• Users Online: 91
  • Print this page
  • Email this page

 
Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 64  |  Issue : 1  |  Page : 1-15

Lack of effect of dopamine receptor blockade on SKF83959-altered operant behavior in male rats


1 Department of Psychology, National Cheng-Chi University, Taipei, Taiwan
2 Institute of Neuroscience; Research Center for Mind, Brain and Learning, National Cheng-Chi University, Taipei, Taiwan
3 Department of Psychology; Institute of Neuroscience; Research Center for Mind, Brain and Learning, National Cheng-Chi University, Taipei, Taiwan

Date of Submission02-Nov-2020
Date of Decision14-Jan-2021
Date of Acceptance25-Jan-2021
Date of Web Publication25-Feb-2021

Correspondence Address:
Dr. Chih-Chang Chao
Institute of Neuroscience, National Cheng-Chi University, Taipei
Taiwan
Dr. Ruey-Ming Liao
Department of Psychology, National Cheng-Chi University, 64, Sec. 2, Zhinan Road, Taipei City - 116 011
Taiwan
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CJP.CJP_92_20

Rights and Permissions
  Abstract 


Dopamine (DA) is important for the performance of operant behavior as revealed by psychopharmacological studies that manipulate the activity of DA subtype receptors. However, the effects of SKF83959, an atypical DA D1 receptor agonist, on operant behavior and the underlying pharmacological mechanisms remain unclear. The present study sought to determine whether blockade of DA D1- and D2-subtyped receptors would reverse the operant behavior altered by SKF83959. Male rats were trained to respond on either a fixed-interval 30 s (FI30) schedule or a differential reinforcement of low-rate response 10 s (DRL10) schedule, two timing-relevant tasks but with distinct reinforcement contingencies. Pharmacological evaluation was conducted with injection of a selective D1 (or D2) receptor antagonist alone or in combined with SKF83959 (1.0 mg/kg) following a stable baseline of behavioral performance. The results showed that SKF83959 treatment alone significantly disrupted the performance of FI30 and DRL10 behaviors mainly by showing the decreases of the response-related measures, and the distinct profiles of the behavior altered by the drug were manifested by the qualitative analysis of inter-response time data on both tasks. The effects of SKF83959 were not significantly affected/reversed by the pretreatment of either SCH23390 or eticlopride injected at the doses of 0.02 and 0.06 mg/kg; however, a subtle reversal effect was observed in the treatment of low-dose eticlopride. Despite that these results confirm the FI30 and DRL10 behaviors changed by SKF83959, the absence of pharmacological reversal effect by DA receptor antagonist suggests that either D1- or D2-subtyped receptors may not play a critical role in the alteration of timing-relevant operant behavior produced by SKF83959.

Keywords: Atypical dopamine receptor agonist, behavioral pharmacology, eticlopride, SCH23390, schedule-controlled behavior


How to cite this article:
Liu PP, Chao CC, Liao RM. Lack of effect of dopamine receptor blockade on SKF83959-altered operant behavior in male rats. Chin J Physiol 2021;64:1-15

How to cite this URL:
Liu PP, Chao CC, Liao RM. Lack of effect of dopamine receptor blockade on SKF83959-altered operant behavior in male rats. Chin J Physiol [serial online] 2021 [cited 2021 Apr 21];64:1-15. Available from: https://www.cjphysiology.org/text.asp?2021/64/1/1/310131




  Introduction Top


Brain dopamine (DA) has a crucial role in motivation control and movement regulation.[1],[2],[3],[4],[5] DA receptor (DAR) D1 and D2 subtypes, categorized in terms of biochemical and genetic aspects,[6],[7] have heterogeneous functions based on both pharmacological and physiological approaches,[8],[9] behavioral studies,[10],[11] and associated psychiatric disorders.[12],[13],[14] Although animal models have been developed and used to investigate the behavioral function of DA in preclinical studies, the exact roles of D1 and D2 receptor subtypes in behavioral functioning in terms of reward motivation and/or cognitive processing are still a matter of debate. The operant behaviors trained and maintained at different schedules of reinforcement demand distinct motivational and/or cognitive processes,[15] which may be used to tackle this issue. As noted in behavioral pharmacology, the operant behavioral paradigms provide well-adopted animal models to examine the distinct effects of different classes of psychoactive drugs.[16],[17]

SKF83959, a phenylbenzazepine derivative, is an atypical agonist on D1-like DARs,[18] which has been identified to activate calcium/calmodulin-dependent protein kinase II (CaMKII) through D1 receptor-coupled Gq/11 protein.[19],[20] Along with research that probe the neurochemical actions of SKF83959, a number of studies examined the effects of this compound through various behavioral tests in rats including acoustic startle reflex,[21] eye blinking,[22] maternal behavior,[23] locomotor activity,[24],[25] anxiety-like response,[26],[27] and DA drug-induced dyskinesia.[25] The behavioral effects of SKF83959 have also been studied in primates, but mostly been examined by using reflexive behavioral models close to the aforementioned rodent tasks (e.g.,[28]). Apart from these studies, the behavioral effects of SKF83959 on the instrumental/operant conditioning paradigm have scarcely been examined.

Here, we focused on two timing-relevant operant behaviors that the participants were trained by a fixed-interval (FI) schedule or a differential reinforcement of low-rate response (DRL) schedule. Despite the timing process involved in common, operant behavior performed on FI task was distinctively different from that preformed on DRL task. For example, in terms of response rate, FI behavior is apparently higher than DRL behavior. As suggested by the principle of response rate dependency in behavioral pharmacology,[29] the effectiveness of a particular drug on behavior could be dependent on the baseline response rate in the absence of that drug. Indeed, we recently found task-dependent effects of SKF83959 on these two operant behaviors.[30] However, the functional role of SKF83959 on operant behavior and its underlying pharmacological mechanisms on DAR subtypes remain to be elucidated. This study was then designed to examine the pharmacological specificity of DAR subtypes on FI and DRL behaviors altered by SKF83959 with the administrations of the selective D1 and D2 DAR antagonists, SCH23390 and eticlopride, respectively. We hypothesized that (1) the effects of SCH23390 and eticlopride were dissociable on reversing the SKF83959-altered operant behavior and (2) the pharmacological antagonism might be dependent on behavioral tasks.


  Materials and Methods Top


Subjects

Male Wistar rats (BioLASCO Taiwan Co., Ltd) that weighted approximately 250 g upon receipt were used as the participants. The rats were housed in a temperature-controlled colony under a 12/12-h light/dark cycle (light on at 7:30 a.m.). After 10 days of acclimatization to the food and water provided ad libitum with being handled daily, the rats were maintained on a water-restriction regimen, that is, the rats had 10 ± 5 min access to tap water in the home cage 30 min after the end of each daily experimental session. Food pellets were continuously available in each home cage. The body weight was carefully monitored and allowed to increase throughout the entire experiment on a delayed-growth curve. Training and/or test sessions were conducted daily at the same time (10:00–15:00) each day. The temperature of the colony and the behavioral test room was maintained at 23°C ± 1°C throughout the experiment. All procedures were conducted in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and approved by the institutional committee of animal use and care of National Cheng-Chi University (100BPSY001 and 104-07).

Apparatus

Operant behavioral measures were conducted using a custom-made operant system with four chambers located in a room separate from the animal colony. The interior dimensions of each chamber were 20 × 25 × 30 cm3 (MED Associated, St. Albans, VT, USA). Aluminum panels formed the front and back walls, and clear Plexiglas comprised the remaining sides and the top. Stainless steel rods (5 mm diameter) were set 11 mm apart to provide flooring. Each chamber was equipped with a lever positioned 7.3 cm above the floor and 4 cm from the right corner of the front panel. A liquid dispenser was set outside of the front panel of the chamber. The reinforcer delivery mechanism gave 0.04 ml of tap water at each presentation. The water was delivered into a receiving dish (25 mm diameter) located at the center of the front panel and 2 cm above the floor. The chamber was illuminated by a small light bulb located 10 cm above the floor and positioned 5 cm from the left corner of the front panel. Each chamber was enclosed in a plywood box with a fan to provide necessary ventilation and mask any outside noise. The four operant chambers were serviced and controlled by a microcomputer with an in-house designed program to control the operant environment and allow data collection (e.g., [31]).

Drugs

SKF83959 hydrobromide (Tocris Bioscience) was dissolved in the vehicle containing 10% ethanol in 0.9% physiological saline. SCH23390 hydrochloride (Tocris Cookson, Bristol, UK) and eticlopride hydrochloride (Tocris Bioscience) were dissolved in 0.9% physiological saline. The drug was intraperitoneally (i.p.) injected at a volume of 1 ml/kg of body weight.

Training of fixed-interval 30 s and differential reinforcement of low-rate response 10 s behaviors

The water-deprived rats were subjected to magazine training, during which they learned to associate water with the metal receiving dish. Then, the rats were run for three daily sessions (30 min each) of shaping by pressing a lever to acquire the water reinforcer based on the fixed-ratio 1 schedule of reinforcement. All of the rats were able to make at least 65 lever presses in a 30-min training session to meet the criterion of this stage. The rats were then trained under either FI or DRL schedule of reinforcement.

In the FI task, the reinforcer was contingent to the first lever press made after the time interval had elapsed since the time point of a prior reinforcer delivery. Lever presses made during the time interval had no reinforcement contingencies. Rats in the FI group began daily training under 1-h sessions of the FI 10-s schedule for 10 days before shifting to daily 30-min training sessions under FI 30-s (FI30) for 25 days. The average number of total responses reached 600 per day across the past 3 days of FI30 training and was used as a criterion of baseline performance before the commencement of the pharmacological test sessions (see below). In the DRL task, the rats had to wait a specified number of seconds between the lever presses to obtain a chance to respond to acquire the reinforcer. Any response made before the criterion time would reset the DRL clock and would not be reinforced. The rats in the DRL group were trained by hourly sessions of the DRL 10-s (DRL10) schedule for 10 days followed by daily 30-min training sessions for 25 days. The testing of drug-induced performance began when their average number of total responses reached 200 per day across the last 3 training days. Over the course of the operant training, stable baseline performances on both tasks were indicated by the criterion of less than 10% of variation in the average response rates for 3 consecutive days.

Procedures of pharmacological test

The effects of DAR antagonist given alone and in combination with SKF83959 were evaluated on operant response of FI30 or DRL10 task, which procedure consisted of two i. p. injections during each session of pharmacological test. The first injection of DAR antagonist (or saline) was given 60 min before the behavioral test, and the second injection of 1 mg/kg of SKF83959 (or vehicle) was given 30 min before the behavioral test. On the first test day, all rats were subjected to control treatments (the double injection of saline-vehicle). After a 2-day retraining, the rats went on to receive the drug treatments of saline-SKF83959, DAR antagonist-saline, and DAR antagonist-SKF83959 in the orders of a Latin square on test sessions each spaced apart by 2 days of retraining. SKF83959 was injected at 1.0 mg/kg, which was chosen as an effective dose based on a report from this laboratory.[30] SCH23390 and eticlopride were both tested at 0.02 and 0.06 mg/kg, based on previous studies from this laboratory (e.g., [32]) and others'.[33],[34] Two cohorts of rats were used to test separately in the effects of SCH23390 (Experiment 1) and eticlopride (Experiment 2) interacting with SKF83959 following this protocol of pharmacological test.

Experiment 1 examined the effects of SCH23390 pretreated with SKF83959 on FI30 and DRL10 task. A group of 18 rats with water deprivation for 2 weeks were divided into two subgroups to receive operant training under either the FI30 or DRL10 (n = 9 each) schedules of reinforcement in the procedures as described above. After reaching the stable baseline, the rats were subjected to the tests with 0.02 mg/kg SCH23390 pretreatments. The rats were retrained for 3 days and were then subjected to testing with 0.06 mg/kg SCH23390 pretreatments. Experiment 2 evaluated the effects of eticlopride pretreated with SKF83959 on FI30 and DRL10 task. A separate batch of 18 rats was divided into the FI30 and DRL10 groups (n = 9 each) for operant training as described above. When they reached stable baseline performance, the rats were subjected to operant testing with 0.02 mg/kg eticlopride pretreatments. After 3 days of retraining, they were again subjected to testing with 0.06 mg/kg eticlopride pretreatments. [Table 1] illustrates the experimental design of these pharmacological tests.
Table 1: Experimental design of pharmacological tests

Click here to view


Statistical Analysis

In regarding to FI30 behavioral measurement, each lever press was classified in terms of its associated inter-response time (IRT; the time in millisecond elapsed since the prior response), and the resulting dataset on IRT was grouped and plotted into a distribution that consisted of response frequencies for 30 consecutive 1-s time bins. The total number of responses and the number of reinforcers were analyzed in addition to the aforementioned IRT distribution within a 30-sec interval. The post-reinforcement pause (PRP) represented the duration of the first response made within a 30-s interval since the time point of the preceding reinforcement. The index of PRP on FI schedule typically refers to the duration of time lapse from receiving a reinforcer to making the next lever press in the following interval.

In DRL10 behavioral measurement, the dataset on IRT was grouped and plotted into a distribution that consisted of response frequencies for 21 consecutive 1-s time bins. Seven dependent variables were studied for the quantitative analyses: (1) total responses; (2) reinforced responses, lever press with IRT ≥10 s; (3) nonreinforced responses, lever press with IRT <10 s; (4) burst responses, lever response with IRT <2 s; (5) peak rate; (6) peak time and (7) the modified response efficiency (MRE). Peak time and peak rate were calculated from the de-burst IRTs (IRT >2 s), in which a moving average based on four consecutive 1-s bins with a 1-s step size was applied to smoothen the distribution. After the identification of the maximum frequencies for a 4-s epoch, the peak time was designated as the average value (in millisecond) of all IRTs that fell within the four bins (i.e., the maximal epoch). The peak time measurement indicated at which time point the rats pressed the lever with the highest IRT frequency, that is, the peak time was their expected time for obtaining the reinforcer. Peak rate was calculated from the summed responses in the aforementioned four bins divided by four. This parameter indicated how strongly the rats were motivated to press the lever at the expected criterion time. This smoothing procedure has been previously used (e.g., [35]). The MRE is defined as the ratio between reinforcement rate and overall response rate after the subtraction of burst responses – defined by lever presses with an IRT < 2 s. Burst responding was excluded in determining the MRE, because previous studies have suggested that these rapid responses are more related to behavioral inhibition and emotional reactivity (e.g., frustration, impulsivity, and the failure of self-control) than to timing per se.[36],[37],[38] Therefore, it seems reasonable to use MRE measuring the performance of DRL behavior in terms of response efficiency to earn reinforcer.

Some rats appeared to completely cease or become balking their operant response upon the administration of SKF83959 alone or in combined with DAR antagonist. Cases of such low (number of total responses <5) were still included in the analysis, because the exclusion of these cases in notable numbers may introduce bias to the results. Hence, all of the actual numbers of responses made by the subject were used in the analysis of response-based indexes. However, the group mean was substituted in these cases of missing data in other indexes: PRP in the FI30 task; peak time, peak rate and MRE in the DRL10 task.

The data are presented in mean ± the standard error of the mean and were analyzed with the analysis of variance (ANOVA) using Statistica (version 7.1, StatSoft). Post hoc comparisons were conducted using Tukey's honestly significant difference test with a significance level of P < 0.05.


  Results Top


Experiment 1: Examination of effects of SCH23390 on SKF83959-altered operant behavior

FI 30-s performance. [Figure 1] illustrates the effects of SCH23390 treatment alone and combined with SKF83959 administration on the IRT curve of FI30 performance. One of the nine rats was excluded from the analysis due to unnoticed equipment errors that have interrupted with proper operant training. The treatment of 0.02 mg/kg SCH23390 alone did not greatly alter the typical scallop-shaped FI response curve relative to the saline-vehicle treatment, whereas the pretreatment of 0.02 mg/kg SCH23390 before SKF83959 injection resulted in decreased responding in a similar manner as the treatment of SKF83959 alone [Figure 1]a. In contrast, when 0.06 mg/kg SCH23390 was treated alone or pretreated with SKF83959, the response rates on the FI 30-s IRT were decreased in a pattern similar to that of the treatment of SKF83959 alone [Figure 1]b.
Figure 1: The fixed-interval 30 s inter-response time curve after SCH23390 pretreatment in a within participants design (n = 8): 0.02 mg/kg SCH23390 (a) and 0.06 mg/kg SCH23390 (b). Neither doses of SCH23390 appeared to reverse the SKF83959-induced decline in response frequency on the fixed-interval 30 s schedule (Experiment 1).

Click here to view


[Figure 2] displays the behavioral results from the FI30 test in terms of the specified indexes under SCH23390 treatment at two doses. From the tests of 0.02 mg/kg SCH23390 administrations [Figure 2]a, [Figure 2]b, [Figure 2]c, one-way ANOVA showed that there were significant differences across the drug treatments on the numbers of total responses, F(3, 21) = 8.06, P < 0.001, reinforced responses, F(3, 21) = 7.23, P < 0.001, and PRP, F(3, 21) = 9.66, P < 0.001. Post hoc test showed that when rats were treated with SKF83959 alone, they exhibited significantly reduced numbers of total responses, P < 0.01 [Figure 2]a and reinforced responses, P < 0.05 [Figure 2]b. The administration of 0.02 mg/kg SCH 23390 alone did not have significant effects on these two response-based indexes. The pretreatment of 0.02 mg/kg SCH23390 with SKF83959 similarly reduced the numbers of total responses, P < 0.01, and reinforced responses, P < 0.01, as the treatment of SKF83959 alone. In addition, the rats that were given the combined treatment of 0.02 mg/kg SCH23390 and SKF83959 showed a significant increase in the PRP, P < 0.001. The individual treatments of SKF83959 and SCH23390 did not produce significant effects on the PRP [Figure 2]c.
Figure 2: Total responses, reinforced responses, and post-reinforcement pause measured in fixed-interval 30 s behavior after SCH23390 pretreatment (n = 8): 0.02 mg/kg SCH23390 (a-c) and 0.06 mg/kg SCH23390 (d-f). High dose SCH23390 alone affected the total response rates to a greater extent than the low dose. Neither doses of SCH23390 reversed the effects of SKF83959 on the fixed-interval 30 s behavioral measurement. * P < 0.05; ** P < 0.01; *** P < 0.001 in comparison to the respective vehicle (Experiment 1).

Click here to view


At the administration of 0.06 mg/kg SCH23390 [Figure 2]d, [Figure 2]e, [Figure 2]f, one-way ANOVA has found significant differences in the numbers of total responses, F(3, 21) = 6.18, P < 0.01, and reinforced responses, F(3, 21) = 7.10, P < 0.01, across treatment conditions. Post hoc test revealed that when rats were treated with SKF83959 alone, they exhibited significantly decreased total responses relative to vehicle, P < 0.05, [Figure 2]d. This effect was not observed under the treatment of 0.06 mg/kg SCH23390 alone. The pretreatment of high-dose SCH23390 with SKF83959 significantly reduced the numbers of total responses, P < 0.01, in a similar pattern as that under SKF83959 alone. The individual administrations of SKF83959 and 0.06 mg/kg SCH23390 did not have statistically significant effects on the numbers of reinforced responses, although the rats under SKF83959 injections did display a trend of decrease [Figure 2]e. Alternatively, the rats under the combined treatment of 0.06 mg/kg SCH23390 and SKF83959 exhibited significantly reduced numbers of reinforced responses, P < 0.01. One-way ANOVA did not find significant differences across treatment conditions on the index of PRP [Figure 2]f.

DRL10 performance. [Figure 3] shows the effects of SCH23390 alone and pretreated with SKF83959 on the IRT curve of DRL10 performance. As shown in both panels, the drug treatments did not shift the peak time. In [Figure 3]a, the effects of 0.02 mg/kg SCH23390 alone on the DRL10 IRT curve were almost the same as that of vehicle treatments, whereas in [Figure 3]b, the treatment of 0.06 mg/kg SCH23390 alone showed a minor effect in reducing the response rate. Neither dose of SCH23390 pretreated with SKF 83959 was found to exhibit reversal effects on the SKF83959-induced declines in response rate.
Figure 3: The differential reinforcement of low-rate response 10 s inter-response time curve after SCH23390 pretreatment in a within-subjects design (n = 9): 0.02 mg/kg SCH23390 (a) and 0.06 mg/kg SCH23390 (b). Neither doses of SCH23390 appeared to reverse the SKF83959-induced decline in response frequency on the differential reinforcement of low-rate response 10-s schedule (Experiment 1).

Click here to view


[Figure 4] and [Figure 5] illustrate the quantitative analyses of the IRT data on DRL10 tests. In respective to the response-based indexes [Figure 4]a, [Figure 4]b, [Figure 4]c, [Figure 4]d, one-way ANOVA indicated the presence of significant differences across the 0.02 mg/kg SCH23390 treatment conditions on the numbers of total responses, F(3, 24) = 19.25, P < 0.001, reinforced responses, F(3, 24) = 7.20, P < 0.01, nonreinforced responses, F(3, 24) = 13.82, P < 0.001, and burst responses, F(3, 24) = 4.13, P < 0.05. Post hoc analysis revealed that when the rats were administered with SKF83959 alone, they exhibited significant reductions in the numbers of total responses, P < 0.001 [Figure 4]a, reinforced responses, P < 0.05 [Figure 4]b, nonreinforced responses, P < 0.01 [Figure 4]c, and burst responses, P < 0.05 [Figure 4]d. The administration of 0.02 mg/kg SCH23390 alone did not have significant effects on any of these four response-based indexes relative to the vehicle treatment. Moreover, the pretreatment of 0.02 mg/kg SCH23390 with SKF83959 yielded significant reductions in the numbers of total responses, P < 0.001, reinforced responses, P < 0.05, nonreinforced responses, P < 0.001, and burst responses, P < 0.05, producing almost the same effects as the treatments of SKF83959 alone. On the other DRL10 indexes [Figure 5]a, [Figure 5]b, [Figure 5]c, one-way ANOVA indicated significant differences across treatment conditions on the peak rate, F(3, 24) = 13.10, P < 0.001 [Figure 5]a, and MRE, F(3, 24) = 7.76, P < 0.001 [Figure 5]c. No significant differences were found across the treatment conditions on the peak time [Figure 5]b. As shown in [Figure 5]a, post hoc tests found the rats to exhibit significantly reduced peak rates relative to vehicle under the treatments of SKF83959 alone, P < 0.01. The administration of 0.02 mg/kg SCH23390 alone did not have significant effects on the peak rate. The pretreatment of 0.02 mg/kg SCH23390 with SKF83959 also induced a decline in peak rates, P < 0.001. In respective to the MRE ratio, the rats exhibited a significantly increased MRE when they were treated with SKF83959 alone, P < 0.01. No significant differences in MRE were found under the treatment of 0.02 mg/kg SCH23390 alone or the combined treatments of SCH23390 and SKF83959 [Figure 5]c.
Figure 4: The differential reinforcement of low-rate response 10 s response-based indexes after SCH23390 pretreatment (n = 9): 0.02 mg/kg SCH23390 (a-d) and 0.06 mg/kg SCH 23390 (e-h). Neither doses of SCH23390 reversed the effects of SKF83959 on the differential reinforcement of low-rate response 10-s indexes. * P < 0.05; ** P < 0.01; *** P < 0.001 to vehicle (Experiment 1).

Click here to view
Figure 5: The peak rate, peak time, and modified response efficiency measured in differential reinforcement of low-rate response 10 s behavior after SCH23390 pretreatment (n = 9): 0.02 mg/kg SCH23390 (a-c) and 0.06 mg/kg SCH23390 (d-f). Neither doses of SCH23390 reversed the SKF83959-induced decline in peak rates. The drug treatments did not affect the peak time. * P < 0.05; ** P < 0.01; *** P < 0.001 in comparison to respective vehicle (Experiment 1).

Click here to view


The results of 0.06 mg/kg SCH23390 treatments closely resembled the findings from administering the lower drug dose. One-way ANOVA indicated significant differences across treatment conditions in the numbers of total responses, F(3, 24) = 12.77, P < 0.001, reinforced responses, F(3, 24) = 6.79, P < 0.01, nonreinforced responses, F(3, 24) = 11.15 P < 0.001, and burst responses, F(3, 24) = 8.79, P < 0.001. As shown in the panel E through panel H of [Figure 4], post hoc test revealed that under the injection of SKF83959 alone, the rats performed with significant reductions in the numbers of total responses, P < 0.01, nonreinforced responses, P < 0.001, and burst responses, P < 0.01. Although the injections of 0.06 mg/kg SCH23390 alone did not have significant effects on the response-based indexes, they produced decreases in the numbers of total responses, nonreinforced responses, and burst responses to a greater extent than what was observed from 0.02 mg/kg SCH23390 injections. Under the injections of SKF83959 with 0.06 mg/kg SCH23390 pretreatment, the rats exhibited significantly decreased numbers of total responses, P < 0.001, reinforced responses, P < 0.01, nonreinforced responses, P < 0.001, and burst responses, P < 0.001. One-way ANOVA detected significant differences in peak rate, F(3, 24) =7.39, P < 0.01 [Figure 5]d, and MRE, F(3, 24) =3.38, P < 0.05 [Figure 5]f, across treatment conditions, whereas no significant differences in peak time were found [Figure 5]e. As shown in [Figure 5]d, post hoc tests indicated that the rats performed with significant reductions in the peak rate under the treatments of SKF83959 alone, P < 0.01, and SKF83959 pretreated with 0.06 mg/kg SCH23390, P < 0.01, but not under the treatment of 0.06 mg/kg SCH23390 alone. In [Figure 5]f, the rats performed with a significantly increased MRE ratio under the combined treatment of SKF83959 with high dose SCH23390, P < 0.05, but not under the sole treatment of SKF83959 or SCH23390. While the administration of 0.06 mg/kg SCH23390 alone did not produce significant effects on the peak rate, peak time, and MRE, it appeared to decrease the DRL10's peak rate to a greater extent than the treatment of 0.02 mg/kg SCH23390 alone.

Experiment 2: Examination of effects of eticlopride on SKF83959-altered operant behavior

FI 30-s performance. [Figure 6] illustrates the effects of 0.02 mg/kg and 0.06 mg/kg eticlopride on the IRT curve of FI30 performance. The treatment of 0.02 mg/kg eticlopride alone resulted in a curve very similar to that of vehicle treatment, whereas the treatments of 1.0 mg/kg SKF83959 alone and SKF83959 with low dose eticlopride resulted in more flattened curves that reflected decreases in response rates [Figure 6]a. In contrast, while the treatments of SKF83959 alone and combined with 0.06 mg/kg eticlopride similarly resulted in reduced response rates [Figure 6]b. Moreover, notice that the treatment of high dose eticlopride alone appeared to decrease responding to a greater extent than the administration of low dose eticlopride alone.
Figure 6: The fixed-interval 30 s inter-response time curve after eticlopride pretreatment in a within participants design (n = 9): 0.02 mg/kg eticlopride (a) and 0.06 mg/kg eticlopride (b). Low dose eticlopride appeared to partially reverse the SKF83959-induced decline in response frequency on the fixed-interval 30 s schedule, while high dose eticlopride did not have such an effect (Experiment 2).

Click here to view


As shown in [Figure 7]a, [Figure 7]b, [Figure 7]c, one-way ANOVA on each of the FI30 indexes showed that the treatment conditions had significant effects on the numbers of total responses, F(3, 24) = 6.54, P < 0.01, reinforced responses, F(3, 24) = 10.87, P < 0.001, and PRP, F(3, 24) = 7.17, P < 0.01. Post hoc tests found the treatment of SKF83959 alone to significantly reduce the numbers of total responses, P < 0.01 [Figure 7]a, and reinforced responses, P < 0.01 [Figure 7]b, while not producing significant effects on the PRP [Figure 7]c. The treatment of low dose eticlopride alone did not have significant effects on any of these indexes. In contrast, the condition of SKF83959 pretreated with low dose eticlopride produced a near-significant decrease in the number of total responses relative to vehicle, P = 0.061, at the same time significant drops in the number of reinforced responses, P < 0.01 and increased PRP duration, P < 0.01, were observed. Under 0.06 mg/kg eticlopride treatments [Figure 7]d, [Figure 7]e, [Figure 7]f, significant drug effects were detected on total responses, F(3, 24) = 3.62, P < 0.05, reinforced responses, F(3, 24) = 7.62, P < 0.001, and PRP, F(3, 24) = 3.02, P < 0.05. Post hoc tests showed that the treatment of SKF83959 alone had a near-significant effect on decreasing the total responses, P = 0.058 [Figure 7]d. It has significantly reduced the reinforced responses, P < 0.01 [Figure 7]e, without affecting the duration of the PRP [Figure 7]f. The administration of high-dose eticlopride alone did not have significant effects on these indexes despite a trend of a slight decrease in the total response. Alternatively, when SKF83959 was pretreated with high-dose eticlopride, the rats exhibited significant decreases in the numbers of total responses (P < 0.05) and reinforced responses (P < 0.05) and a significant increase in the duration of PRP (P < 0.05).
Figure 7: Total responses, reinforced responses, and postreinforcement pause measured in fixed-interval 30 s behavior after eticlopride pretreatment (n = 9): 0.02 mg/kg eticlopride (a-c) and 0.06 mg/kg eticlopride (d-f). Low dose eticlopride had a partial reversal effect on the SKF83959-induced decline in total response rate on the fixed-interval 30 s schedule. * P < 0.05; ** P < 0.01 relative to vehicle (Experiment 2).

Click here to view


DRL 10-s performance. [Figure 8] displays the effects of 0.02 mg/kg and 0.06 mg/kg eticlopride alone and pretreated with SKF83959 on the IRT distribution of DRL10 performance. One of the nine rats (#2) was removed from the statistical analysis because it exhibited seizure-like symptoms during the progress of behavioral testing. As shown in [Figure 8]a, the injection of low dose eticlopride alone resulted in a curve very similar to that of the vehicle treatment. SKF83959 alone reduced the height of the curve, while SKF83959 pretreated with low dose eticlopride reduced the response rate on DRL10 to a lesser extent than SKF83959 alone. In contrast, the injections of high dose eticlopride alone and SKF83959 alone both reduced the response rates on the IRT curve. Moreover, the administration of SKF83959 pretreated with high dose eticlopride drastically flattened the IRT distribution curve [Figure 8]b.
Figure 8: The differential reinforcement of low-rate response 10 s inter-response time curve after eticlopride pretreatment in a within-subjects design (n = 8): 0.02 mg/kg eticlopride (a) and 0.06 mg/kg eticlopride (b). Low dose eticlopride appeared to partially reverse the SKF83959-induced decline in response frequency on the differential reinforcement of low-rate response 10 s schedule, while high dose eticlopride almost completely diminished the response frequency (Experiment 2).

Click here to view


In the examination of the response-based indexes of the DRL10 task, one-way ANOVA revealed significant differences across low dose eticlopride treatments in the numbers of total responses, F(3, 21) = 4.65, P < 0.05 [Figure 9]a, and non-reinforced responses, F(3, 21) = 4.08, P < 0.05 [Figure 9]c, but not for the numbers of reinforced responses [Figure 9]b and burst responses [Figure 9]d. Post hoc analysis showed the treatment of SKF83959 alone to reduce the total response, P < 0.05 [Figure 9]a, and non-reinforced response, P < 0.05 [Figure 9]c, on the DRL10 task. The respective treatments of low dose eticlopride alone and SKF83959 pretreated with low dose eticlopride did not produce significant effects on the response-based indexes, although a trend of decrease was observed in the latter treatment. Apart from these response-based indexes, one-way ANOVA has found significant differences across treatment conditions on the peak rate of DRL 10-s performance, F(3, 21) = 8.10, P < 0.001. As shown in [Figure 10]a, post hoc test indicated that the rats performed with significantly reduced peak rates when they were treated solely with SKF83959, P < 0.01. The conditions of low dose eticlopride alone and SKF83959 pretreated with low dose eticlopride did not produce significant effects on peak rate, although the latter treatment produced a trend of decrease. One-way ANOVA did not find significant differences in peak time [Figure 10]b or MRE [Figure 10]c across the treatment conditions with low dose eticlopride.
Figure 9: The differential reinforcement of low-rate response 10 s response-based indexes after eticlopride pretreatment (n = 8): 0.02 mg/kg eticlopride (a-d) and 0.06 mg/kg eticlopride (e-h). Low dose eticlopride had a partial reversal effect on the SKF83959-induced declines in response rates on the differential reinforcement of low-rate response 10 s schedule. High dose eticlopride did not have such an effect. * P < 0.05; *** P < 0.001 relative to vehicle (Experiment 2).

Click here to view
Figure 10: The peak rate, peak time, and modified response efficiency measured in differential reinforcement of low-rate response 10 s behavior after eticlopride pretreatment (n = 8): 0.02 mg/kg eticlopride (a-c) and 0.06 mg/kg eticlopride (d-f). Low dose eticlopride had a partial reversal effect on the SKF 83959-induced decline in peak rate. High dose eticlopride did not have such a reversal effect. ** P < 0.01; *** P < 0.001 in comparison to the respective vehicle (Experiment 2).

Click here to view


Under the treatment conditions of high dose eticlopride [Figure 9]e, [Figure 9]f, [Figure 9]g, [Figure 9]h, one-way ANOVA yielded significant drug effects in all four response-based indexes across conditions: Total responses, F(3, 21) = 27.27, P < 0.001, reinforced responses, F(3, 21) = 16.14, P < 0.001, non-reinforced responses, F(3, 21) = 9.91, P < 0.001, and burst responses, F(2, 14) = 5.03, P < 0.05. The sole administration of SKF83959 significantly reduced the numbers of total responses, P < 0.001 [Figure 9]e, reinforced responses, P < 0.05 [Figure 9]f, nonreinforced responses, P < 0.05 [Figure 9]g, and burst responses, P < 0.05 [Figure 9]h. The sole administration of high dose eticlopride did not have significant effects on these response-based indexes. The administration of SKF83959 with high dose eticlopride pretreatment reduced the numbers of total responses, P < 0.001, and reinforced responses, P < 0.001, to a greater extent than the effects of SKF83959 alone. It actually diminished the average numbers of non-reinforced response down to 1.25, P < 0.001, and burst responses to zero. As shown in panels d, e, and f of [Figure 10], one-way ANOVA has also found significant differences in peak rate, F(3, 21) = 39.99, P < 0.001, peak time, F(3, 21) = 9.81, P < 0.001, and MRE, F(3, 21) = 5.22, P < 0.01, across the treatment conditions. Post-hoc test found the sole treatment of SKF83959 to significantly reduce the peak rate, P < 0.01 [Figure 10]d, without significantly affecting the peak time [Figure 10]e or the MRE [Figure 10]f. The administration of high dose eticlopride alone did not produce significant effects on the peak rate, peak time, or the MRE of DRL10. Alternatively, the treatment of SKF83959 with high dose eticlopride significantly reduced the peak rate, P < 0.001, whereas it significantly increased the peak time, P < 0.01, and the MRE ratio, P < 0.01.


  Discussion Top


The present study sought to determine whether SCH23390 or eticlopride could pharmacologically reverse operant behavior altered by SKF83959. The results of this study showed the profound effects of SKF83959 alone on FI30 and DRL10 schedule-controlled behaviors which effectiveness is dependent on baseline response rate. The administration of SCH23390 or eticlopride alone had little effect on FI30 and DRL10 behaviors. Moreover, the pretreatment of noneffective dose of SCH23390 or eticlopride did not reverse SKF83959-altered operant response on either task, except the low dose of eticlopride tested on the measures of total response and peak arte of DRL10 behavior.

Differential effects of SKF83959 on fixed-interval 30 s and differential reinforcement of low-rate response 10 s behaviors

Consistent with those reported in the other study from this laboratory,[30] the effects of SKF83959 on rat's operant response were profound. However, these effects were differential between the FI30 and DRL10 tasks in terms of the magnitudes of drug effect. Namely, the drug is more potent in affecting FI30 behavior than DRL10 behavior on response-related measures. Relative to the vehicle, the acute administration of SKF83959 reduced the total responses on the FI30 schedule by approximately six folds and decreased that on the DRL10 schedule by about two folds. The observed difference in drug effects may be attributed to distinct motivation/cognitive demands in the FI and DRL tasks, despite the timing process involved in common. In terms of response rate, FI behavior is apparently higher than DRL behavior. The rats trained on DRL schedule were required to withhold lever pressing for a minimum specified period of time (i.e., 10 s here) to obtain a chance that the response results in the attainment of the reinforcer. Any “premature” response made before the interval elapsed leads to no reinforcement and also resets the interval clock, which is critically different to the reinforcement contingency required for FI behavior. The present findings of SKF83959 treatment alone lend additional support to the view of the hypothesis of response rate dependency addressed in behavioral pharmacology;[29] that is, the effectiveness of a particular drug on behavior could be dependent on the baseline response rate maintained in the behavioral task.

Pharmacological reversal effect of dopamine receptor antagonist is minimum

The results of pharmacological test in the present study on a whole show that the pretreatment of SCH23390 or eticlopride did not reverse SKF83959-altered operant response on either task. Using the strategy of pharmacological antagonism similar to that reported here, Deveney and Waddington[39] tested the respective pretreatments of the D1 DAR antagonists (SCH23390 and BW737C) and the D2 DAR antagonist (YM09151-2) before SKF83959 injections on the behaviors of intense grooming and vacuous chewing in rats. The respective administrations of D1 and D2 DAR antagonists successfully reversed the SKF83959-induced increases in intense grooming, whereas the D1 DAR antagonists failed to exhibit the same reversal effects on SKF83959-induced increases in vacuous chewing, and the D2 DAR antagonist actually enhanced such an effect.[39] The treatments of D1 and D2 DAR antagonists yielded different patterns of reversal effects on SKF83959-increased grooming and chewing responses. Hence, the relationship between different behavioral tasks under drug treatment and the underlying pharmacological interactions appears to be more complex than previously anticipated.

With respect to biochemical assay, Rashid et al.[20] reported that the respective pretreatments of SCH23390 and raclopride (a D2 receptor antagonist) blocked the activation of the CaMKII by co-administered SKF83959 and quinpirole (a D2 receptor agonist). Moreover, D1 and D2 DAR knock-out mice did not exhibit the same pattern of increases in CaMKII levels upon SKF83959 and quinpirole co-administration.[20] Similarly, in vitro assays of the incorporation of G proteins using radioactively labelled GTP in D1 and/or D2 receptors expressing HEK cells and membrane preparations from mice striatum have found the co-administration of SKF83959 with quinpirole to activate Gq/11 proteins, which was also blocked by the pretreatments of either SCH23390 or raclopride.[20] The activation of striatal phosphorylation of CaMKII by SKF83959 injections (1.0 mg/kg) in vivo was blocked either pretreatments of SCH23390 (1.0 mg/kg) or raclopride (0.5 mg/kg).[40] These findings indicate the crucial involvement of both D1 and D2 receptors in the pharmacological mechanism of SKF83959. Unfortunately, to date, this observation has not been tested in the behavioral models at the level of instrumental/operant conditioning.

In opposition to our hypothesis, neither doses of SCH23390 pretreatments (0.02 or 0.06 mg/kg) had successfully reversed the SKF83959-induced reductions in response rates on the FI30 and DRL10 schedules of reinforcement. While Ng et al.[40] observed the respective pretreatments of SCH23390 and raclopride to biochemically reverse the drug-induced increases in striatal phospho-CaMKII, it was noted that the DAR antagonists were employed in much higher doses (1.0 and 0.5 mg/kg) relative to those in the present study (0.02 and 0.06 mg/kg). The application of DAR antagonists at such high doses was effective in reversing the biochemical effects of SKF83959, but it is supposed to impair the rat's behavioral performance which renders it unsuitable for use in the present study. Other studies have reported finding the pharmacological antagonism of SKF83959-induced behaviors to show mixed patterns as described above.[39] Hence, the absence of reversal effects by SCH23390 reported here may be attributed to the factors of dose-related or task-specific differences from other studies.

The present pretreatment of low-dose eticlopride appeared to significantly antagonize the SKF83959-induced declines in the total responses [Figure 9]a and peak rate [Figure 10]a of DRL10 behavior. Intriguingly, similar reversal effects were not observed with the pretreatment of high-dose eticlopride. Previous reports on the effects of D2 DAR antagonists in counteracting SKF83959 also suggested behavior-dependent differences. For example, the pretreatments of YM09151-2 reversed SKF83959-induced increases in intense grooming, but it enhanced the increases in vacuous chewing by SKF83959 treatments.[39]

Assays of competition binding between SKF83959 and radioactively labelled raclopride on D2 receptors in D1-D2 co-expressing HEK cells revealed that SKF83959 bound to D1-D2 HEK cells with a higher affinity than only D2 expressing HEK cells, and this binding was not eliminated upon treatments with pertussis toxin which disrupt the D2-receptor-mediated Gi/o protein activation.[20] These findings suggested that SKF83959 bound with higher affinities to a pertussis toxin-resistant binding site on the D2 receptors that did not couple to Gi/o activation.[20] Thus, it is possible that the pretreatment of 0.02 mg/kg eticlopride binding to D2 receptor could interfere the availability of binding site for SKF83959; which blocked Gq-mediated CaMKII activation to exhibit a partial reversal effect in the drug-reduced response rates. Surprisingly, similar effects of antagonism were not observed in the pretreatments of eticlopride at 0.06 mg/kg in the present study. Moreover, the co-administration of SKF83959 with the high dose eticlopride greatly diminished DRL10 responding and significantly increased the peak time, suggesting that the dose might have been too high for the present behavioral measures.

Study limitations

The task of finding potentially effective doses of DAR antagonists that could antagonize the behavioral effects of SKF83959 without affecting operant behaviors was challenging. The present low-dose DAR antagonists used may have been too low to achieve a reversal effect; more combinations of relatively higher doses (e.g., 0.4 mg/kg) may need to be tested. Alternatively, a lower dose of SKF83959 (e.g., 0.75 mg/kg) can be considered to test with the pretreatment of DAR antagonist, given it is still effective in altering operant behavior. Furthermore, with regard to the experiment of pharmacological antagonism, as the present drug administrations were given through the peripheral route that were assumed to affect the whole brain, future work with an approach to conduct brain-region specific microinjection may provide more direct evidence on the specific sites of SKF83959 actions as injected alone or in combined with DAR antagonist. Furthermore, a growing body of evidences suggests that sex differences in the effects of psychoactive drugs may exist in mammals. Female rats were recently reported to be more susceptible to the pro-depressive and anxiogenic-like effects produced by SKF83959 than male rats.[26] Thus, with a notion that the present study only tested the male rats, further studies may recruit female participants comparing with male subject to test the sex differences of the effects of SKF83959 on the present operant tasks.


  Conclusions Top


The present study investigated whether the behavioral effects of SKF83959, an atypical DA D1 receptor agonist, could be reversed by selective D1 and D2 DAR antagonists. Task-dependent differences in SKF83959-altered operant response were manifested by rats in FI30 and DRL10 schedules of reinforcement. The absence of pharmacological reversal effect by SCH2330 or eticlopride indicates that the operant behavior altered by SKF83959 is dispensable to either D1 or D2 DAR. Notwithstanding the null effect of DAR blockade, the results from the present study add to an emerging body of literature in evaluating the behavioral effects of SKF83959 and the underlying pharmacological mechanisms.

Financial support and sponsorship

This study was supported in part by grants from the Ministry of Science and Technology, Taiwan (MOST 104-2410-H-004-047-MY3).

Conflicts of interest

There are no conflicts of interest. Dr. Ruey-Ming Liao, an editor at Chinese Journal of Physiology, had no role in the peer review process of or decision to publish this article.



 
  References Top

1.
Bamford NS, Wightman RM, Sulzer D. Dopamine's effects on corticostriatal synapses during reward-based behaviors. Neuron 2018;97:494-510.  Back to cited text no. 1
    
2.
Haber SN, Knutson B. The reward circuit: Linking primate anatomy and human imaging. Neuropsychopharmacology 2010;35:4-26.  Back to cited text no. 2
    
3.
Phillips AG, Vacca G, Ahn S. A top-down perspective on dopamine, motivation and memory. Pharmacol Biochem Behav 2008;90:236-49.  Back to cited text no. 3
    
4.
Lammel S, Lim BK, Malenka RC. Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 2014;76:351-9.  Back to cited text no. 4
    
5.
Salamone JD, Correa M. The mysterious motivational functions of mesolimbic dopamine. Neuron 2012;76:470-85.  Back to cited text no. 5
    
6.
Neve KA, Seamans JK, Trantham-Davidson H. Dopamine receptor signaling. J Recept Signal Transduct Res 2004;24:165-205.  Back to cited text no. 6
    
7.
Nishi A, Kuroiwa M, Shuto T. Mechanisms for the modulation of dopamine D1 receptor signaling in striatal neurons. Front Neuroanat 2011;5:43.  Back to cited text no. 7
    
8.
Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 2011;63:182-217.  Back to cited text no. 8
    
9.
Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: From structure to function. Physiol Rev 1998;78:189-225.  Back to cited text no. 9
    
10.
Beninger RJ, Miller R. Dopamine D1-like receptors and reward-related incentive learning. Neurosci Biobehav Rev 1998;22:335-45.  Back to cited text no. 10
    
11.
Floresco SB, Magyar O. Mesocortical dopamine modulation of executive functions: Beyond working memory. Psychopharmacology (Berl) 2006;188:567-85.  Back to cited text no. 11
    
12.
Lauzon NM, Laviolette SR. Dopamine D4-receptor modulation of cortical neuronal network activity and emotional processing: Implications for neuropsychiatric disorders. Behav Brain Res 2010;208:12-22.  Back to cited text no. 12
    
13.
Seeman P. Schizophrenia and dopamine receptors. Eur Neuropsychopharmacol 2013;23:999-1009.  Back to cited text no. 13
    
14.
Vallone D, Picetti R, Borrelli E. Structure and function of dopamine receptors. Neurosci Biobehav Rev 2000;24:125-32.  Back to cited text no. 14
    
15.
Ferster CB, Skinner BF. Schedules of Reinforcement. New York: Appleton-Century-Crofts, Inc.; 1957.  Back to cited text no. 15
    
16.
Sanger DJ, Blackman DE. Operant behavior and the effects of centrally acting drugs. In: Boulton AA, Baker GB, Greenshaw AJ, editors, Neuromethods. Clifton, NJ: Humana Press; 1989. p. 299-334.  Back to cited text no. 16
    
17.
van Haaren F. Schedule-controlled behavior: Positive reinforcement. In: van Haaren F, editor. Techniques in the Behavioral and Neural Sciences. Methods in Behavioral Pharmacology. Vol. 10. Amsterdam: Elsevier; 1993. p. 81-99.  Back to cited text no. 17
    
18.
Neumeyer JL, Kula NS, Bergman J, Baldessarini RJ. Receptor affinities of dopamine D1 receptor-selective novel phenylbenzazepines. Eur J Pharmacol 2003;474:137-40.  Back to cited text no. 18
    
19.
Hasbi A, Pan T, Alijaniaram M, Nguyen T, Perreault ML, O'Dowd BF, et al. Calcium signaling cascade links dopamine D1-D2 receptor heteromer to striatal BDNF production and neuronal growth. Proc Natl Acad Sci U S A 2009;106:21377-82.  Back to cited text no. 19
    
20.
Rashid AJ, So CH, Kong MM, Furtak T, El-Ghundi M, Cheng R, et al. D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci U S A 2007;104:654-9.  Back to cited text no. 20
    
21.
Zhang ZJ, Jiang XL, Zhang SE, Hough CJ, Li H, Chen JG, et al. The paradoxical effects of SKF83959, a novel dopamine D1-like receptor agonist, in the rat acoustic startle reflex paradigm. Neurosci Lett 2005;382:134-8.  Back to cited text no. 21
    
22.
Desai RI, Neumeyer JL, Bergman J, Paronis CA. Pharmacological characterization of the effects of dopamine D1 agonists on eye blinking in rats. Behav Pharmacol 2007;18:745-54.  Back to cited text no. 22
    
23.
Stolzenberg DS, Zhang KY, Luskin K, Ranker L, Bress J, Numan M. Dopamine D1 receptor activation of adenylyl cyclase, not phospholipase C, in the nucleus accumbens promotes maternal onset in rats. Hormon Behav 2010;57:96-104.  Back to cited text no. 23
    
24.
Cools AR, Lubbers L, van Oosten RV, Andringa G. SKF 83959 is an antagonist of dopamine D1-like receptors in the prefrontal cortex and nucleus accumbens: A key to its antiparkinsonian effect in animals? Neuropharmacology 2002;42:237-45.  Back to cited text no. 24
    
25.
Zhang H, Ma L, Wang F, Chen J, Zhen X. Chronic SKF83959 induced less severe dyskinesia and attenuated L-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease. Neuropharmacology 2007;53:125-33.  Back to cited text no. 25
    
26.
Hasbi A, Nguyen T, Rahal H, Manduca JD, Miksys S, Tyndale RF, et al. Sex difference in dopamine D1-D2 receptor complex expression and signaling affects depression- and anxiety-like behaviors. Biol Sex Differ 2020;11:8.  Back to cited text no. 26
    
27.
Shen MY, Perreault ML, Bambico FR, Jones-Tabah J, Cheung M, Fan T, et al. Rapid anti-depressant and anxiolytic actions following dopamine D1-D2 receptor heteromer inactivation. Eur Neuropsychopharmacol 2015;25:2437-48.  Back to cited text no. 27
    
28.
Platt DM, Rowlett JK, Spealman RD. Dissociation of cocaine-antagonist properties and motoric effects of the D1 receptor partial agonists SKF 83959 and SKF 77434. J Pharmacol Exp Ther 2000;293:1017-26.  Back to cited text no. 28
    
29.
Dews PB. Studies on behavior. I. Differential sensitivity to pentobarbital of pecking performance in pigeons depending on the schedule of reward. J Pharmacol Exp Ther 1955;113:393-401.  Back to cited text no. 29
    
30.
Liu PP, Chao CC, Liao RM. Task-dependent effects of SKF83959 on operant behaviors associated to distinct changes of CaMKII signaling in striatal subareas. Int J Neuropsychopharmacol (under revision) 2020.  Back to cited text no. 30
    
31.
Liao RM, Cheng RK. Acute effects of d-amphetamine on the differential reinforcement of low-rate (DRL) schedule behavior in the rat: Comparison with selective dopamine receptor antagonists. Chin J Physiol 2005;48:41-50.  Back to cited text no. 31
    
32.
Cheng RK, Liao RM. Dopamine receptor antagonists reverse amphetamine-induced behavioral alteration on a differential reinforcement for low-rate (DRL) operant task in the rat. Chin J Physiol 2007;50:77-88.  Back to cited text no. 32
    
33.
Fowler SC, Liou JR. Haloperidol, raclopride, and eticlopride induce microcatalepsy during operant performance in rats, but clozapine and SCH 23390 do not. Psychopharmacology (Berl) 1998;140:81-90.  Back to cited text no. 33
    
34.
Schindler CW, Carmona GN. Effects of dopamine agonists and antagonists on locomotor activity in male and female rats. Pharmacol Biochem Behav 2002;72:857-63.  Back to cited text no. 34
    
35.
Chiang FK, Cheng RK, Liao RM. Differential effects of dopamine receptor subtype-specific agonists with respect to operant behavior maintained on a differential reinforcement of low-rate responding (DRL) schedule. Pharmacol Biochem Behav 2015;130:67-76.  Back to cited text no. 35
    
36.
Cheng RK, MacDonald CJ, Meck WH. Differential effects of cocaine and ketamine on time estimation: Implications for neurobiological models of interval timing. Pharmacol Biochem Behav 2006;85:114-22.  Back to cited text no. 36
    
37.
Cheng RK, MacDonald CJ, Williams CL, Meck WH. Prenatal choline supplementation alters the timing, emotion, and memory performance (TEMP) of adult male and female rats as indexed by differential reinforcement of low-rate schedule behavior. Learn Mem 2008;15:153-62.  Back to cited text no. 37
    
38.
Wiley JL, Compton AD, Golden KM. Separation of drug effects on timing and behavioral inhibition by increased stimulus control. Exp Clin Psychopharmacol 2000;8:451-61.  Back to cited text no. 38
    
39.
Deveney AM, Waddington JL. Pharmacological characterization of behavioural responses to SK&F 83959 in relation to 'D1-like' dopamine receptors not linked to adenylyl cyclase. Br J Pharmacol 1995;116:2120-6.  Back to cited text no. 39
    
40.
Ng J, Rashid AJ, So CH, O'Dowd BF, George SR. Activation of calcium/calmodulin-dependent protein kinase IIalpha in the striatum by the heteromeric D1-D2 dopamine receptor complex. Neuroscience 2010;165:535-41.  Back to cited text no. 40
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]
 
 
    Tables

  [Table 1]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusions
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed705    
    Printed6    
    Emailed0    
    PDF Downloaded89    
    Comments [Add]    

Recommend this journal