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Published in final edited form as: Neurosci Lett. 2020 May 1;729:134987. doi: 10.1016/j.neulet.2020.134987

Chemogenetic Inhibition of Dopamine D1-expressing Neurons in the Dorsal Striatum does not alter Methamphetamine Intake in either Male or Female Long Evans Rats

Martin O Job 1,2, Michael R Chojnacki 1, Atul P Daiwile 1, Jean L Cadet 1
PMCID: PMC8153194  NIHMSID: NIHMS1592358  PMID: 32371155

Abstract

The biochemical and molecular substrates of methamphetamine (METH) use disorder remain to be elucidated. In rodents, increased METH intake is associated with increased expression of dopamine D1 receptors (D1R) in the dorsal striatum. The present study assessed potential effects of inhibiting striatal D1R expression on METH self-administration (SA) by rats. We microinjected Cre-activated adeno-associated viruses to deliver the inhibitory DREADD construct, hM4D (Gi) –mCherry, into neurons that expressed Cre-recombinase (D1-expressing neurons) in the dorsal striatum of male and female transgenic Long Evans rats (Drd1a-iCre#3). Two weeks later, we trained rats to self-administer METH. Once this behavior was acquired, intraperitoneal injections of clozapine-N-Oxide (CNO) or its vehicle (sterile water) were given to rats before each METH SA session to determine the effect of DREADD-mediated inhibition on METH intake. After the end of the experiments, histology was performed to confirm DREADD delivery into the dorsal striatum. There were no significant effects of the inhibitory DREADD on METH SA by male or female rats. Post-mortem histological assessment revealed DREADD expression in the dorsal striatum. Our results suggest that inhibition of D1R in the dorsal striatum does not suppress METH SA. It remains to be determined if activating D1R-expressing neurons might have differential behavioral effects. Future studies will also assess if impacting D1R activity in other brain regions might influence METH SA.

Keywords: dorsal striatum, dopamine D1, methamphetamine, chemogenetic, DREADD, self-administration

INTRODUCTION

Psychostimulant use disorders are among the leading causes of morbidity and mortality around the world. Understanding the basic mechanisms that drive excessive intake of psychostimulants is necessary for the development of data-based therapeutic intervention strategies. Acute administration of methamphetamine (METH) leads to increases in the actions of dopamine in several regions of the brain, including the ventral and dorsal striatum [1,2] where they act on dopamine receptors including the D1 and D2 subclasses of receptors [3]. Exposure to METH, by either investigator-administered drug or via self-administration (SA), is associated with changes in transcriptional factors, neurotrophins, and neuropeptides in the dorsal striatum [4–9]. Some of these METH-induced biochemical changes are associated with METH-induced stimulation of striatal D1R [5,6,9].

Dorsal striatal D1R may play a role in the SA of METH for several reasons. First, D1R plays a role in METH intake generally. For example, systemic administration of the selective D1 antagonist, SCH-23390, attenuated METH SA [10]. Second, METH SA is associated with increases in D1R expression in the dorsal striatum [11]. Third, as mentioned above, METH-induced stimulation of striatal D1R may exert biochemical changes in the striatum which in turn may influence METH taking behavior.

However, dorsal striatal D1R do not appear to play a role in the intake of another psychostimulant: cocaine [12–15]. More studies were needed to further clarify the role of D1R on METH intake. We designed METH SA experiments to investigate the potential effects of chemogenetic inhibition of D1R-containing striatal neurons in male and female transgenic Long Evans rats. As our study was ongoing, another group of investigators [16] reported that chemogenetic activation and inhibition of D1R in the dorsal striatum had no effect and enhanced METH intake, respectively. Our findings with regards to a role, or the lack thereof, of striatal D1R in METH self-administration are discussed.

MATERIALS AND METHODS

Animals

Male and female transgenic Long Evans (Drd1a-iCre#3) rats were obtained from the National Institute on Drug Abuse (NIDA) breeding facility in Baltimore, MD. These rats were generated to express the enzyme Cre-recombinase under the Drd1a promoter. All rats weighed between 300–350 grams before surgery. All procedures and treatments were approved by the National Institute on Drug Abuse Animal Care and Use Committee and followed the guidelines outlined in the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals. Rats were single housed on a 12-hour reversed light/dark cycle with free access to food and water. For this study a total of twelve male and twenty-six female rats were used.

Experimental Design

The experimental design is shown and described in Fig 1A. Intracranial injections of AAV (AAV1-hSyn-DIO-hM4D (Gi)-mCherry; Addgene #44362; titer: 9.57 × 10^11 VG/mL) and jugular catheter implantations, were performed to prepare rats for drug SA. The viral construct has been used and found to be efficacious by other labs [17]. For the intracranial intra-dorsal striatal injections, the following coordinates (from Bregma) [18] were used: A/P +1.6, M/L ±3.0, D/V −5.0. The AAV injection volume was 1 μL, and the injection was done over 5 min using 10-μL Hamilton syringes (Hamilton, Reno, NV) driven by microsyringe pump attached to a controller (World Precision Instruments, Sarasota, FL). The intravenous catheter insertion has been previously described [19]. The SA protocol for METH (0.1 mg/kg/infusion) was described previously [19]. The experimental timeline is shown in Fig 1B. Briefly, surgeries to implant jugular catheters for SA and intra-dorsal striatum injection of AAV carrying DREADD constructs for inhibition of D1-expressing neurons in the dorsal striatum were done (see example in 1F). After two weeks of recovery, rats were allowed to self-administer METH (or SAL) for 4 weeks. For the week after, vehicle or CNO (1 mg/kg i.p.) were injected 30 min before METH (or SAL) SA sessions every day, except the day immediately after the weekend recess. The next week, rats self-administered METH (or SAL) without any pretreatment injections. The week afterwards, rats that had received CNO previously now received vehicle, and vice versa. Thus, the CNO/vehicle administration was counterbalanced.

Fig 1. Experimental details and METH intake acquisition data for male and female transgenic Long Evans rats.

Fig 1.

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Fig A shows the experimental design. Fig B shows the experimental timeline. Fig C shows the METH intake time course during acquisition. Fig D shows the summation of METH intake over time during acquisition. Fig E shows the rate of change of average METH intake over time during acquisition. Fig F shows an example of histological analysis of injection site in the dorsal striatum. Data analysis summary: Mixed model analysis and two-way ANOVA, respectively, showed that there were no sex differences in METH intake time course or total METH intake (C, D). However, linear regression analysis showed that there were sex differences in the rate of change of METH intake with time during acquisition (E). After the experiments, we determined, via visual confirmation of mCherry staining, that the injections of the AAV were in the dorsal striatum. The AAV injections are represented by mCherry expression. The AAV injections were found mainly in the dorsal striatum. An example of AAV injection site in the dorsal striatum is shown (F).

Verification of injection sites

Rats were euthanized after the last testing day by decapitation. The brains were extracted and the brain region containing the incision site was cut out from the rest of the brain and fixed in 4% buffered paraformaldehyde (PFA) as a fixative. The brain tissue was stored in 4% PFA at 4°C. 60 μm sections were obtained using a cryostat (Leica CM3050 S; Leica Biosystems, Buffalo Grove, IL), placed on slides and stored at 4°C. The injection sites were identified using confocal microscope. Olympus cellSens Dimension 1.11 imaging software was used to obtain images at 0.63x, and images were analyzed with Image J software.

Statistics

We used mixed model ANOVA for the time course analysis, two-way ANOVA to analyze total METH intake and total infusions per week after treatment conditions and the rate of change of intake over time, and regression analysis to compare acquisition rate and CNO effects on METH intake in males and females. For outlier tests we used Grubb’s method in GraphPad Prism (GraphPad, San Diego, CA). Statistical significance was set at p < 0.05 for all analyses.

RESULTS

There were no sex differences in the METH intake over the training sessions.

The numbers of animals per experimental group are shown (Fig 1A). A Mixed Model ANOVA was used in analysis of the time course data with SEX (males, females), DRUG (SAL, METH) and TIME (sessions 1–20) as factors and METH intake as the dependent variable. This yielded the following: main effect of SEX [F (1, 36) = 2.81, P= 0.1026], DRUG [F (1, 36) = 31.74, P<0.0001], TIME (F (19, 670) = 5.27, P<0.0001], interactions for SEX × DRUG [F (1, 36) = 0.72, P=0.4028), SEX × TIME [F (19, 670) = 1.19, P=0.2587], DRUG × TIME [F (19, 670) = 3.65, P<0.0001] and SEX × DRUG × TIME [F (19, 670) = 0.34, P=0.9964). Analysis of the total METH intake over training sessions (summation of the number of METH infusions over training sessions) was done using 2-way ANOVA with SEX (males, females) and DRUG (SAL, METH) as factors. This yielded a main effect of DRUG [F (1, 34) = 27.59, P<0.0001], but no effect of SEX [F (1, 34) = 0.4410, P=0.5111] and no interaction [SEX × DRUG, F (1, 34) = 0.6137, P=0.4388]. This analysis showed that there were differences between METH intake and SAL intake time course (Fig 1C) and total intake (Fig 1D), but no differences between sexes.

We analyzed the rate of change of average METH intake over training sessions. To do this we employed linear regression modeling with the predictor variable (x-axis) as time (time1time20) and the criterion variable (y-axis) as average METH intake (Fig 1E). For females [F (1, 18) =106.4, P<0.0001, r = 0.923] and males [F (1, 18) =304.0, P<0.0001, r = 0.969], the equations that model METH intake over time for females and males, respectively, were 1.515 × (time) + 28.73 infusions and 2.333 × (time) + 30.18 infusions. There were significant differences (P =0.0002) between the slopes for males (slope = 2.333± 0.1338) and females (slope= 1.515± 0.1469), with males>females. This implies that the males acquire METH intake faster than females (Fig 1E).

CNO had no effect on METH intake in male and female rats.

Two females in the METH group were excluded because they were outliers. The dependent variable was the total METH intake per week expressed as percentage (%) change from baseline METH intake. The weeks when rats were without any pretreatment of either CNO or vehicle (the weeks before and between METH/SAL SA) were averaged and termed the baseline. For SAL (Fig 2A), Two-way ANOVA, with independent variables (Treatment (CNO, vehicle) and sex (males, females) yielded the following: No main effect of Treatment [F (2, 22) = 0.06756, P = 0.9349] and SEX [F (1, 11) = 3.089, P = 0.1066] and no SEX × Treatment interaction [F (2, 22) = 0.3971, P=0.6770]. For METH (Fig 2B), the following were obtained: No main effect of Treatment [F (2, 46) = 0.7921, P=0.4590] and SEX [F (1, 23) = 3.526, P=0.0731] and no interaction [F (2, 46) = 1.914, P= 0.1591]. The interpretation of the average weekly intake data is that there is no effect of CNO compared to vehicle in males or female rats.

Fig 2. Effect of CNO or vehicle injection on saline or METH intake in male and female rats.

Fig 2.

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Fig A shows the graph of total infusions for saline/week expressed as percent of baseline (untreated). Fig B shows the graph of total infusions for METH/week expressed as percent of baseline (untreated). Fig C and E show the correlation between weekly METH intake when there was no treatment and weekly METH intake following VEH or CNO in individual male and female rats, respectively. Each circle represents an individual rat (Fig C-H). Fig D and F are graphs of the slopes of the regression lines in C and E, respectively. Fig G shows the relationship between weekly METH intake after VEH and weekly METH intake after CNO in individual male and female rats, respectively. Fig H are graphs to show the comparison of the slopes estimated in Fig G for males and females. The summary is that neither CNO nor VEH altered weekly METH intake in males and females.

Linear regression analysis was used to determine if there were relationships between baseline METH intake (intake without any pretreatments) and intake after CNO and vehicle for individual male and female rats. For males, relative to baseline, the slopes of METH intake after vehicle and CNO were 0.9448 ±0.1174 and 0.8538 ± 0.1187, respectively (Fig 2C). For females, relative to baseline, the slopes of METH intake after vehicle and CNO were 1.188 ±0.1258 and 0.9466 ± 0.2104, respectively (Fig 2E). There are no differences for males (P=0.5946) and females (P=0.3327) between the slopes for CNO and vehicle (Fig 2D, F). This showed that for individual rats, their intake after CNO and vehicle were comparable to their baseline METH intake. We have a mathematical linear regression model that predicts that for males and females with comparable METH intake, the effects of CNO and vehicle are not different (Fig 2G, H).

DISCUSSION

Systemic administration of the selective D1 antagonist, SCH-23390 blocked psychostimulant SA [10,20–23], suggesting that D1R in several brain regions or specific areas such as the dorsal striatum might play a role in this behavior. For our study, we investigated the effects of chemogenetic inhibition of striatal D1R-containing neurons on METH intake using a SA paradigm. We found that there was no effect on METH intake per se, similar to studies that investigated the effects on cocaine intake of D1R inhibition using both chemogenetic and pharmacological approaches [12–15]. Our study contributes to the accumulated knowledge that suggests that, unlike in the ventral striatum [12,13,15,24,25], D1R in the dorsal striatum do not seem to play a role in psychostimulant intake.

Interestingly, we detected sex differences when the rate of change of METH intake over time was considered, corroborating a previous study from our lab and others [19,26,27] that had found that male rats escalated their intake faster than female rats. While, we show that there are no sex differences in METH intake as do some previous studies [28,29], a closer examination of those studies reveals that males did have a steeper slope for the rate of change of METH intake with time during acquisition though this was not analyzed in detail [28,29]. The regression model that we employed detected sex differences in the behavior of males and females even when this was not apparent in the level of their METH intake, making it a more sensitive analytical approach for future studies of this kind.

There are some limitations in our study with regards to CNO [30,31], which we had addressed with adequate controls. One limitation is that even though AAV injections were found mainly in the dorsal striatum in several animals, there were still detectable AAV expression in somatosensory cortical regions. We thus obtained a relative proportion showing the distribution between the two regions and excluded animals that showed injection regions with less than 90% mCherry expression in the dorsal striatum and higher than 10% in the cortical region. While it could be argued that D1R inhibition occurring at the level of the somatosensory cortex might have influenced our results, the fact that there are much lower levels of dopamine and D1R in the somatosensory cortex compared to the dorsal striatum [32,33] mitigate against that argument. In addition, D1R activation in the somatosensory cortex is ineffective in altering neuronal activity in that brain region [34] and D1R blockade in the cortex does not alter psychostimulant intake [35].

Another explanation for our negative findings may be related to the observations that reinforced behaviors, such as lever pressing, are reported to become dopamine-independent and/or striatum-independent once they are well-established. Therefore, disrupting dopamine neurotransmission may not affect such behavioral responses even though these behaviors may have been acquired, initially, via dopamine-dependent reinforcement processes [36–38].

In conclusion, we show that chemogenetic inhibition of D1R in the dorsal striatum does not alter METH intake in a SA model. Our studies confirm previous studies with cocaine, suggesting that psychostimulant intake does not appear to be dependent on activation of D1R in the dorsal striatum. Nevertheless, D1 receptors may still be involved in other stimulant-mediated behaviors, such as incubation of METH seeking, cue-induced reinstatement of cocaine-seeking, compulsive drug seeking, as well as relapses to drug taking [14,39–41]. Similar manipulations of other brain regions need to be executed to further dissect the role of D1R in METH SA-related behaviors. This finding adds to the field seeking to understand the functional neuroanatomy of METH intake.

Highlights.

  • METH intake is associated with increased expression of dopamine D1 receptors (D1R) in the dorsal striatum

  • However, it is not clear that D1R in the dorsal striatum play a role in METH intake

  • Chemogenetic Inhibition of D1R-expressing dorsal striatal neurons does not alter METH intake

  • D1R in the dorsal striatum do not appear to play a role in METH intake

ACKNOWLEDGEMENTS

This work is supported by the Department of Health and Human Services/ National Institutes of Health/ National Institute on Drug Abuse/ Intramural Research Program.

Footnotes

CONFLICTS OF INTEREST

The authors declare no conflict of interest.

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