SKF38393

Effects of intrastriatal injection of the dopamine receptor agonist SKF38393 and quinpirole on locomotor behavior in hemiparkinsonism rats

Mengnan Guo a, 1, Tianyu Xiang a, 1, Min Li a, Yue Sun a, Shuang Sun a, Dadian Chen a, Qingmei Jia a, Yuchuan Li a, Xiaomeng Yao b, Xiaojun Wang c, Xiao Zhang d, Feng He a,*, Min Wang a,*
a Key Laboratory of Animal Resistance Biology of Shandong Province, College of Life Science, Shandong Normal University, Jinan, People’s Republic of China
b School of Nursing Qilu Institute of Technology, Jinan, 250200, People’s Republic of China
c The First Hospital Affiliated With Shandong First Medicine University, Jinan, People’s Republic of China
d School of Computer Science and Technology, Shandong Jianzhu University, Jinan, 250200, People’s Republic of China

A B S T R A C T

Dopamine (DA) in the striatum is essential to influence motor behavior and may lead to movement impairment in Parkinson’s disease (PD). The present study examined the different functions of the DA D1 receptor (D1R) and DA D2 receptor (D2R) by intrastriatal injection of the D1R agonist SKF38393 and the D2R agonist quinpirole in 6-hydroXydopamine (6-OHDA)-lesioned and control rats. All rats separately underwent dose-response behavior testing for SKF38393 (0, 0.5, 1.0, and 1.5 μg/site) or quinpirole (0, 1.0, 2.0, and 3.0 μg/site) to determine the effects of the optimal modulating threshold dose. Two behavior assessment indices, the time of latency to fall and the number of steps on a rotating treadmill, were used as reliable readouts of motor stimulation variables for quantifying the motor effects of the drugs. The findings indicate that at threshold doses, SKF38393 (1.0 μg/site) and quinpirole (1.0 μg/site) produce a dose-dependent increase in locomotor activity compared to vehicle injection. The ameliorated behavioral responses to either SKF38393 or quinpirole in lesioned rats were greater than those in unlesioned control rats. Moreover, the dose-dependent increase in locomotor capacity for quin- pirole was greater than that for SKF38393 in lesioned rats. These results can clarify several key issues related to DA receptors directly and may provide a basis for exploring the potential of future selective dopamine therapies for PD in humans.

Keywords: Parkinson’s disease Dopamine receptor SKF38393, Quinpirole Intracerebral injection

1. Introduction

Parkinson’s disease (PD) is a neurodegenerative disease commonly seen in middle-aged and elderly people, and the characteristic symptoms include bradykinesia, tremor, shaking, postural instability and autonomic abnormalities [1]. The mechanism of neuropathology is the loss of dopaminergic neurons in the substantia nigra. The main treatment of PD relies on dopamine (DA) replacement with the DA precursor L-3, 4-dihydroXyphenylalanine (L-Dopa). Chronic replacement therapy with L-Dopa can relieve symptoms, and it remains the mainstay of treatment for PD [2]. Long-term therapy with L-Dopa, however, is associated with a loss of drug efficacy and eventually may lead to involuntary abnormal movement called L-Dopa-induced dyskinesia (LID), which becomes a therapeutic limitation [3]. In DA replacement therapy for PD, DA receptor agonists that activate DA receptors in the striatum are also commonly administered. DA receptor agonists have shown equal evi- dence of being clinically useful both as monotherapy and as adjuncts to L-Dopa in PD patients [4,5]. Unfortunately, chronic DA receptor treat- ment also leads to DA receptor sensitization and the development of a spectrum of side effects, including motor fluctuations and abnormal involuntary movements, such as L-DOPA-induced dyskinesia [6,7]. To date, functional studies are still conflicting regarding the involvement of DA receptors in the treatment to enhance the motor activity of PD [8]. Therefore, the important issue concerns the nature of the dopamine receptor involved in either the reversal of the motor symptoms of PD or in the production of dyskinesias [9–11].
As the main input nucleus of the basal ganglia, the striatum plays an important role in motor control and motor learning [12,13]. Striatum neurons receive the densest dopamine innervation from the substantia nigra. However, the substantia nigra also sends dopamine projections to other brain regions, leading to widespread network adaptations with their loss in PD [14,15]. Dopamine acts in the striatum via two main classes of receptors that are based on intrinsic structural, pharmaco- logical, and signaling properties: D1-like receptors (D1R and D5R) and D2-like receptors (D2R, D3R and D4R) [4,8]. The loss of DA is associated with abnormal neuronal activity in the basal ganglia-thalamocortical circuits [12,14]. In the basal ganglia, dopamine activates direct pathway neurons of the striatum though D1Rs, whereas D2Rs inhibit indirect pathway neurons of the striatum [16]. The loss of dopaminergic neurons in the substantia nigra pars compacta leads to a dopaminergic imbalance between the two output pathways [17].
PD is proposed to increase the efficacy of the indirect pathway basal ganglia circuit and decrease the efficacy of the direct pathway circuit originating in the striatum [18]. Therefore, it is important to control the output mechanism of the basal ganglia for the development of a new treatment for PD [19]. Dopamine receptor agonists mimic the action of dopamine to stimulate DA receptors and to reduce the abnormal excit- ability of the internal pallidum in the dopaminergic basal ganglia loop. Unfortunately, the treatment of dopamine receptor agonists does not halt or cease PD pathogenesis but only provides symptomatic relief for a short period of time.
Despite compelling research support on dopamine receptor agonists through systemic administration in therapy, intrastriatal microinjection has been limited in in vivo work. More importantly, recent anatomical and behavioral data argue against the simplistic framework of the two pathway theory, and pharmacological interrogation of the two pathway roles has been challenging and inconsistent [12,20]. Therefore, under- standing the mechanisms of dopamine receptor agonists is crucial in the remained stable during the experiment. Every effort was made to minimize the number of animals used and to reduce the harm to the animals caused by the experimental setting.

2. Materials and methods

2.1. Ethical approval

All studies were carried out in accordance with the Institutional Animal Care and Use Committee of National Institutes of Natural Sci- ences. The principles for the care and use of laboratory animals were strictly followed. All agreements were reviewed and approved by the Ethics Review Committee of Shandong Normal University. We made all efforts to minimize the pain or its incidence when we use experimental animals.

2.2. Animals

Male Wistar rats (animal center of Shandong University, China) weighing 280 g–320 g were used for the experiment. Food and water were available ad libitum during the experiment. Feeding occurred in the rat cage, and body weights were monitored daily to ensure that they evidence to support the success of parkinsonian rats. The detailed pro- cess and representative images are described in our previous article [24, 25].

2.3. 6-Hydroxydopamine lesions of dopamine neurons

Rats that received vehicle or unilateral 6-hydroXydopamine (6- OHDA) lesions were treated as described previously [21,22]. Briefly, each rat was anesthetized with urethane (1.0–1.2 g/kg, Sigma. IP) and placed in a stereotaxic apparatus (RWD 68001, Shenzhen, China) sup- plemented with an additional dose (0.2 g/kg), as required. Body temperature was maintained at 37 ± 0.5 ◦C by a homoeothermic heating device. Ophthalmic lubricant was placed over the rats’ eyes to maintain moisture during anesthesia. The neurotoXin 6-OHDA (hydrochloride salt; Sigma) was dissolved immediately before use in ice-cold 0.9 % w/v NaCl solution containing 0.02 % w/v ascorbate to a final concentration of 4 mg/mL, and 3 μl was injected into sites on the right medial forebrain bundle (anterior: +2.2 mm from the bregma; lateral: +2.1 mm; ventral: 8.40 mm and 8.65 mm, from the skull surface) at a rate of 1 μl/min and completed within 3 min. The control rats only received the same volume of vehicle (0.02 % ascorbic acid in physiological saline) at the same coordinates. Ultimately, the long-acting analgesic carprofen (5 mg/kg, Sigma) was injected subcutaneously. Animals received post- operative care and were checked every day for 1 week after the surgery. The extent of dopamine-lesioned neurons was assessed two weeks after 6-OHDA injection by challenge with apomorphine (0.05 mg/kg, s. c.; Sigma). The lesion is considered successful in those animals that make over 70 net contralateral rotations in rats with unilateral lesions of the nigrostriatal pathway within 10 min [23]. To identify 6-OHDA le- sions on dopaminergic neurons in the substania nigra, immunohisto- pursuit of better pharmacotherapy with fewer aversive site effects. What chemical staining with tyrosine hydroXylase was used to provide the roles of DA receptor agonists are in PD pathogenesis and how they are associated with pharmacologic profiles in dopamine receptor neu- rogenesis are still unknown.
In this investigation, we mainly addressed the role of either the D1R agonist SKF38393 or the D2R agonist quinpirole in the expression of parkinsonian-like motor deficits in a unilateral 6-OHDA-lesion model using behavioral approaches. To examine the specific role of D1R and D2R agonists in reversal movement performance directly, either the D1R agonist SKF38393 or the D2R agonist quinpirole was microinjected via chronic indwelling cannulae into the DLS of rats performing on a rotating treadmill. The results revealed an appropriate dose–response relationship for either PD or control rats to facilitate behavioral mea- sures, including a ceiling effect of the higher concentrations used in this study, and provided insight into which particular aspects of dopamine receptor agonists are critical points in Parkinsonian pharmacotherapy to treat PD.

2.4. Chemicals and doses

Three different drug solutions were prepared in this experiment. The D1R agonist, SKF38393 (SKF38393 hydrochloride, ( )1-phenyl-2,3,4,5- tetrahydro-1H-benzazepine-7,8-diol hydrochloride) and the D2R agonist, quinpirole (quinpirole monohydrochloride, trans-(-)-4aR- 4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline monohydrochloride) (Sigma-Aldrich, USA) were dissolved in double distilled water. For intrastriatal infusions, rats underwent dose-response behavior testing for the D1R agonist SKF38393 (at doses of 0.5, 1.0, and 1.5 μg/site) and the D1R agonist quinpirole (at doses of 1.0, 2.0, and 3.0 μg/site). The control group (0 doses) was treated with the corresponding vehicle. All solutions were prepared prior to testing and were administered at a volume of 0.5 μl per site. Apomorphine (apomorphine hydrochloride, (6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g] quinoline-10,11-diol hydrochloride) (Sigma-Aldrich, USA) was intra- muscularly injected (0.05 mg/kg).

2.5. Apparatus

A circular rotating treadmill was used to perform the behavioral testing. The experimental apparatus consisted of a cylinder and two site walls, which were modified according to previous studies [26–28]. The cylinder is covered by wood material 15 cm in diameter and 20 cm in length, with surface covers sticking coarser and heavier cloth to facili- tate gripping, which is positioned 25 cm from the ground by a wooden shelf and moves around its longitudinal axis. Before the surgical procedures, rats were trained to walk unidirectionally on the surface of a rotating treadmill to examine their ability to navigate ambulatory walking tasks at different rounds per min (RPM). After repeated training, rats remained stable with whiskers moving naturally and had no incontinence on the treadmill. Fig. 1A.

2.6. Implantation of the intrastriatal cannula and microinjection

Surgical implantation of intrastriatal cannula was performed in Parkinsonian and control rats (the sham-operated and dopamine-intact groups). During implantation, the rat was anesthetized with urethane (1.0–1.2 g/kg IP) supplemented with an additional dose (0.2 g/kg) as required. According to the rat brain atlas, a hole was drilled in the head over the injection site, and 22 gauge stainless steel guide cannulae were implanted 1 mm above the corresponding infusion site to minimize tissue damage in the target. The measured coordinates were used to calculate the anterior/posterior (AP) and medial/lateral (ML) skull sites relative to the bregma for the unilateral dorsolateral striatum (AP 1.44 mm; ML －3.0 mm; V 4 mm), which is the ipsilateral hemi-parkinsonism rat. To stabilize the guide cannulae further, 3 stainless steel screws were planted on the surface of the skull and fiXed with dental cement. A stainless steel obturator was installed, protruding 1.5 mm out of the guide casing tip. After the surgical procedure, rats were given carprofen (5 mg/kg) to prevent infection and pain treatment. Rats were given at least 7 days to recover from surgery before testing. Body weights were continuously monitored on a daily basis to ensure a steady weight during this recovery period.
Drug microinjection and behavioral tests were performed at least one week after the implantation of the guide cannula surgery. Intrastriatal drug microinjection was performed using a 5 μL Hamilton microsyringe driven by a Stoelting apparatus pump (789311S, U.S.A.) The micro- syringe needle was connected to 80 cm polyethylene-20 tubing that was in turn connected to a 26 gauge internal cannula. The microinjection equipment was first verified for leaks by filling the microsyringe and tubing with 0.9 % saline solution to ensure that there was no leak in the system. Then, the drug solution was drawn into the internal cannula after a small pocket of air was pulled into the tubing to facilitate the visual monitoring of the movement of the small volume, colorless drug solution in the tubing. Furthermore, after the rat was restrained by the experimenter, the steel obturator was removed, and an internal injection cannula that was 1 mm longer than the guide cannulas was inserted into the guide cannulas in the dorsolateral striatum. Finally, the syringe pump was initiated, the dopamine receptor agonist and the same volume of vehicle were injected at a flow rate of 100 nL/min, and the injection of 0.5 μL drug solution lasted 5 min. The internal cannula was kept in the brain for an additional 5 min to allow the drug to diffuse into the surrounding tissue. The internal cannula was removed carefully, the obturator cannula was replaced, and the rats were subjected to the follow-up experiment.
Rats were sacrificed with an overdose of sodium urethane (1.0–1.2 g/kg, i.p.) after completing all experiments. Then, a histologi- cal method of making an electrolytic lesion via the implanted intrastriatal cannula and then with cresyl violet stained coronal sections of rat brain was carried out to identify the cannula tip placement, as described in our previous articles [25,29]. Only the guiding cannula tips with correct sites in the dorsolateral striatum were used in further analysis. An example is illustrated in Fig. 1B, and individual cannula locations within the dorsolateral striatum are shown in Fig. 1C.

2.7. Behavior and assessment

Animal behavior evaluation consisted of two periods, i.e., adaptation period and test period. Before the surgical procedures, rats were trained to walk unidirectionally on the surface of a circular rotating treadmill as previously explained. The rat was placed on the surface of the running treadmill. To maintain this position, the rat had to walk forward on the opposite direction of the revolving treadmill, where rats were chal- lenged to navigate ambulatory walking at different rotational speeds for one week. After surgery for unilateral dopamine cell lesions and im- plantation of an intrastriatal cannula, rats were re-exposed to the treadmill and examined for their ability to walk again. Ultimately, the speed of the testing rotation was adjusted at 12 r/min, and both control and lesion Parkinsonian rats could increase their speed compatible with steady steps that gently encouraged forward walking on the treadmill.
During the test period, animal behavior evaluation was quantified by the latency to fall and step testing. The protocol used to test each animal was as follows: to habituate to the apparatus, prior to the tests, each rat was left for 2 min on the running treadmill surface of the stationary rotating treadmill at 12 r/min. Then, each animal was tested to walk forward to avoid falling off the treadmill for 10 min with a 5 20 minute rest period. Each animal was given five independent trials. During each test trial, the time spent an animal walking on the rotating treadmill was measured and expressed as the latency to fall. The latency to fall means the rat total time spent on the treadmill in each 10-minute test trial, excluding the time fall off from the treadmill. The total amount of time any given rat fell off the rotating treadmill was summed up by a stop- watch, i.e., each time a mouse fell off the treadmill, the stopwatch that was used to time the test was halted, the rat was immediately placed back onto the rotating treadmill, and the stopwatch was restarted [26]. In addition, during each 10-minute test trial, the total number of steps taken while walking on the treadmill was counted, expressed as step testing. The number of steps in each rat was counted, with only sequential consecutive steps of each limb (left and right forelimb and hindlimb cycle) analyzed in which the frequency of lifting a hind limb in a control rat or the contralateral-to-lesion hind limb of a 6-OHDA rat was quantitatively evaluated.
To examine the effects of different doses of the D1R or D2R agonist, fifty-two rats were allocated into four groups. Because of cannula loss or injections outside the target areas in some rats, each group ended up with a different number of animals. Only data from rats with correctly placed cannulae were analyzed. The first group (control vehicle, n 13) received the vehicle solution for unlesioned control rats, and the second group (PD vehicle, n 11) received the vehicle solution for 6- OHDA-lesioned rats. The third group (PD SKF38393, n 7) received the D1R agonist SKF38393 for 6-OHDA-lesioned rats, and the fourth group (PD quinpirole; n 9) received the D2R agonist quinpirole for 6-OHDA-lesioned rats. To avoid potential dopaminergic sensitization effects, each of these drugs was injected into a fresh and separate group of animals.

2.8. Statistical analysis

All values are expressed as the mean standard error of the mean (SEM). In the behavioral experiment of drug screening, the difference of the time of latency to fall, the number of steps and other data were calculated by the two-way repeated ANOVA (drug doses time intervals) with repeated measures on the time factor and on the dose factor, followed by post hoc Dunnett’s tests comparisons to vehicle controls at each dose and time point. Comparisons of treatment with different dopamine receptor agonists in each group were made by using one-way ANOVA (treatment as a between factor), followed by post hoc Tukey’s test for comparisons between two groups with different treat- ments. A level of p < 0.05 was considered significant, and p < 0.01 was considered highly significant. 3. Results 3.1. The effects of D1R agonist SKF38393 administration on locomotor activity Animals were microinjected with SKF38393 at four different doses (0, 0.5, 1.0, and 1.5 μg/site) within subjects. A dose-response curve was generated for the D1 receptor-mediated movement response after administration of SKF38393 into the dorsolateral striatum for 6-OHDA- treated and control rats. The treatment effect on the latency to fall and step counts were analyzed among different groups after intrastriatal microinjection of SKF38393. Dose and time course analyses revealed latency to fall and step counts in Figs. 2 and 3, respectively. For control rats, the latency to fall data demonstrate that SKF38393 induces a significant influence on the main effects of the treated dose (F (3, 10) = 4.61, p = 0.028) and on the main effect of time (F (4, 40) = 5.57, p = 0.012) compared with the vehicle infusion and with no dose £ time interaction (F (12, 40) =0.88, p = 0.579). Post hoc Dun- nett’s tests analyses reveal (Fig. 2A) that when rats were treated with a dose of 1.0 μg/site, it induced an increased latency to fall, which was different from the vehicle treatment (p = 0.016), but no effect was observed at the dose of 0.5 μg/site (p = 0.178). However, upon micro- injection of a high dose of SKF38393 (1.5 μg/site), there was no significant difference from the vehicle infusion groups in the rotarod treadmill (p 0.056), which means that microinjection was ineffective in improving locomotor activity. Subtle slow movement is observed in some rats. On the other hand, over the course of time, at a dose of 1.0 μg/ site, the effects of SKF38393 were apparently different after 20 min (p 0.02) and lasted for up to 50 min (p 0.012) compared with the vehicle infusion. During the 20 50 min period, SKF38393 had an effect on the latency to fall (one-way repeated measures ANOVA, F (3, 13) = 5.92, p = 0.011). The post hoc Dunnett’s test revealed that there was a significant increase (598.9 ± 1.82 vs. 587.3 ± 0.77, p = 0.04) with respect to the vehicle infusion (Fig. 2A’). Therefore, the SKF38393 dose of 1.0 μg/site during the 20 50 min is selective as a threshold dose to evaluate for facilitating movement in control rats, given its induction of increased time of latency to fall on a rotating treadmill. For PD rats, administration of SKF38393 into the dorsolateral stria- tum exhibited a significant influence on the main effect of the dose (F (3, 13) = 7.61, p = 0.003) and on the main effect of time (F (4, 52) = 11.57, p = 000) compared with the vehicle infusion and with no dose × time interaction (F (12, 52) 1.81, p 0.071). Post hoc Dunnett’s test an- alyses revealed that (Fig. 2B) when rats were treated with a dose of 1.0 μg/site (p 0.000), the latency to fall increased significantly, which was different from the vehicle treatment, but there was no effect at a dose of 0.5 μg/site (p 0.202). However, the dose of SKF38393 (1.5 μgsite) was not significantly different from that of the vehicle infusion groups (p 0.924), which means that SKF38393 was ineffective in improving locomotor activity. Instead, an inhibitory component started to appear with movements becoming temporarily slow or body freezing, and then abnormal stereotypic movements were exhibited, including sniffing, rearing, grooming, and head nodding. Some rats triggered an asymmetric rotation, turning predominantly in the direction contralat- eral to the lesion. On the other hand, over the course of time, at a dose of 1.0 μg/site, the effects of SKF38393 were apparent after 20 min (p = 0.000) and lasted for up to 50 min (p = 0.000). During the 20—50 min time points, SKF38393 had a significant effect on the latency to fall (one-way repeated measures ANOVA, F (3, 13) = 10.10, p = 0.000). The post hoc Dunnett’s tests revealed that there was an increase in the latency to fall (593.5 ± 2.9 vs. 552.1 ± 6.3, p = 0.001) with respect to vehicle (Fig. 2B’). Therefore, the SKF38393 dose of 1.0 μg/site during the 20 50 min is selective as a threshold dose to evaluate for facilitating movement in lesioned rats, given its induction of increased time of latency to fall on a rotating treadmill. The effect of SKF38393 on motor activity was also evaluated by testing the rat step counts, which showed a temporal course similar to that of the latency to fall. For control rats, microinjection of SKF38393 into the dorsolateral striatum influenced the main effect of the treated dose (F (3, 20) = 4.83, p = 0.024) and the main effect of time (F (4, 80) = 6.56, p = 0.017) compared with vehicle infusion and no dose £ time interaction (F (12, 80) 1.89, p 0.076). Post hoc Dunnett’s test analyses reveal that (Fig. 3A) when rats were treated with a dose of 1.0 μg/site, the number of steps increased relative to the vehicle (p = 0.031), but there was no effect at the dose of 0.5 μg/site (p 0.426). However, the dose of SKF38393 (1.5 μg/site) showed a tendency with no significant differences from the vehicle infusion groups in the rotating treadmill (p 0.104), which means that SKF38393 was ineffective in improving locomotor activity. Subtle slow movement is observed in some rats. On the other hand, over the course of time, compared with the vehicle infusion, the effects of SKF38393 were apparent after 20 min (p = 0.017) and lasted for up to 50 min (p 0.032) at a dose of 1.0 μg/site. During the 20 50 min time points, SKF38393 had a significant effect on the number of steps (one-way repeated measures ANOVA, F (3, 20) = 12.83, p = 0.020). The post hoc Dunnett’s tests revealed that there was an increase in the number of steps (400.5 ± 2.98 vs. 384.8 ± 2.19, p = 0.002) with respect to the vehicle infusion (Fig. 3A’). Therefore, the SKF38393 dose of 1.0 μg/site during the 20 50 min is selective as a threshold dose to evaluate for facilitating movement in control rats, given its induction of increased numbers of steps on a rotating treadmill. For PD rats, SKF38393 administered to the dorsolateral striatum exhibited a significant influence on the main effect of the dose (F (3, 20) = 29.43, p = 0.003) and on the main effects of time (F (4, 80) = 7.53, p = 0.000) compared with the vehicle infusion and no dose £ time interaction (F (12, 80) = 1.88, p = 0.76). Post hoc Dunnett’s test ana- lyses reveal that (Fig. 3B) when rats were treated with a dose of 1.0 μg/ site (p = 0.001) the number of steps increased significantly compared with the vehicle infusion, with no effect at the dose of 0.5 μg/site (p 0.184). However, the dose of SKF38393 (1.5 μg/site) was not significantly different from that of the vehicle infusion groups (p 0.000), which means that SKF38393 was ineffective in improving locomotor activity. Instead, abnormal movement in sequence was exhibited, including initiation inhibition, stereotypic movements and asymmetric rotation as described in the test of latency to fall. On the other hand, over the course of time, compared with the vehicle infusion, the effects of SKF38393 were apparent after 20 min (P = 0.000) and lasted for up to 50 min (p = 0.008). At the 20—50 min time point, at a dose of 1.0 μg/site, SKF38393 had a significant effect on the number of steps (one-way repeated measures ANOVA, F (3, 20) = 29.43, p = 0.002). The post hoc Dunnett’s tests revealed that there was an increase in the number of steps (398.2 ± 5.0 vs. 364.3 ± 3.09, p = 0.000) with respect to vehicle (Fig. 3B’). Therefore, the SKF38393 dose of 1.0 μg/site during the 20 50 min is selective as a threshold dose to evaluate for facilitating movement in lesioned rats, given its induction of increased numbers of steps on a rotating treadmill. 3.2. The effects of D2R agonist quinpirole administration on locomotor activity Animals were microinjected with quinpirole at four different doses (0, 1.0, 2.0, and 3.0 μg/site) within subjects. A dose-response curve was generated for the D2 receptor-mediated movement response after administration of quinpirole into the dorsolateral striatum of 6-OHDA- treated rats and control rats. The treatment effects on latency to fall and step counts were analyzed among different groups after intrastriatal microinjection of quinpirole. Dose and time course analyses reveal la- tency to fall and step counts in Figs. 4 and 5, respectively. For control rats, quinpirole was microinjected into the dorsolateral striatum to evaluate animal movement by the time of latency to fall, and it exhibited a significant influence on the main effect of the treated dose (F (3, 15) = 9.26, p =0.004) and on the main effect of time (F (4, 60) = 22.18, p = 0.000) compared with the vehicle infusion and with no dose £ time interaction (F (12, 60) = 2.056, p = 0.098). Post hoc Dunnett’s tests reveal that (Fig. 4A) the time of latency to fall was significantly increased compared with the vehicle infusion when rats were treated with doses of 1.0 μg/site (p = 0.002) and 2.0 μg/site (p 0.000). However, the dose of 3.0 μg/site (p 0.163) showed no significant difference compared with the vehicle infusion on the rotating treadmill, which means an ineffective tendency for improving locomo- tor activity. On the other hand, over the course of time, at a dose of 1.0 μg/site, the effects of quinpirole were apparent within 5 min (p = 0.021) and lasted for up to 50 min (p = 0.000) compared with the vehicle infusion. At a dose of 2.0 μg/site, the effects of quinpirole were apparent within 5 min (p = 0.002) and lasted for up to 50 min (p = 0.000) with respect to the vehicle infusion. During the time period of 5—50 min, the effect of quinpirole on the latency to fall was signifi- cantly altered (one-way repeated measures ANOVA, F (3, 15) = 5.88, p = 0.002). The Post hoc Dunnett’s tests revealed that there was enhancement (588.6 ± 2.03 vs. 572.19 ± 1.25, p = 0.000) at doses of 1.0 μg/site and (597.6 ± 1.24 vs. 572.19 ± 1.25, p = 0.000) at doses of 2.0 μg/site (Fig. 4A’). Therefore, the quinpirole dose of 1.0–2.0 μg/site during the 5 50 min time is selective as a threshold dose to evaluate for facilitating movement in control rats, given its induction of increased time of latency to fall on a rotating treadmill. For PD rats, quinpirole was microinjected into the dorsolateral striatum to evaluate animal movement by the time of latency to fall, and it exhibited a significant influence on the main effect of time (F (4, 80) = 61.59, p = 0.000) compared with the vehicle infusion and with no dose £ time interaction (F (12, 80) = 1.19, p = 0.627). Post hoc Dun- nett’s test analyses reveal that (Fig. 4B) the latency to fall was signifi- cantly increased compared with the vehicle infusion when rats were treated with doses of 1.0 μg/site (p = 0.007) and 2.0 μg/site (p = 0.000). However, at a dose of 3.0 μg/site, quinpirole showed no significant difference compared with the vehicle infusion on the rotating treadmill (p 0.154), which indicates an ineffective tendency for improving lo- comotor activity. Instead, an inhibitory component started to appear with movements becoming temporarily gait slow or body freezing; then abnormal stereotypic involuntary movements were exhibited, including sniffing, rearing, grooming, head nodding, and taffy pulling (repeated movement of the paws toward and then away from the snout). Some rats triggered an asymmetry in rotation, turning predominantly in the di- rection contralateral to the lesion. Upon the effect of time course, at a dose of 1.0 μg/site, the effect of quinpirole was apparent after 5 min (p 0.004) and lasted for up to 50 min (p 0.000). At a dose of 2.0 μg/ site, the effects of quinpirole were apparent after 5 min (p 0.000) and lasted for up to 50 min (p 0.000). During the 5 50 min period, quinpirole had a significant effect on the latency to fall (one-way repeated measures ANOVA, F (3, 15) = 5.88, p = 0.002). The post hoc Dunnett’s tests revealed that compared with the vehicle infusion, there was an increase in the latency to fall (553.2 ± 1.6 vs. 518.8 ± 4.16, p = 0.001) at the doses of 1.0 μg/site and (586.0 ± 1.6 vs. 518.8 ± 4.16, p = 0.000) at the doses of 2.0 μg/site (Fig. 4B’). Therefore, quinpirole doses of 1.0 and 2.0 μg/site during the 5 50 min are selective as effective doses to evaluate for facilitating movement in lesioned rats, given its induction of increased time of latency to fall on a rotating treadmill. The locomotor responses are induced by quinpirole, and step counts are also observed for the same observation period. For control rats, quinpirole was microinjected into the dorsolateral striatum and exhibited a significant influence on the main effect of the treated dose (F (3, 13) = 53.28, p = 0.000) and on the main effect of time (F (4, 52) = 45.12, p = 0.000) compared with the vehicle infusion and with no dose £ time interaction (F (12, 52) =1.47, p = 0.737). Post hoc Dun- nett’s tests analyses reveal that (Fig. 5A) when rats were treated with doses of 1.0 μg/site (p 0.004) and 2.0 μg/site (p 0.000), the number of steps significantly increased with respect to the vehicle infusion. However, the dose of 3.0 μg/site (p 0.079) showed no significant difference effect compared with the vehicle infusion on the rotating treadmill, which indicates an ineffective improvement in locomotor activity. Regarding the effect of time course, at a dose of 1.0 μg/site, the effects of quinpirole were apparent after 5 min (p = 0.03) and lasted for up to 50 min (p = 0.000) relative to the vehicle infusion. At a dose of 2.0 μg/site, the effects of quinpirole were apparent after 5 min (p = 0.002) and lasted for up to 50 min (p = 0.000) with respect to the vehicle infusion. During the 5 50 min period, at a dose of 1.0 μg/site, compared with the vehicle infusion, quinpirole had a significant influence on the number of steps (one-way repeated measures ANOVA, F (3, 13) 4.62 p 0.002). The post hoc Dunnett’s tests revealed that compared with the vehicle infusion, there was an increase in the number of steps (444.5 ± 4.26 vs. 408.0 ± 1.67, p = 0.001) at the dose of 1.0 μg/ site and (469.4 ± 5.46 vs. 408.0 ± 1.67, p = 0.000, LSD test) at the dose of 2.0 μg/site (Fig. 5A’). Therefore, quinpirole doses of 1.0 and 2.0 μg site during the 5 50 min are selective as effective doses to evaluate for facilitating movement in control rats, given its induction of increased numbers of steps on a rotating treadmill. For PD rats, quinpirole was microinjected into the dorsolateral striatum and exhibited a significant influence on the main effect of the treated dose (F (3, 23) = 17.69, p = 0.000) and on the main effect of time (F (4, 92) = 50.23, p = 0.000) compared with the vehicle infusion and the no dose £ time interaction (F (12, 92) = 1.15, p = 0.734). Post hoc Dunnett’s test analyses revealed that (Fig. 5B) when rats were treated with doses of 1.0 μg/site (p 0.000) and 2.0 μg/site (p 0.000), the number of steps significantly increased compared with the vehicle infusion. However, the dose of 3.0 μg/site (p 0.638) showed no effect compared with the vehicle infusion on the rotating treadmill. Instead, an abnormal movement in sequence was exhibited, including sniffing, rearing, grooming, head nodding, taffy pulling and asymmetry in rota- tion as described in the test of latency to fall. On the other hand, upon the effect of time course, compared with the vehicle infusion, at the dose of 1.0 μg/site, the effects of quinpirole were apparent after 5 min (p = 0.03) and lasted for up to 50 min (p = 0.000), and at the dose of 2.0 μg/site, the effects of quinpirole were apparent after 5 min (p 0.00) and lasted for up to 50 min (p 0.000). During the 5 50 min, compared with the vehicle infusion, quinpirole significantly increased steps (one-way repeated measures ANOVA, F (3, 23) = 15.69, p 0.000). The post hoc Dunnett’s tests revealed that compared with the vehicle infusion, there was an increase in the number of steps (356.3 ± 6.75 vs. 302.4 ± 5.43, p = 0.000) at the doses of 1.0 μg/site and 367.38 ± 4.46 vs. 302.4 ± 5.43, p = 0.000) at the doses of 2.0 μg/site (Fig. 5B’). Therefore, quinpirole doses of 1.0 and 2.0 μg/site during the 5 50 min are selective as effective doses to evaluate for facilitating movement in lesioned rats, given its induction of increased time of la- tency to fall on a rotating treadmill. In summary, comparison of the results for dose ranges and time courses of intrastriatally administered SKF38393 or quinpirole alone, on either the latency to fall or step counts of performance on a rotating treadmill for all rats, suggest that rats being treated with SKF38393 at the dose of 1.0 μg/site or treated with quinpirole at the dose of 1.0–2.0 μg/site can experience significantly facilitated locomotor ac tivity during 20 50 min for SKF38393 or 5 50 min for quinpirole, respectively. Under this condition, either dopamine-lesioned or unle- sioned rats are suitable to evaluate the treatment effect on movement. In addition, the role of facilitated locomotor activity of either SKF38393 or quinpirole in the dorsolateral striatum of lesioned rats was considerably greater than that in unlesioned rats. Slowed movement and stereotypic behaviors occurred to a greater degree in the 6-OHDA-lesioned rats than in unlesioned controls. 3.3. Comparison of the effect of SKF38393 and quinpirole administration on locomotor activity After threshold doses were established from the abovementioned experiments, i.e., that the dopamine D1 receptor agonist SKF38393 at a dose of 1.0 μg/site and the D2 receptor agonist quinpirole at a dose of 1.0 μg/site elicited a significant increase in motor performance, we next compared the effects of SKF38393 and quinpirole intrastriatal injection on locomotor activity in 6-OHDA-lesioned rats. The results are as shown in Fig. 6. One-way ANOVA indicated significant treatment effects (treatment as a between factor) on the time of latency to fall (F (3, humans. 68) = 87.66, p = 0.000) (Fig. 6A) and on the numbers of steps (F (3, 74) 101.07, p 0.000) (Fig. 6B). Post hoc Tukey’s test revealed that the lesioned rats demonstrated significantly decreased latency to fall compared to unlesioned rats (518.81 4.16 vs. 570.61 1.85, p 0.000), and 6-OHDA-lesioned rats treated with either SKF-38393 or quinpirole showed significantly increased latency (562.25 6.42 vs. 518.81 4.16, p 0.000) and quinpirole (594.94 1.81 vs. 518.81 4.16, p 0.000), respectively, compared to lesioned rats treated with the vehicle infusion; the rats treated with quinpirole among the lesioned rats showed significantly increased latency compared to rats treated with SKF-38393 (594.94 1.81 vs. 562.25 6.42, p 0.000) (Fig. 6A). In addition, post hoc Tukey test comparisons revealed that the 6- OHDA-lesioned rats demonstrated significantly decreased numbers of steps on the treadmill compared to dopamine-unlesioned rats (306.19 3.98 vs 383.61 1.58 p 0.000); and the lesioned rats treated with either SKF-38393 or quinpirole showed significantly increased numbers of steps on the treadmill (355.33 5.13 6.42 vs 306.19 3.98, p 0.000) and (385.39 3.41 vs 306.19 3.98, p 0.000), respectively, compared to lesioned rats treated with the vehicle infusion; and the treated with quinpirole of lesioned rats showed significantly increased numbers compared to the SKF 38393-treated lesioned rats (385.39 3.41 vs 355.33 5.13 p 0.000) (Fig. 6 B). In summary, at selective threshold doses, both SKF38393 and quin- pirole intrastriatal injection into 6-OHDA-lesioned rats induced greater ameliorated motor responses, and the ameliorated motor response to quinpirole was obviously more pronounced than that to SKF38393 in 6- OHDA-lesioned rats. 4. Discussion We utilized PD model rats to research the positive role of DA receptor agonists as a treatment for PD. In this investigation, we mainly addressed the role of the dopamine D1R agonist SKF38393 and D2R quinpirole in the expression of parkinsonian-like motor deficits in damaged unilateral nigrostriatal rats. The data demonstrate that at the threshold dose of intrastriatal injection, either SKF38393 or quinpirole has the ability to enhance locomotor activity and reverse the motor impairments of 6-OHDA-lesioned rats. However, both SKF38393 and quinpirole can induce multiple subtle effects, leading to increased ac- tivity at the threshold dose and slow activity or abnormal stereotypic movements at high doses. Moreover, both SKF38393 and quinpirole intrastriatal injection into 6-OHDA-lesioned rats induced greater behavioral responses than control rats. Quinpirole administration more pronouncedly ameliorated the motor response than SKF38393 admin- istration in 6-OHDA-lesioned rats. The results can directly clarify several key issues regarding DA receptors and may provide a basis for exploring the potential of future selective DA strategies or therapies for PD in SKF38393, the prototype benzazepine D1R agonist, however, it only exhibits partial agonist activity, SKF38393 is the first compound to selectively act on the D1 receptor, with only 45–70 % intrinsic activity. As a behaviourally significant receptor has been either questioned or denied when compared with that the full D1R agonist, such as SKF82958. Because systemic administration of SKF38393 does not induce immediate early gene expression in striatal projection neurons [30], failed to modify DA release and metabolism [31], and neither interfere with the rat beam-walking test [32] nor induce any typical stereotyped behaviour [33]. But it is still used in much of the research examining DA receptor subtypes and is especially used extensively as a tool to stimulate central D1R agonists selectively [11,34,35],particu- larly in the striatum. The striatum receives dopaminergic afferents from the substantia nigra pars compacta and possesses high levels of DA re- ceptors, predominantly the D1R and D2R subtypes [12,36]. It’s worth noting is that these drugs employed have different effects when administered systemically versus locally. In addition to its specific dopamine D1R-mediated effects, recently research showed striatally applied SKF38393 can induce an increase in striatal dopamine effluX [37,38]. We found that the D1R agonist SKF38393, under the condition of a selective threshold dose, caused dose-dependent enhancement of movement, including in the time of latency to fall and step frequency on the rotating treadmill for control and DA-lesioned rats, which suggests that the D1R agonist may be effective in facilitating and reversing parkinsonian motor deficits. This outcome is consistent with previous studies showing that SKF38393 ameliorates motor function in parkin- sonian rats after infusion into the dorsolateral striatum [39,40] and markedly improves motor deficits [41,42]. Recently, using the perfo- rated patch-clamp recording technique demonstrated that dopaminergic transmission powerfully enhances the intrinsic excitability of D1 receptor-expressing striatal projection neurons, which can support sustained behavioral control [43]⋅ However, our study data also show that SKF38393 has multiple subtle effects on movement: high-dose intra- striatal injection of SKF38393 induced slowness or abnormal stereotypic movements. The results are similar to previous studies showing that dopamine-lesioned and normal primate, administration of SKF38393 did not stimulate locomotor activity but weakly inhibited movement and marginally increased the severity of motor deficits [44,45]. More- over, we need to note the more important issue concerning the nature of SKF38393 involved in either reversal of the motor symptoms of PD or in enhancing the severity of motor deficits and the production of dyski- nesia, abnormal involuntary movements, which included limb dyskinesia, axial dyskinesia, tongue dyskinesia and locomotive dyskinesia [10,46–48]. A body of evidence has shown that high concentration and prolonged stimulation of the D1R agonist SKF38393 results in the development of dyskinesias [10,49,50]. The main reason for these changes is the sensitization of D1R which is located on the projection neurons of the striatum [51]. In the striatum of PD, the density of D1R in the serosal membrane is increased [52].Combined with the existing literature, these data suggest that D1R plays a part in the development and expression of dyskinesias [53]. In short, the present study, together with an earlier report [54,55], clearly implies that there are dose-related quantitative and qualitative differences in the effects of striatally applied SKF38393, which lead to heterogeneous changes in the func- tional and pharmacological properties of receptors and result in the development of either motor fluctuations or abnormal involuntary movements of L-DOPA-induced dyskinesia. We speculate that this apparently paradoXical finding of the D1R agonist SKF38393 may be explained by previous reports that D1R activation exerts multiple actions on striatal dopaminoceptive neurons [12,54,56] because D1Rs are located mostly extrasynaptically at the plasma membrane of the cell bodies, dendrites, and spines in the stria- tum [41]. The activation of dopamine receptors by their agonist should provoke a dramatic modification of their subcellular distribution in neurons, including internalization in the endosome and recycling at the membrane in striatal neurons [41]. Moreover, once a D1R agonist binds to a receptor, it causes parallel or consecutive activation of multiple downstream signaling pathways, thus exerting multidimensional effi- cacy [8,57]. It is noteworthy that dyskinesia is associated with abnormal D1R localization at the membrane and intraneuronal trafficking dysre- gulation [56,58]. Another reason for the discrepancy may be that D1R is embeded in a rich neuronal network involving variations in both project neurons and interneurons in the striatum that are modulated by DA [59, 60]. Therefore, functional studies are still conflicting regarding the involvement of D1 receptors in the modulation of animal behavior activity. D2R agonist quinpirole, similar to the action of SKF38393, at selec- tive threshold dose, injections in the striatum also motivated movement and antiparkinsonian effects without inducing dyskinesias. Treatment with high administration, however, can diminish the role of improve- ment movement and induce slowness or abnormal stereotypic move- ments. Importantly, quinpirole injections in the striatum are more effective in changing animal behavior and reversing the effects of DA depletion on animal motor impairment. This finding suggests that D2R has a relatively strong ability to reverse motor deficits induced by these DA-lesioned animals. These data complement those of research showing that highly selective D2R compounds have been effective in reversing motor deficits in MPTP-treated primates [44,61] and in alleviating the symptoms of PD patients [62] but conflict with a recent study showing that D2R agonists inhibit movement in a Parkinson’s disease mouse model [63]. The discrepancy between studies can be attributable to heterogeneity in D2Rs [64]. Although D1R and D2R share a high level of homology of their transmembrane domains, the roles of D2R are much more complex than those of D1R in anatomical, physiological, signaling, and pharmacological properties [65]. In particular, the activation of D2R is able to express both presynaptic and postsynaptic proteins on neurons [66,67]. Presynaptic D2R plays a key role in maintaining extracellular dopamine levels within constant levels [68]. Indeed, pre- synaptically localized autoreceptors generally provide a negative feed- back mechanism to moderate movements, so D2 autoreceptors are activated by a lower concentration of dopamine agonists than necessary to activate postsynaptic receptors [8]. Notably, both SKF38393 and quinpirole coordinate in facilitating motor function, which seems to contrast with the expected classic model in which direct (D1R) and indirect (D2R) pathways of the basal ganglia have opposing roles in movement control [18]. This consequence is possibly related to the bidirectional responses of the striatum during increasing dopamine input levels [69]. Recently, rapidly growing evi- dence suggests that the classic model oversimplifies coordinated activity and that spatiotemporal organization and neuronal ensembles of both pathways are critical to behavior [69,70]. Although several possibilities may account for this coordinated activity, our result suggests the most likely one is drug concentration, as higher dose administrations of SKF38393 or quinpirole into both 6-OHDA-lesioned and control rats are responsible for the slowly activity or abnormal stereotypic movements seen in our experiments. A further important result is that D1R and D2R agonist administra- tion to 6-OHDA-lesioned rats induces a greater enhancement of behav- ioral responses than that seen in control rats. After microinjection of SKF38393 or quinpirole into the dorsolateral striatum, the time of la- tency to fall and step frequency on the treadmill of the lesioned rats have greater improvement than that observed in control rats, which would suggest that in the lesioned animals locomotor responses are largely sensitive than in the control animals. This underlying reason may be interpreted as dopaminergic functional compensation for dopamine deficiency, mainly by upregulating DA receptor function and manifest- ing intrinsic synaptic homeostatic plasticity [13,36,71]. Under this compensation mechanism, dopamine receptors become supersensitive to adjust motor abnormalities. The increasing sensitivity of dopamine receptor agonists suggests that the dopamine receptor may possess a degree of implications for understanding changes in behavior associated with drug use. Although we have shown that D1R or D2R receptor agonist can either improve performance mainly at optimal doses, or induce these stereotypic behaviors even dyskinesia at higher doses. A limitation of this study lack of test by receptor antagonist challenge, it is well-known that the characteristics of D1 or D2 receptor agonist on individual be- haviours should be assessed following dopamine receptor antoagonist challenge, to indicate that the agonist interacts with the same receptors that mediate the effects of the antagonist. Such as some previous sys- temic or intra-striatal D1 or D2 receptor antagonist administration were verified the effects of a threshold dose of SKF38393 and quinpirole, respectively, on motor coordination and balance [32,72] enhanced cognitive function [35,73], the DA metabolism [31,74] and modify behavior flexibly [75]. Even so, it cannot discard the possibility that the results include some concomitant effects on motor coordination after the total activation and/or blockade of dopamine two or more distinct re- ceptors, for previous research have demonstrated behavioral conse- quences of cross receptor mediated effects due to two DA receptors cooperativity [76]. Therefore, another limitation of this study is lack of evaluation of the synergic effect for D1R agonist SKF38393 with D2R agonist quinpirole. At our selected threshold, concurrent microinjection of the SKF38393 and quinpirole occurred stereotypic behaviors char- acterized by incidence of rearing, sniffing licking and head weaving, etc, and triggered more rotations than the sum of the rotations induced by each of these two agonists separately. We reasoned that this situation may function synergistically to produce stronger hyperactivity and this dose was too high to measure animal behavior. This situation also accounted for key role of drug concentration. It is necessary that after setting up the suitable microinjection dose before start a test in further. In summary, SKF38393 or quinpirole is able to activate D1R and D2R and play an important role in facilitating and stimulating motor function at threshold drug concentrations. However, how activation of D1R and D2R leads to downstream behavior alterations is a complicated problem that relates to the specifics of the task structure, injection method (systemic or intracerebral infusions) or the extent of dopamine loss. Therefore, how to identify dopamine receptor-related functions and provide a reasonable therapeutic opportunity for dopamine-related disorders will continue to evolve in the future. 5. Conclusion The findings of the present study indicate that, D1/D2 dopamine receptor agonists induce behavior responses when administrated into the dorsolateral striatum of both 6-0HDA-lesioned rats and unlesioned rats, and 6-OHDA-lesioned rats induce greater locomotor responses than unlesioned rats. At threshold dose, the behavior response of SKF38393 produced is considerably less than that observed after quinpirole microinjection into the dorsal striatum. 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