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. Author manuscript; available in PMC: 2020 Sep 1.
Published in final edited form as: Behav Pharmacol. 2019 Sep;30(6):506–513. doi: 10.1097/FBP.0000000000000485

Optogenetic inhibition of the medial prefrontal cortex reduces methamphetamine-primed reinstatement in male and female rats

Rebecca Cordie a, Lisa M McFadden a
PMCID: PMC6685740  NIHMSID: NIHMS1526890  PMID: 31033525

Abstract

Preclinical findings suggest sex-differences exist in drug-seeking behavior following methamphetamine (METH) self-administration. The medial prefrontal cortex (mPFC), is thought to contribute to the reinstatement of drug-seeking in males. Glutamatergic neurons project from the prelimbic portion of the mPFC to various brain regions modulating activity; thus the prelimbic region of the mPFC is thought to contribute to drug-seeking behaviors. Although studied in males, little research has investigated this in females. The purpose of this study was to investigate if the prelimbic mPFC plays a role in METH-seeking behavior in both male and female rats. Animals were allowed to self-administer METH, and underwent extinction and two reinstatement sessions. Reinstatement sessions were counterbalanced such that optogenetic inhibition targeting the prelimbic cortex of the mPFC occurred only during one reinstatement session. Results revealed an increase in METH consumption during self-administration in male and female animals. During extinction, lever-pressing behavior decreased as training progressed. Under sham conditions, female rats exhibited significantly higher drug-seeking behavior during reinstatement. However, when optogenetic inhibition was applied, both male and female animals significantly decreased drug-seeking. In both males and females, the prelimbic mPFC plays an important role in drug-seeking behavior as related to METH use.

Keywords: Methamphetamine, self-administration, optogenetics, sex-differences, medial prefrontal cortex, rat

Introduction.

Methamphetamine (METH) addiction is a worldwide health problem. Recent epidemiological data suggest that METH use and overdoses are on the rise both within the United States and throughout the world (Warner et al., 2016; Darke et al., 2017). The use of METH contributes to negative consequences for not only the user but also society as a whole (Courtney & Ray, 2014; Enns et al., 2017). Despite these consequences, there are no broadly effective pharmacological treatments for METH addiction (Morley et al., 2017). Understanding the neurobiology underlying METH use is critical for developing effective pharmacological interventions.

Of importance, both males and females abuse METH. In the United States, approximately 40% of adult METH users and approximately 50% of adolescent METH users are female (Chen et al., 2014). Both preclinical and clinical studies suggest that sex-differences exist in METH use. In clinical studies, females report becoming addicted to METH at a younger age and have a greater severity of dependence compared to their male counterpart (Rawson et al., 2005; Dluzen & Liu, 2008). Similarly, some self-administration studies suggest that females may escalate METH-intake more readily than males (Kucerova et al., 2009; Roth & Carroll, 2004; Reichel et al., 2012). Additionally, studies suggest that females exhibit more drug-seeking behavior during the reinstatement of METH-seeking compared to their male counterpart (Holtz et al., 2012; Reichel et al., 2012; Cox et al., 2013). The development of interventions that are effective in both sexes is imperative for reducing METH use.

The medial prefrontal cortex (mPFC) is thought to play a critical role in the reinstatement of drug-seeking following the self-administration of psychostimulant drugs. Inactivation of the mPFC with γ-aminobutyric acid (GABA) agonists or tetrodotoxin reduced the cocaine-primed reinstatement of cocaine-seeking (Capriles et al., 2003; Peters et al., 2008). Further, optogenetic inhibition of the prelimbic cortex portion of the mPFC decreased cocaine and cue-primed reinstatement (Stefanik et al., 2013). Little is known about the role of this region following METH self-administration. Further, whether this brain region plays a similar role in drug-seeking in female rats has not been explored. Therefore, the goal of this study was to understand the role of the mPFC, in particular the prelimbic cortex, in the reinstatement of drug-seeking following psychostimulant self-administration in both males and females.

The purpose of this study was to investigate the role of the mPFC specifically targeting the prelimbic cortex during the reinstatement of METH-seeking in male and female rats. Male and female rats received bilateral injections of the inhibitory opsin into the prelimbic portion of the mPFC. After recovery, animals received METH self-administration, and two extinction and METH-primed reinstatement sessions. Results revealed that males and females self-administered similar amounts of METH during the 7 day period. Female rats had a greater reinstatement of drug-seeking behavior compared to males following a METH-priming injection under sham conditions. However, when the prelimbic portion of the mPFC was inhibited, both sexes reduced the reinstatement drug-seeking behaviors following METH-priming. These findings suggest that although sex-differences existed in drug-seeking behavior, modulation of activity in the prelimbic portion of the mPFC may serve as an effective intervention in both sexes.

Methods.

Subjects.

Adult male and female freely cycling Sprague Dawley rats (approximately 56 days old; Envigo) were housed in pairs by sex in transparent plastic cages. Following surgeries, each rat was housed individually. Rats were food restricted during food training however, no rat fell below 90% of their starting body weight. Water was freely available. Rats were maintained under the same 12:12 h light/dark cycle in the animal facility and in the operant chambers. All experiments were approved by the University of South Dakota’s Institutional Animal Care and Use Committee, in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and the University of South Dakota’s Internal Biosafety Committee.

Food Training.

A timeline of experimental protocols can be found in Figure 1. Using operant chambers (Coulbourn Instruments, Whitehall, PA USA), rats underwent four to five overnight food training sessions (14-h each) where rats were trained to press a lever for a 45 mg food pellet, as previously described (McFadden et al., 2012). Prior research has suggested that food training is not in itself sufficient to maintain lever-pressing behavior during the self-administration protocol used in the current study, because male and female saline self-administering rats rapidly extinguish active lever pressing during self-administration, whereas METH self-administering rats increase active lever pressing (Johansen et al., 2017). Food training was followed by surgeries to implant an indwelling catheter and to deliver the inhibitory opsin AAV2-CAG-ARCH-GFP into the mPFC targeting the prelimbic cortex.

Figure 1.

Figure 1.

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A timeline of experimental protocols. All animals underwent food training, surgeries, recovery, self-administration and 10 days of extinction. To account for individual differences in reinstatement behavior a counterbalanced, within-subject design was utilized. Half of the animals received optogeneitic inhibition of the prelimbic cortex (laser on) during the first session while remainder of animals received no optogenetic inhibition during this session (laser off). Following an additional 5 days of extinction training, a second reinstatement session was given utilizing the opposite optogenetic manipulation that was given in the first session, thus counterbalancing the manipulation.

Surgery.

Prior to surgeries, flunixin was administered as an analgesic, and was administered 24 h after surgery. Using ketamine HCl (100 mg/kg, i.p.) and xylazine HCl (Females: 5 mg/kg, i.p.; Males: 7 mg/kg, i.p.), animals were anesthetized. A jugular catheter was then implanted as previously described (McFadden et al., 2012). Each day through the duration of self-administration, catheters were flushed with 0.1 mL cefazolin followed by 0.05 mL heparin and 0.05 mL heparinized glycerol lock solution.

The injection of the opsin occurred immediately after the catheter implantation. Animals were placed in a stereotaxic frame (Stoelting, Wood Dale, IL USA), holes were drilled above the area of interest, and then an injection of opsin AAV2-CAG-ARCH-GFP (University of North Carolina Gene Therapy Center, Chapel Hill, NC USA; Lot: AV4568; 1.5 × 10e12 virus molecules per mL) was delivered bilaterally (0.7 µL at a rate of 0.7 µL/min) into the mPFC targeting the prelimbic cortex (4.2 mm anterior, 0.6 mm lateral, and 3.9 mm ventral to bregma at approximately a 13° angle), and the syringe was left in place for 7 min to allow for diffusion of the opsin. The use of a CAG promotor virus was chosen to be consistent with previous cocaine self-administration studies (see Stefanik et al., 2013; Suska et al., 2013; Stefanik et al., 2016). The holes in the skull were then filled with bone wax (CP Medical, Portland, OR USA), and the incision was sutured closed.

In a separate surgery on Day 7 or 8 of extinction training, the indwelling fiber optic probes (ceramic ferrules: O.D. 1.25 mm, fiber length: 4.5 mm, fiber NA: 0.37) were implanted stereotaxically through the holes used for injecting the opsin at approximately a 13° angle. In addition, two anchoring screws and dental acrylic were used to secure the optic probes. Dust caps were kept on the externalized end of the ferrule for the duration of the experiment when not in use.

Self-Administration and Extinction Training.

Following a short recovery period after catheter surgery, animals underwent 7 days of self-administration (8 h/day) of METH (Females: 0.09 mg/infusion; Males: 0.12 mg/infusion; concentrations expressed as free base), during the light cycle as previously described (Johansen & McFadden, 2017). The infusion concentrations of METH were chosen to be consistent with previous studies, to ensure animals that escalate intake without changing experimental parameters such as duration of each self-administration session or the ratio for response, and because it produces similar lever pressing and METH intake between experimental cohorts and sexes (see Johansen & McFadden, 2017 and citations within). Active lever presses resulted in the retraction of the levers, and an infusion of 10 uL of METH over 5 seconds. The levers remained retracted for 20 s following an infusion. Although recorded, inactive lever presses had no consequences. Only animals with patent catheters were included.

Animals then underwent 10 days (2h/day) of extinction training in the operant chambers, where rats were tethered as during self-administration. Lever presses were recorded, but did not have consequences. A METH-primed reinstatement session occurred as described below, which was followed by an additional 5 days of extinction training.

Optical Inhibition and METH-Primed Reinstatement.

Two METH-primed reinstatement sessions were given per rat. Briefly, animals were given a METH-priming injection (1 mg/kg, i.p.) approximately 10 min prior to the start of the session. This dose of METH was chosen on the basis of previous findings that it elicited maximal pressing in both male and female rats when a dose-response curve of METH-priming dose vs. reinstatement behavior was assessed (Reichel et al., 2012). Rats were connected to fiber-optic leashes via ceramic sleeves to the bilateral fiber-optic probes during the sessions. The fiber optic leashes were attached to a 2:1 splitter (Doric Lenses, Quebec, Canada) by FC/PC connectors (200 µm, 0.39 NA; Thor Labs, Trenton, New Jersey USA) to allow for bilateral stimulation. During optical inhibition sessions, a 561nm laser (300 mW; Opto Engine LLC, Midvale, UT USA) connected to the fiber optic cables was illuminated for the duration of the reinstatement session. Laser output was measured using a fiber optic power meter and was adjusted to provide 10 mW illumination.

A two-hour reinstatement session then occurred where levers were extended and presses were recorded but had no consequences. During one session, the laser was illuminated to produce optical inhibition of the prelimbic cortex for the entire duration of the session. During the other sham session, the laser was not illuminated. Sessions were counterbalanced such that approximately half of all animals received the optical inhibition during the first session and the other half received inhibition during the second session (see Figure 1).

Histology.

Rats were sacrificed one day after the last reinstatement session. Animals were overdosed with a pentobarbital cocktail (390 mg/mL; Vortech Pharmaceuticals, Dearborn, MI USA), and were perfused with 100 mL of PBS followed by 100 mL of 4% paraformaldehyde in PBS. Brains were then removed and stored in 4% paraformaldehyde overnight followed by 30% sucrose buffer until sliced. Coronal slices were taken of the mPFC to be evaluated for green florescent protein (GFP) to assess for the presence of the opsin through immunohistochemistry (Vectastain Elite ABC Kit; Vector Laboratories, Burlingame, CA USA). Tissues were washed in PBS solution, followed by a brief 10 min incubation in 5% blocking solution (normal goat serum). Next, sections were gently agitated and refrigerated 24 h in anti-GFP primary antibody (A11122, Invitrogen, Eugene, OR, USA) solution (2% goat serum, 0.4% Triton X, 1 µL primary antibody: 5 mL PBS; Vector Laboratories, Burlingame, CA USA). Sections were again washed in PBS followed by a 1 h incubation in biotinylated anti-rabbit secondary antibody solution (0.3% Triton X, 5 µL anti-rabbit secondary antibody: 1 mL PBS; Vector Laboratories, Burlingame, CA USA). Sections were incubated in ABC reagent for 1 h and developed using a DAB Peroxidase Substrate Kit (Vector Laboratories, Burlingame, CA USA). Tissues were mounted to a slide, allowed to dry, and cover slipped. Opsin expression and probe placement were then verified, and only rats with both opsin expression and optic probes terminating in the prelimbic cortex were used. Rats with insufficient expression of opsin in the prelimbic cortex or spread encompassing surrounding regions were excluded. Of note, animals that had probes placed outside the prelimibic cortex or that had insufficient spread of the virus did not exhibit reduced reinstatement behavior reinstatement when the laser was illuminated, further confirming that these animals were misses.

Drugs.

Rats were anesthetized with ketamine (90 mg/kg; VetOne, Boise, ID, USA) and xylazine (5–7 mg/kg; Sigma-Aldrich, St. Louis, MO, USA). Cefazolin (10 mg/mL; West Ward Pharmaceutical Corp, Eatontown, NJ, USA) was dissolved in heparin (63.33 U/ml; Sigma-Aldrich, St. Louis, MO, USA) and used as an antibiotic following surgery and for the extent of self-administration. Flunixin meglumine (1.1 mg/kg; VetOne, Boise, ID, USA) was administered as an analgesic prior to surgery. Racemic-METH hydrochloride (generously provided by the National Institute on Drug Abuse’s Drug Supply Program, Research Triangle Institute, Research Triangle Park, NC 27709, USA) dissolved in 0.9% sterile saline was used for METH self-administering rats. Prior to self-administration, catheter patency was tested with 0.1 mL methohexital sodium (10 mg/mL; Par Pharmaceutical Companies, Spring Valley, NY, USA) in all animals.

Statistical Analysis.

Statistical analysis occurred in GraphPad Prism (La Jolla, CA USA) or SAS Studio (North Cary, NC USA). Analyses of pressing behavior during self-administration, extinction training, and reinstatement sessions were conducted by a two-way repeated measures (ANOVA) followed by a Bonferroni posthoc test. Significance was determined by p<0.05. Graphs represent the mean ± the standard error of the mean of 7 to 8 rats per sex.

Results.

Self-Administration.

Animals were allowed to self-administer METH for 7 days (Figure 2). Daily METH intake was normalized to their daily body weight (mg METH infused/kg body weight), due to sex-differences in weight. Overall, METH self-administering rats increased consumption over the 7 days (Day: F(6,78)=81.07, p<0.05). No overall sex differences were observed (F(1,78)=0.24, NS), but there was a significant Day x Sex interaction (Day x Sex (F(1,78)=2.52, p<0.05): males had a greater increase in drug intake between Day 1 and Day 2 compared to females. Given that animals self-administered on a FR1, the active lever press findings mirrored that of METH intake (Sex: F(1,78)=0.06, NS; Day: F(6,78)=79.09, p<0.05; Sex x Day: F(6,78)=2.35, p<0.05; Figure 2B). Inactive lever pressing decreased with time (Day: F(1,78)=13.91, p<0.05). Only on the second day of self-administration were sex-differences in inactive lever pressing observed (Sex: F(1,78)=1.12, NS; Sex x Day: F(6,78)=5.98, p<0.05; Figure 2C).

Figure 2.

Figure 2.

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METH self-administration. A: Male and female METH self-administering rats had similar consumption over the course of the 7 days of self-administration, but both increased intake over the 7 days. Male rats had a slightly greater increase in METH intake between days 1 and 2 compared to females. B: Active lever presses mirrored METH intake during self-administration. C: Inactive lever presses decreased with time. On Day 2, males had significantly higher inactive lever presses compared to females, but no other differences between the sexes were noted. @p<0.05 Effect of Day; * p<0.05 Male vs. Female Increase from Day 1 to Day 2.

Extinction.

Following self-administration, animals underwent 10 days of extinction training where lever presses had no consequences (Figure 3A). As a result, a decrease in drug-seeking behavior occurred as measured by lever presses of the former active lever (Day: F(9,117)=12.17, p<0.05). No significant sex difference or Day x Sex interaction were observed during the first extinction session (Sex: F(1,117)=3.67, p=0.08; Sex x Day: F(9,117)=1.43, NS). No significant differences in lever presses of the formerly active lever were observed either between the sexes during the extinction session on the day prior to the first reinstatement session (t(13)=1.03, NS), or in pressing of the formerly inactive lever (Sex: F(1,117)=0.33, NS; Day: F(9,117)=1.74, NS; Sex x Day: F(9,117)=1.14, NS; Figure 3B).

Figure 3.

Figure 3.

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Extinction training. A: Rats underwent 10 days of extinction training where lever presses had no consequences. As a result, a decrease in drug-seeking behavior occurred over time, as assessed by the pressing of the formerly active lever. B: No significant differences were observed in the pressing of the formerly inactive lever during the first 10 days of extinction training. C: After the first reinstatement session, a second extinction session occurred. Male rats had an increase in drug-seeking behavior compared to females, as assessed by the pressing of the formerly active lever. D: No significant differences in the pressing of the former inactive lever were observed during the second extinction session. @p<0.05 Effect of Day; *p<0.05 Male vs. Female.

After the first METH-primed reinstatement, which was after Day 10 of extinction training, a second block of extinction sessions occurred (Figure 3C). During this second extinction block, males had increased lever-pressing behavior on the formerly active lever compared to females (Sex: (1,52)=6.48, p<0.05), which was partially driven by males having a greater number of lever presses compared to females on the first day of this extinction period (Sex x Day: F(4,52)=2.48, p=0.056; Day: F(4,52)=0.57, NS). No significant differences between the sexes were observed in the pressing of the formerly active lever on the last day of this extinction period (t(13)=1.14, NS), or in pressing of the formerly inactive lever (Sex: F(1,52)=0.56, NS; Day: F(4,52)=0.99, NS; Sex x Day: F(4,52)=0.69, NS; Figure 3D).

Reinstatement.

A METH-priming injection (1 mg/kg) was used to reinstate drug-seeking behavior (Figure 4A). Females showed significantly higher drug-seeking behavior than males, as evidenced by lever presses on the formerly active lever during reinstatement, when the laser was off (Sex: F(1,13)=3.36, p=0.09; Laser x Sex: F(1,13)=8.12, p<0.05). When the laser was on, drug-seeking was decreased in both males and females (Laser: F(1,13)=32.02, p<0.05). No significant differences were noted in the pressing of the inactive lever (Sex: F(1,13)=2.36, NS; Laser: F(1,13)=0.03, NS; Sex x Laser: F(1,13)=0.01, NS; Figure 4B). Finally, there was no significant difference in reinstatement behavior as measured by presses on the formerly active lever in those that received the sham conditions during the first reinstatement session versus the second session (Session: F(1,11)=0.29, NS; Sex: F(1,11)=3.57, NS; Sex x Session: F(1,11)=0.39, NS), suggesting that the order of receiving the optogenetic manipulation did not change reinstatement behavior. Following the last reinstatement session, animals were sacrificed and histology was preformed to confirm the opsin and probe placement (Figure 4C).

Figure 4.

Figure 4.

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Reinstatement of drug-seeking and histological confirmation. A: Animals received a 1 mg/kg priming injection of METH approximately 10 min prior to each reinstatement session. The reinstatement sessions were counterbalanced such that half of the animals received optogenetic inhibition during the first session whereas the other half received inhibition during the second session. When the laser was off, female rats had greater drug–seeking behavior compared to males, as assessed by pressing of the formerly active lever. However, both sexes showed a reduction in drug-seeking behavior when the laser was used to induce optogenetic inhibition of the mPFC. B: Pressing of the formerly inactive lever did not change with optogenetic inhibition. C: Representative histology of opsin and probe placement (represented by the triangles). The dashed lines represent the approximate boundaries of the prelimbic cortex. *p<0.05 Male vs. Female in Laser Off Condition. $ p<0.05 Laser Off vs. Laser On Condition.

Discussion.

Overall, the findings of the current study suggest that the prelimbic portion of the mPFC is important for the reinstatement of METH-seeking in both males and females. Males and females self-administered similar amounts of METH over the course of the 7 days. Despite consuming similar amounts of METH, under sham conditions, females exhibited a greater reinstatement of drug-seeking behaviors following a METH-priming injection. Although these sex-differences occurred in sham conditions, when optogenetic inhibition of the prelimbic portion of the mPFC occurred during the reinstatement of drug-seeking, no sex-differences occurred. Further, the inhibition of the mPFC reduced drug-seeking behavior in both sexes. Lastly, this reduction in pressing behavior by optogenetic inhibition was specific to the pressing of the formerly active lever. Pressing of the formerly inactive lever did not differ in sham or optogenetic inhibition conditions suggesting that these changes are not simply due to a reduction in motor activity. These findings suggest that the prelimbic portion of the mPFC may play an important role in METH-induced reinstatement of drug-seeking in both sexes.

Previous studies utilizing cocaine self-administration suggest that the mPFC is important for the reinstatement of drug-seeking in male rats. Optogenetic inhibition of the prelimbic cortex following cocaine self-administration reduced cocaine or cue-primed reinstatement of drug-seeking (Stefanik et al., 2013; Martin-Garcia et al., 2014). Similarly, inactivation of the dorsal mPFC by drugs such as tetrodotoxin, lidocaine, or GABA agonists also reduced drug-primed reinstatement of cocaine-seeking (Capriles et al., 2003; Di Pietro et al., 2006; Vassoler et al., 2013). Cue-induced reinstatement of cocaine-seeking was also attenuated by inactivating the mPFC pharmacologically (McLaughlin & See, 2003; Di Pietro et al., 2006; Gipson et al., 2013). Further, inactivation of the dorsal mPFC by tetrodotoxin or GABA agonists blocked stress and drug-primed reinstatement of cocaine-seeking (Capriles et al., 2003; McFarland et al., 2004). The importance of the dorsal mPFC in the reinstatement of drug-seeking may not be limited to cocaine.

Similarly, previous studies suggest that the prelimbic portion of the mPFC is also important for the reinstatement of METH-seeking. Microinfusions of lidocaine into the prelimbic cortex of male rats reduced METH- and cue-primed reinstatement of drug-seeking behavior (Hiranita et al., 2006). However, microinfusions of lidocaine into the infralimbic cortex had no effect on drug-seeking behavior after cue- or METH-priming (Hiranita et al., 2006). Similarly, infusion of GABAa/GABAb agonists into the prelimbic cortex reduced METH- and cue-primed reinstatement of drug-seeking following METH self-administration in male rats (Rocha & Kalivas, 2010). In contrast to METH and cocaine, bilateral inactivation of the prelimbic cortex with GABA receptor agonists did not change reinstatement behavior for sucrose-seeking following sucrose self-administration, suggesting that the prelimbic cortex may not play a role in all rewarding behaviors (Schmidt et al., 2005). These findings suggest activation of the mPFC, in particular the prelimbic cortex, plays a critical role in the reinstatement of drug-seeking in male rats following METH self-administration but did not provide any insight into this behavior in females, although they account for 40% of METH users in the clinical population. Similar to prior work with psychostimulants, the current study found that inhibition of the prelimbic portion of the mPFC via optogenetic manipulation, reduced drug-seeking following METH-priming in animals with a history of METH self-administration. However, the current study extended these findings in that inhibition of the prelimbic portion of the mPFC was effective in both males and females following METH self-administration.

Although sex-differences in the reinstatement of psychostimulant drug-seeking is well established, few studies have sought to test interventions in both sexes. Consistent with findings in the current study, others have observed greater drug-seeking behavior in females compared to males following a METH-priming injection (Holtz et al., 2012; Reichel et al., 2012; Cox et al., 2013). Of note, the stage of the estrous cycle does not seem to influence the reinstatement of METH-seeking (Cox et al., 2013; Westenbroek et al., 2017), suggesting that factors beyond circulating hormone levels may also play a role in differences in reinstatement behavior in females. To our knowledge, this is the first study to investigate the use of optogenetics to inhibit drug-seeking in both males and females following METH self-administration. Given greater drug-seeking behavior in females compared to males during sham conditions, it is unknown whether inhibition of the prelimbic portion of the mPFC would produce similar effects between the sexes. Optogenetic inhibition not only decreased drug-seeking behavior in both sexes, but also reduced lever pressing behavior in the females to that similar to males. This may suggest that alteration in the prelimbic portion of the mPFC may play an important role in reinstatement behavior in both sexes.

Overall, the current study suggests that the prelimbic portion of the mPFC plays an important role in the reinstatement of drug-seeking following a METH-priming injection. Further, optogenetic inhibition of this brain region reduced sex differences in drug-seeking behavior. The prelimbic cortex and its projecting fibers likely play an important role in drug-seeking behavior and may be a good target for both males and females following METH use.

Acknowledgments

Funding: This work was supported by the National Institutes of Health (grant numbers: DA036012, DA033674, GM115458). These agencies had no further role in the study design, the collection, analysis and interpretation of data, the writing of the report, and the decision to submit the article for publication.

Acknowledgements: Methamphetamine was generously supplied by the National Institute on Drug Abuse, National Institute of Health, Bethesda, MD. We would also like to thank Drs. Ryan LaLumiere and Mary Huffman for their technical assistance and Ms. Alexandra Dolezal and Marie Severson for their editing assistance.

Footnotes

Conflict of Interest: The authors have no conflicts of interest to disclose.

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