mg/kg.

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Relation Between Rat Data and Human Clinical Data Human Clinical Potency (mg)

These data are consistent with previous reports of potential antiparkinsonian activity of this drug in rodents [1] and in MPTP-treated primates [8,30,31]. In addition, the present data are consistent with the clinical report of Emre et al. [26], who reported that CY 208–243 could suppress resting tremor in human Parkinsonian patients. Data from several studies has suggested that the ability of D1 agonists to suppress cholinomimetic-induced tremulous jaw movements could be related to the degree of intrinsic activity for stimulating cyclic-AMP production. The high efficacy D1 agonist, SKF 82958, was shown to suppress tremulous jaw movements induced by tacrine [19] and the muscarinic agonist pilocarpine [48]. In the present study, CY 208–243 also suppressed tacrine-induced tremulous jaw movements. In terms of D1 receptor mediated stimulation of cyclic-AMP production in rat tissue, SKF 82958 has very high intrinsic activity, while CY 208–243 has moderately high intrinsic activity [34]. In contrast, the weak partial agonist, SKF 38393, which is capable of only modest stimulation of cyclic-AMP production [34], failed to suppress tacrine-induced tremulous jaw movements in rats [19]. This observation is particularly interesting in view of reports indicating that SKF 38393 is not antiparkinsonian in either MPTP-treated primates [9,17] or in human patients [10]. Moreover, SKF 38393 induces jaw movements in rats when administered alone, and also increases tacrine-induced jaw movements [19]. Studies involving tremulous jaw movements in rats could be used in the future to assess novel D1 agonists for potential tremorolytic activity, and could be used to further explore the relation between the effects of D1 agonists on motor activity and signal transduction mechanisms such as cyclic-AMP production [47]. Together with other published data, the present results demonstrate that DA agonists with different pharmacological characteristics, including non-selective drugs such as apomorphine and pergolide, D1 selective drugs such as SKF 82958 and CY 208–203, and D2 selective compounds such as bromocriptine and ropinirole, all act to decrease cholinomimetic-induced jaw movements. Moreover, the DA precursor L-DOPA also was shown to decrease cholinomimetic-induced tremulous jaw movements [19]. Although these drug-induced decreases in tremulous movements can be accompanied by changes in other behaviors, such as locomotion, there is considerable evidence indicating that the production of tremulous jaw movements is not simply an artifact of changes in gross locomotion or rearing [35,68]. In general, the relative potency of the suppressive effects of dopaminergic drugs on jaw movement activity is consistent with the relative potency of these drugs in MPTP-treated primates, and also is consistent with clincally effective doses used in Parkinsonian humans (see Fig. 4). Thus, studies with the jaw movement model have shown that pergolide is extremely potent, with effects in the range of 0.25 mg/kg, while l-DOPA requires much higher doses to suppress tremulous jaw movements (e.g., 50.0 mg/kg; [19]). These observations suggest that the cholinomimetic-induced tremulous jaw

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TJM Suppression Potency in the Rat (mg/kg) Fig. 4. Scatterplot showing the relation between estimated potency for suppression of tacrine-induced jaw movements (TJM; expressed as minimum significant dose) and estimated clinical dosage, for six dopaminergic drugs. Rat jaw movement data are from the present paper, or are minimum significant doses from Cousins et al. [19]. Human data were obtained from articles specifically showing effects on tremor. The 4.7 mg dose for apomorphine was the average dose listed in Levy et al. [43], and the 0.5 mg dose for pergolide was obtained from Navan et al. [51]. Both doses are within the range of effective doses listed in Oertel and Doedel [53]. The 40 mg dose in humans was estimated for CY 208–243 based upon Temlett et al. [71], and this dose is within the range studied in Emre et al. [26]. The antitremorogenic doses for ropinirole, bromocriptine and L-DOPA were mean total daily doses from Schrag et al. [66], studies 2 and 3. The regression line was statistically significant (P < 0.05; r2 = 0.88).

movement model in rats could be useful for assessing the potential antitremorogenic effects of dopaminergic agents with various pharmacological profiles. In addition, this model could be used as a tool for understanding the brain mechanisms that underlie tremorogenesis.

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