Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2021 Aug 5.
Published in final edited form as: Eur J Pharmacol. 2020 May 13;880:173175. doi: 10.1016/j.ejphar.2020.173175

Partial MHC/neuroantigen peptide constructs attenuate methamphetamine-seeking and brain chemokine (C-C motif) ligand 2 levels in rats

Jennifer M Loftis a,b,c, Tommy Navis d, Jonathan Taylor a,b, Rebekah Hudson a, Ulziibat Person b, K Matthew Lattal d, Arthur A Vandenbark a,e,f, Renee Shirley g, Marilyn Huckans a,b,c,h
PMCID: PMC7326336  NIHMSID: NIHMS1596193  PMID: 32416183

Abstract

There are no medications that target the neurotoxic effects or reduce the use of methamphetamine. Recombinant T-cell receptor ligand (RTL) 1000 [a partial major histocompatibility complex (pMHC) class II construct with a tethered myelin peptide], addresses the neuroimmune effects of methamphetamine addiction by competitively inhibiting the disease-promoting activity of macrophage migration inhibitory factor to CD74, a key pathway involved in several chronic inflammatory conditions, including substance use disorders. We previously reported that RTL constructs improve learning and memory impairments and central nervous system (CNS) inflammation induced by methamphetamine in mouse models. The present study in Lewis rats evaluated the effects of RTL1000 on maintenance of self-administration and cue-induced reinstatement using operant behavioral methods. Post-mortem brain and serum samples were evaluated for the levels of inflammatory factors. Rats treated with RTL1000 displayed significantly fewer presses on the active lever as compared to rats treated with vehicle during the initial extinction session, indicating more rapid extinction in the presence of RTL1000. Immunoblotting of rat brain sections revealed reduced levels of the pro-inflammatory chemokine (C-C motif) ligand 2 (CCL2) in the frontal cortex of rats treated with RTL1000, as compared to vehicle. Post hoc analysis identified a positive association between the levels of CCL2 detected in the frontal cortex and the number of lever presses during the first extinction session. Taken together, results suggest that RTL1000 may block downstream inflammatory effects of methamphetamine exposure and facilitate reduced drug seeking—potentially offering a new strategy for the treatment of methamphetamine-induced CNS injury and neuropsychiatric impairments.

Keywords: Brain, Chemokine, Drug discovery, Inflammation, Psychostimulant, Self-administration

1. Introduction

To successfully treat methamphetamine use disorder and reduce the social, economic, and environmental costs, new interventions are needed that help people regain lost function, re-engage in meaningful work and relationships, and refrain from continued use of methamphetamine. Our research and an expanding literature indicate that neuroimmune effects play a critical role in perpetuating the neuronal injury and neuropsychiatric impairments associated with methamphetamine and other drugs of abuse [reviewed in (Crews et al., 2011; Hutchinson and Watkins, 2014; Loftis and Janowsky, 2014; London et al., 2015)]. Protracted abstinence reverses some methamphetamine-induced brain insults (e.g., reductions in dopamine terminals), but other neurotoxic processes can persist and contribute to neuropsychiatric impairments during and following drug exposure (Sekine et al., 2008; Volkow et al., 2001; Zhuang et al., 2016). Research links immune factor signaling with neural and behavioral aspects of addiction, such as impaired cognitive function (Loftis et al., 2011), drug seeking behaviors, and resilience to relapse (Blednov et al., 2012b, 2012a; Schwarz et al., 2011; Zhang et al., 2012). Immunotherapeutic strategies to treat substance use disorders show efficacy in preclinical (Beardsley et al., 2010; Snider et al., 2013) and clinical studies (Birath et al., 2017; Worley et al., 2016).

In this study we test recombinant T-cell receptor ligand (RTL) 1000 [a partial major histocompatibility complex (pMHC) class II construct with a tethered myelin peptide (pDR2/myelin oligodendrocyte glycoprotein35–55 (MOG35–55)] for the treatment of methamphetamine drug seeking behavior and methamphetamine-induced central nervous system (CNS) injury. Partial MHC constructs like RTL1000 have neuroprotective and anti-inflammatory effects that can treat neuroinflammatory conditions, such as experimental stroke (Benedek et al., 2017; Pan et al., 2014; Subramanian et al., 2009) and experimental autoimmune encephalomyelitis (a model of multiple sclerosis) (Sinha et al., 2010, 2007; Vandenbark et al., 2003). RTLs bind to and downregulate expression of the invariant chain CD74 - the primary receptor for macrophage migration inhibitory factor (MIF) and a key inflammatory mediator in a number of diseases, including substance use disorders [e.g., (Freeman et al., 2012)]. When CD74 is activated, the intracellular domain of CD74 can translocate to the nucleus and trigger nuclear factor kappa-light-chain-enhancer of activated B cells to induce chemokine (C-C motif) ligand 2 [(CCL2); also known as monocyte chemoattractant protein-1 [(MCP-1)] and other inflammatory signals (Hulkower et al., 1993; Martin-Ventura et al., 2009). MIF binding to CD74 also induces the expression CCL2 via p38 mitogen-activated protein kinase-dependent pathways (Veillat et al., 2010; Xie et al., 2016). CCL2 is upregulated by methamphetamine and likely contributes to addiction-related behaviors and the drug’s adverse cognitive effects (Loftis et al., 2011; Saika et al., 2018; Sriram et al., 2006; Wakida et al., 2014). RTL1000 binding to CD74 may disrupt these pathways and reduce inflammatory signaling following methamphetamine exposure. We previously reported that RTL551 (a mouse pMHC similar to RTL1000) reduces persistent methamphetamine-induced cognitive impairments and attenuates methamphetamine-induced increases in hypothalamic interleukin-2 levels (a pro-inflammatory cytokine induced by MIF) (Loftis et al., 2013), contributing to the growing rationale for using a neuro-immunomodulation strategy for psychostimulant and other substance use disorders [e.g., (Bachtell et al., 2017)]. In this preclinical study, we expand on these findings using a rat self-administration model to test whether or not RTL1000 can promote abstinent-like behavior and reduce relapse, in addition to its cognitive enhancing and anti-inflammatory effects.

2. Materials and methods

2.1. Animals

Twenty male Lewis rats (Charles River Laboratories, Wilmington, Massachusetts, USA), weighing 305 g (SD: 12.02) initially were food restricted to 90% of their weight (274 g) and used for the self-administration behavioral testing and neuroimmunological assessments. Lewis rats were selected, as previous reports indicate that when compared to Fischer 344 rats, Lewis rats: 1) exhibit greater behavioral activation to an acute injection of methamphetamine (as well as cocaine), 2) are more susceptible to methamphetamine-induced sensitization, 3) have higher plasma and brain levels of methamphetamine following a single intraperitoneal (i.p.) injection (2 mg/kg), and 4) demonstrate an increased propensity to reinstate responding following methamphetamine priming injections (Camp et al., 1994; Kruzich and Xi, 2006). Additionally, RTL constructs have been tested in Lewis rats and shown to inhibit clinical and histological signs of experimental autoimmune encephalomyelitis (Burrows et al., 2000). All animal care and experimental manipulations were approved by the Institutional Animal Care and Use Committee at Oregon Health & Science University (protocol number IP00000027) and were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Fig. 1 provides a summary and timeline of the experimental procedures.

Fig. 1. Summary and timeline of the experimental procedures.

Fig. 1.

Open in a new tab

Abbreviations and definitions. Fixed Ratio (FR): rats were individually placed in conditioning chambers where pressing an active lever 1) turned on a light and 2) delivered a dose of drug (FR1 = drug delivered every press, FR5 = drug delivered every fifth press). RTL: rats were injected with 0.1 mL of RTL1000 or vehicle control. Extinction: rats were placed into their conditioning chambers for extinction sessions (2 h) where neither active nor inactive lever presses had any effect. Cue-induced reinstatement: extinction session where a lever press on the active lever led to a light being illuminated but no drug delivery. Spontaneous recovery: extinction session where rat operant behavior was measured in the absence of drug presentation within the conditioning chamber. Methamphetamine-primed: rats were re-exposed to methamphetamine and placed into their conditioning chambers for an extinction session.

2.2. Drugs

Methamphetamine was obtained from the National Institute on Drug Abuse (NIDA) drug supply program (NIDA Chemistry & Physiological Systems Research Branch) and Sigma-Aldrich (St. Louis, Missouri, USA). Methamphetamine was dissolved in 0.9% saline and stored at 4 °C. The stock solution was stored for up to 10 days. The partial major histocompatibility complex (MHC) constructs (pMHCs) were received from Drs. Gregory Burrows and Roberto Meza-Romero of Oregon Health & Science University, Portland, Oregon, USA. RTL1000 is a human recombinant T-cell receptor ligand (RTL) protein comprised of a single polypeptide of 210 amino acids with the structural backbone of a human MHC class II molecule. The RTL single-chain protein consists of three covalently linked regions comprised of the auto-antigenic neuropeptide, MOG35–55 (MEVGWYRSPFSRVVHLYRNGK), linked to a human MHC class II α1 domain linked to an MHC class II β1 domain. The physical properties and mechanisms of action of RTLs have been described in detail previously (Sinha et al., 2009, 2007; Subramanian et al., 2009; Vandenbark et al., 2003; Wang et al., 2006). Recombinant proteins (RTL1000) were obtained from the Vandenbark Lab.

2.3. Surgery

Prior to methamphetamine self-administration training, rats underwent surgery in order to implant jugular vein catheters, which were used to deliver methamphetamine intravenously (IV). Approximately one week following arrival, indwelling jugular catheters were constructed and implanted into the right jugular vein of each rat. Jugular catheters were made of 12 cm long Dow Corning silastic tubing (0.037 mm ID, 0.94 mm OD; Fisher Scientific, Pittsburgh, Pennsylvania, USA) with small beads of 100% silicone rubber sealant at 8.5 cm and 9 cm, respectively. Catheters were allowed to air-dry (or cure) for greater than 1 week, and then autoclaved along with surgical gauze and non-absorbable sutures (Medronic (formerly Covidien), Minneapolis, Minnesota, USA) to maintain sterility. In order to insert the catheter, anesthesia was induced with an i.p. injection of ketamine/xylazine (6 mg/100 g; 1 mg/100 g), and maintained throughout the duration of the surgery by vaporized isoflurane (1%). One end of the catheter was inserted into the right jugular vein and then run subcutaneously below the front right leg and exited the back between the shoulder blades. A stainless steel guide cannula (22 gauge; Plastics One, Roanoke, Virginia, USA) was inserted into an elastomer self-administration harness (Instech Laboratories, Inc., Plymouth Meeting, Pennsylvania, USA), and the jugular catheter was attached to the cannula within the harness (note: when animals were not running through the self-administration procedure a dummy was placed over the cannula to prevent particulate material from entering the catheter). Following surgery, animals received a 0.1 ml IV injection of 100 unit heparin (Sagent Pharmaceuticals, Schaumburg, Illinois, USA) and the antibiotic ticarcillin disodium and clavulanate potassium (Timentin) (238 mg/ml; GlaxoSmithKline, Warren, New Jersey, USA), as well as a subcutaneous (s.c.) injection of carprofen (Rimadyl) (5 mg/kg; Pfizer, New York City, New York, USA) that was administered once daily for 5 days following surgery. To maintain catheter patency, catheters were flushed with 0.1 ml 10 unit heparin prior to self-administration, and 100 unit heparin following a self-administration session. On days where animals were not behaviorally tested catheters still received a flush of 100 unit heparin. In addition, animals received a daily flush of Timentin to reduce the potential for infection. Catheter patency was confirmed via 0.1 ml IV injection of 10 mg/ml sodium brevital.

2.4. Self-administration training

Rats were trained in self-administration of methamphetamine, which was delivered through a catheter following a lever press. Training was conducted over 2-h sessions beginning approximately 7 days after catheter surgery. Rats were initially trained to lever-press on a fixed ratio of 1 (FR1) schedule of reinforcement that resulted in the delivery of a 0.06 mg/kg/infusion of methamphetamine and simultaneous activation of a stimulus light above the lever for 5 s. Following each active lever press there was a 20-s time-out period; during this time-out lever presses were recorded but had no programmed consequences. Similarly, inactive lever presses were recorded but had no programmed consequences throughout the 2-h sessions. Position of the active and inactive levers was counterbalanced among boxes. Daily FR1 training continued for 10 sessions or until animals reached stability criteria, defined as no more than 20% variation from the mean (Pizzimenti et al., 2017; Shaham et al., 1998). Training on an FR5 schedule (5 lever presses resulted in the delivery of a 0.06 mg/kg/infusion of methamphetamine and simultaneous activation of a stimulus light above the lever) began 24 h following the last FR1 training session and was conducted using the same criteria.

2.5. Immunotherapy administration

Rats began treatment with RTL1000 (0.1 mg/animal, s.c.) or vehicle (20 mM Tris, 10% w/v dextrose) 24 h after the last FR5 training session. RTL1000 or vehicle was administered daily for 5 days, 30 min prior to the extinction sessions (described in section 2.6.). In this study, RTL1000 was tested for its impact on extinction as well as relapse following reinstatement challenges (described in section 2.6.).

2.6. Extinction and reinstatement

Extinction began 24 h after the final FR5 training session and consisted of 2-h sessions during which presses on the previously active lever no longer resulted in the delivery of drug, nor the activation of the stimulus light. Extinction occurred until groups met extinction criteria [two consecutive sessions with < 25 responses (Zhou et al., 2012)]. Once criterion was reached, rats were tested for cue- and methamphetamine-induced reinstatement. Each rat was subjected to reinstatement testing using: 1) a light cue (but no drug delivery) when the active lever was pressed, 2) spontaneous recovery, and 3) a methamphetamine priming dose. Drug- primed reinstatement testing consisted of a 1 mg/kg i.p. injection of methamphetamine immediately prior to the extinction session.

2.7. Blood and brain sample collection

Rats were humanely euthanized 5 days following the methamphetamine-primed reinstatement challenge. Following euthanasia, blood was collected via cardiac puncture and brains were rapidly removed. Blood was allowed to clot prior to centrifugation, and serum samples were subsequently collected and stored at −80 °C for the determination of CCL2 levels. Cortical and hippocampal regions were micro-dissected on a cold metal block. Frontal cortex dissections included infralimbic, prelimbic, and cingulate cortex and neostriatum dissections included both caudate and accumbens. Brain samples were immediately snap frozen on dry ice and stored at −80 °C until analysis.

2.8. Enzyme-linked immunosorbent assay (ELISA)

Rat serum samples were used to measure circulating CCL2 levels by ELISA, with a sensitivity of 2 pg/ml and range of 15.6 – 1,000 pg/ml (Quantikine ELISA Mouse/Rat CCL2/JE/MCP-1 Immunoassay, R&D Systems, Inc., Minneapolis, Minnesota, USA). All standards and samples were tested in duplicate per the manufacturer’s protocol. The optical density of each well was determined with a microplate reader set to 450 nm (BenchmarkPlus Spectrophotometer System, Bio-Rad, Hercules, California, USA). Standard curves and results were calculated using Prism 6.05 (GraphPad Software, Inc., La Jolla, California, USA).

2.9. Gel electrophoresis and immunoblotting

Brain tissue was homogenized in 100 vol (original wet weight) of ice-cold buffer [radioimmunoprecipitation assay (RIPA) buffer, pH 7.5, supplemented with sodium orthovanadate (Na3VO4) and protease inhibitors (Complete tablet; Boehringer Mannheim, Germany)]. Homogenate protein concentrations were determined using the BCA protein assay kit (Pierce, Rockford, Illinois, USA). Equal amounts of protein were run on Any kD Criterion TGX precast polyacrylamide gels and transferred onto Immun-Blot low fluorescence PVDF membranes (Bio-Rad, Hercules, California, USA). Membranes were blocked in 3% bovine serum album (BSA) in tris-buffered saline (TBS) with 0.05% Tween-20. After washing, membranes were probed with anti-MCP1 antibody [2H5] (1:50; ab21396) or anti-CD74 antibody (1:500; ab202844), followed by incubation with goat anti-Armenian hamster IgG H&L Alexa Fluor 568 (1:1000; ab175716) or goat anti-rabbit IgG H&L Alexa Fluor 488 (1:500; ab150077), respectively (Abcam, Cambridge, Massachusetts, USA). Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression was used as a loading control on all gels and was detected by GAPDH mouse monoclonal antibody (1:20,000; 600004–1) (Proteintech Group, Inc., Rosemont, Illinois, USA) and goat anti-mouse IgG H&L Cy5 (1:1000; ab6563) (Abcam). Fluorescent blots were read on a Typhoon FLA laser scanner (GE Healthcare Life Sciences, Marlborough, Massachusetts, USA) and the resulting images were quantified with FIJI software (Schindelin et al., 2012). Results were normalized to loading controls (i.e., GAPDH) for quantitative analysis.

2.10. Statistical analysis

Two-way, repeated measures analysis of variance (ANOVA) was used to analyze the self-administration data across time, with treatment (vehicle and RTL1000) as the between subjects factor. Sidak’s multiple comparisons tests were used for post hoc analyses. For the neuroimmunological assessments, Mann-Whitney tests were used to compare CCL2 and CD74 levels in vehicle and RTL1000 treated rats. Pearson correlations evaluated the relationship between lever pressing behavior and CCL2 levels. All results were expressed as mean ± standard error (S.E.M.) and a difference with P < 0.05 between experimental groups was considered statistically significant. Calculations were performed using Prism 6.05 (GraphPad Software, Inc., La Jolla, California, USA).

3. Results

3.1. RTL1000 immunotherapy reduced drug seeking in post dependent rats

Following approximately 3 weeks of operant training and methamphetamine self-administration, rats were treated daily with either vehicle or RTL1000 immunotherapy for 5 days. During and after immunotherapy treatment, rats were exposed to daily extinction trials to assess the reinstatement of drug seeking behavior (Fig. 1). The self-administration pattern of 14 rats over the last 20 days of the experiment is illustrated in Fig. 2 (note: the IV catheters for six rats lost patency and four of these animals were switched to food pellets; see Supplementary material). Active lever pressing and the corresponding quantity of methamphetamine self-administered by the rats increased over FR5 sessions (pre-immunotherapy). During the initial extinction trials, rats treated with RTL1000 displayed fewer presses on the active lever, as compared to controls (Fig. 2). Two-way, repeated measures ANOVA detected a significant effect of time (F(4, 48) = 1.87; P < 0.0001) and treatment (F(1, 12) = 14.46; P = 0.0025). Sidak’s multiple comparisons tests indicated that during the first extinction trial, there was a significant difference between vehicle (n = 7) and RTL1000 (n = 7) groups (P = 0.0009). The group differences in presses on the active lever were not statistically significant during extinction trials 2–5 (Fig. 2). There were also no significant differences in lever pressing during the post-immunotherapy extinction trials, including cue-induced reinstatement, spontaneous recovery, and methamphetamine-primed trials. Although rats treated with RTL1000 had reduced lever pressing during cued reinstatement, as compared to controls (62.29 ± 17.75 and 92.57 ± 14.96 presses on the active lever, respectively), the difference was not statistically significant. Inactive lever pressing was negligible throughout the behavioral assessments, which indicates a clear differentiation between the reinforced (active) and non-reinforced (inactive) levers. Lever pressing behavior for saline subjects emulated that seen on the inactive lever in rats trained to self-administer methamphetamine (data not shown). A pilot experiment found no effect of RTL1000 on extinction of responding for food pellets, suggesting that the effect observed in Fig. 2 was not due to a general effect on extinction (Supplementary material).

Fig. 2. Drug seeking behavior before and after RTL1000 immunotherapy.

Fig. 2.

Open in a new tab

Time course of self-administration behavior across 20 consecutive days. Following methamphetamine self-administration, rats were treated daily with either vehicle (VEH) or RTL1000 for 5 days and exposed to daily extinction (EXT) trials. Two-way, repeated measures ANOVA compared drug seeking behavior during the 5 days of immunotherapy or control treatment and detected a significant effect of time (F(4, 48) = 1.87; P < 0.0001) and treatment (F(1, 12) = 14.46; P = 0.0025). During the initial extinction sessions, rats treated with RTL1000 displayed fewer presses on the active lever, as compared to control animals. Sidak’s multiple comparisons test indicated that during the first extinction trial, there was a significant difference between vehicle (n = 7) and RTL1000 (n = 7) groups. The asterisks denote the significance level (*** P = 0.0009). Group differences in lever pressing behavior were not statistically significant during extinction trials 2–5 or during cue-induced reinstatement (Cued Reinst.), spontaneous recovery (Sp. Rec.), and methamphetamine-primed (Meth-Prime) sessions.

3.2. The effects of RTL1000 immunotherapy on methamphetamine-induced inflammation

To test the mechanistic hypothesis that RTL1000 immunotherapy reduces the levels of inflammatory factors in the MIF/CD74 signaling cascade, immunoblotting of rat brain sections (frontal cortex and hippocampus) was conducted to measure CCL2--a chemokine that we and others have found to be increased in plasma and brain from mice and humans with prior methamphetamine exposure (Loftis et al., 2011; Saika et al., 2018; Sriram et al., 2006; Wakida et al., 2014). In our rat model, RTL1000 treatment reduced CCL2 in animals with a history of methamphetamine self-administration. Fig. 3 shows brain and serum levels of CCL2 in methamphetamine-exposed rats treated with vehicle or RTL1000 immunotherapy. Rats trained to self-administer methamphetamine and treated with RTL1000 had reduced levels of CCL2 in the frontal cortex, as compared to vehicle-treated controls (P = 0.007) (Fig. 3A and 3B). CCL2 levels in the hippocampus and in serum were marginally lower in the RTL1000-treated rats than in the controls, but the differences were not statistically significant between the groups (Fig. 3C and 3D). Given that frontal cortex CCL2 levels differed significantly between vehicle- and RTL1000-treated groups, we also measured CD74 in the frontal cortex. Western blot analysis did not detect significant differences in CD74 expression (P = 0.13) (data not shown).

Fig. 3. CCL2 levels in methamphetamine-exposed mice treated with vehicle or RTL1000 immunotherapy.

Fig. 3.

Open in a new tab

(A) Rats trained to self-administer methamphetamine and treated with RTL1000 had reduced levels of CCL2 in the frontal cortex, as compared to vehicle (VEH)-treated controls. The asterisks denote the significance level (Mann-Whitney test, ** P = 0.007). (B) Representative immunoblot image of CCL2 in frontal cortex. Samples from vehicle-treated animals (lanes 1–10) and RTL1000-treated animals (lanes 11–20) are shown. (C, D) CCL2 levels in the hippocampus and in serum were not statistically significant between the VEH and RTL1000 groups (P = 0.32 and P = 0.80, respectively).

3.3. Post hoc exploratory analysis of CCL2 and drug seeking behavior

Chemokine systems play a key role in regulating the motivational effects of methamphetamine exposure (Saika et al., 2018; Wakida et al., 2014). We therefore tested the association between brain levels of CCL2 and drug-seeking behavior to explain how CCL2 may contribute to methamphetamine reward. Correlational analysis identified a positive association between the levels of CCL2 detected in the frontal cortex and the number of presses on the active lever during the first extinction session (r = 0.58, P = 0.03) (Fig. 4A). The correlation between CCL2 levels in the hippocampus and presses on the active lever during the first extinction session was not statistically significant (r = 0.39; P = 0.17) (Fig. 4B).

Fig. 4. Exploratory correlational analysis of CCL2 and drug seeking behavior.

Fig. 4.

Open in a new tab

(A) Post hoc correlation of brain CCL2 expression and drug-seeking behavior identified a positive association between the levels of CCL2 detected in the frontal cortex and the number of presses on the active lever during the first extinction session (r = 0.58, P = 0.03). (B) The correlation between CCL2 levels in the hippocampus and presses on the active lever during the first extinction session was not statistically significant (r = 0.39; P = 0.17).

4. Discussion

We used a model of methamphetamine self-administration to evaluate the efficacy of RTL1000 immunotherapy in reducing drug seeking behavior and levels of CCL2, an inflammatory chemokine that putatively contributes to addiction. This preclinical study demonstrated that RTL1000 was effective in attenuating methamphetamine seeking behavior during initial extinction sessions, which may be beneficial for treating people with methamphetamine use disorder by helping them establish abstinence early during recovery (potentially via an early change in reward sensitivity). Group differences in cue-induced reinstatement were observed, with RTL1000-treated rats responding less on the active lever than vehicle-treated rats, but the differences were not statistically significant. There were also no significant differences between groups during the spontaneous recovery or methamphetamine-primed sessions (Fig. 2).

Methamphetamine activates reward circuitry and heavy or chronic exposure alters cellular and molecular aspects of neural and immunological function, which results in the altered valuation of drug reward (Ahmed et al., 2002; Ahmed and Koob, 1998; Stolyarova et al., 2015). One interpretation of the reduction in drug seeking is that the RTL1000-treated animals learned quickly that the response no longer led to methamphetamine. Another possibility is that there was a rapid change in the rewarding value of methamphetamine, so RTL1000-treated rats were less likely to respond for it. A change in the rewarding value would be consistent with the change observed in brain CCL2 levels (Fig. 3), as upregulation of CCL2 in the prefrontal cortex is thought to underlie methamphetamine-induced reward (Saika et al., 2018). In the conditioned place preference test, place preference for methamphetamine is attenuated by CC-chemokine receptor 2 (CCR2) antagonists (Saika et al., 2018; Wakida et al., 2014). Similarly, deletion of Ccr2, Ccl2 (females) or Ccl3 genes in mice results in lower preference for alcohol and lower consumption of alcohol in a two-bottle choice test as compared with wild-type mice (Blednov et al., 2005), and alcohol-preferring P rats have innately elevated levels of CCL2 (June et al., 2015).

CCL2, induced by MIF/CD74 signaling pathways (Gregory et al., 2006; Hoi et al., 2006; Leng et al., 2011), attracts monocytes and memory T cells and causes the production of inflammatory cytokines that can influence neurodegeneration, neurogenesis, and neurotransmission (Semple et al., 2010). The effects of methamphetamine on CCL2 expression appear to occur rapidly, under a range of doses, across brain regions involved in reward circuits, and after only a single exposure of methamphetamine. For example, striatal CCL2 mRNA expression is increased in mice 12 h after a single dose of methamphetamine (20 mg/kg, s.c.) (Sriram et al., 2006) and prefrontal cortex CCL2 (as well as CCL7) mRNA is upregulated in mice 60 min after a single administration of methamphetamine (3 mg/kg, s.c.) (Saika et al., 2018). Using a cross-species approach, we found that mice administered methamphetamine (1 mg/kg, s.c.) for seven consecutive days and euthanized at 72 h or three weeks after the last drug dose had higher plasma levels of circulating CCL2, as compared to vehicle-treated mice. This effect was similarly evident in plasma samples from humans in remission from methamphetamine dependence which had increased concentrations of CCL2 relative to samples from controls. Further, the methamphetamine-induced increase in CCL2 and related cytokine levels was accompanied by increased cognitive impairments in adults in remission from methamphetamine dependence (Loftis et al., 2011). These findings show that methamphetamine exposure alters chemokine expression and support the important role that immune factors have in regulating methamphetamine intake and relapse behaviors.

In our rat model, RTL1000 immunotherapy reduced cortical CCL2 levels in animals with a history of methamphetamine self-administration. This action could be attributed to RTL1000’s (and other pMHCs) anti-inflammatory effects. The pMHC moiety produces an antigen non-specific inhibitory effect after binding to and downregulating CD74 mainly on macrophages, including those that cross the blood brain barrier after CNS damage. Binding of RTL constructs with CD74 involves MHC class II-α1/CD74 interactions that inhibit CD74 expression, block activity of MIF, inhibit recruitment of inflammatory cells to brain, and reduce inflammation (Sinha et al., 2007; Vandenbark et al., 2013), including levels of CCL2 (Fig. 3)–mechanisms thought to contribute to its therapeutic effects. Accumulating evidence shows that chemokines can modulate the activity of neurons. Importantly, in rats, CCL2 is expressed in dopaminergic neurons of the substantia nigra pars compacta (Banisadr et al., 2005), and application of CCL2 on dopaminergic neurons increases their excitability, dopamine release, and related locomotor activity effects (Guyon et al., 2009). The RTL1000-induced decrease in CCL2 we observed may have contributed to alterations in dopaminergic signaling in reward pathways thereby impacting the rewarding value of methamphetamine and the associated response for it. Moreover, this behavioral effect was correlated with RTL1000’s anti-inflammatory potential (Fig. 4).

A third interpretation that may account for RTL1000’s attenuation of operant methamphetamine self-administration in post-dependent rats is that the drug caused performance effects, which made the animals press less (change in activity, health, etc.). However, in a pilot study we saw no differences in inactive responding and no differences in rats that received extinction after responding for food pellets (Supplementary material). Further, in experimental models of multiple sclerosis administration of RTL constructs improves, rather than hinders, motor function and CNS damage (Offner et al., 2008; Sinha et al., 2010), suggesting that RTL1000’s impact on lever pressing was not due to a simple performance effect but was due specifically to effects on extinction and reinstatement or to more general effects on lever pressing for methamphetamine.

Our findings should be considered in light of study limitations. These include the use of only male rats and a limited number of control conditions. Our initial preclinical efficacy study was performed using one sex in order to enable sample sizes that would provide sufficient statistical power to detect group differences; however, future studies are needed to determine if RTL1000 is similarly efficacious in female animals exposed to methamphetamine. Further, it would be optimal to include additional control groups to evaluate whether any reduction in drug seeking behavior is due specifically to effects on extinction and reinstatement or to more general effects on lever pressing for methamphetamine. These groups would receive the same RTL1000 (or vehicle) treatment, but not receive extinction; thus, we could evaluate the effects of RTL1000 on methamphetamine seeking that is being maintained at high rates. Any positive effects on methamphetamine seeking would be replicated using sucrose rewards, which would tell us whether the effects that we observe on methamphetamine are specific to methamphetamine or are reflective of more general effects on all rewards.

Earlier work showed that RTL551 (a mouse pMHC similar to RTL1000) reduces persistent methamphetamine-induced cognitive impairments and attenuates methamphetamine-induced increases in hypothalamic interleukin-2 levels (Loftis et al., 2013). These data are supported by work in other models of neuroinflammation which show that pMHCs: 1) reduce numbers of infiltrating inflammatory cells in the CNS, 2) reduce expression of intracellular adhesion molecule and vascular adhesion molecule on vascular endothelial cells, possibly accounting for the reduced infiltration of inflammatory cells, 3) reduce levels of inflammatory cytokines, chemokines, and chemokine receptors, and 4) repair myelin and axonal damage (Sinha et al., 2007; Subramanian et al., 2009; Vandenbark et al., 2003; Wang et al., 2006). RTL1000 has extensive preclinical safety data and has completed Phase 1 clinical trial testing in multiple sclerosis patients (Offner et al., 2011; Yadav et al., 2012). Thus, a growing body of literature indicates that the therapeutic actions of pMHCs may be particularly useful for treating methamphetamine and other substance use disorders, as this immunotherapeutic strategy addresses problems that are central to the underlying pathophysiology of addiction. Interventions that reduce methamphetamine reward value may be effective at reducing relapse and improving recovery outcomes [e.g., (Dennhardt et al., 2015)].

Supplementary Material

1

Acknowledgements

The authors would like to thank Dr. Roberto Meza-Romero and the Vandenbark laboratory for providing the partial MHC constructs (RTL1000). The authors also acknowledge the National Institute on Drug Abuse (NIDA) drug supply program (NIDA Chemistry & Physiological Systems Research Branch) for supplying the methamphetamine. We are grateful to Ms. Nikki Walters at the Oregon National Primate Research Center and the Methamphetamine Abuse Research Center Biostatistics Core at OHSU and the VA Portland Health Care System for analytical support.

Authors JML (Research Scientist), JT (Research WOC Employee), RH (Research Assistant), AAV (Senior Research Career Scientist), and MH (Staff Psychologist and Neuropsychologist) acknowledge their appointments at the VA Portland Health Care System, Portland, Oregon.

Funding

This work was supported by the National Institutes of Health, National Institute on Drug Abuse [P50DA018165, R41DA039632 (JML, MH)]; the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Merit Review Award [1I01BX002061 (JML), 2I01BX000226 (AAV), and Senior Research Career Scientist Award 1IK6BX004209 (AAV)]. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.

Footnotes

Statement of conflict of interest

The Department of Veterans Affairs (VA) and Oregon Health & Science University (OHSU) own the RTL technology used in the RTL research that is described in this report. The VA, OHSU, and Drs. Loftis, Huckans, and Vandenbark have rights to royalties from the licensing agreement with Arielle Immunotherapeutics. These potential conflicts of interest have been reviewed and managed by the Conflict of Interest Committees at the VA Portland Health Care System and OHSU.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  1. Ahmed SH, Kenny PJ, Koob GF, Markou A, 2002. Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat Neurosci 5, 625–626. 10.1038/nn872 [DOI] [PubMed] [Google Scholar]
  2. Ahmed SH, Koob GF, 1998. Transition from moderate to excessive drug intake: change in hedonic set point. Science (80-. ). 282, 298–300. [DOI] [PubMed] [Google Scholar]
  3. Bachtell RK, Jones JD, Heinzerling KG, Beardsley PM, Comer SD, 2017. Glial and neuroinflammatory targets for treating substance use disorders. Drug Alcohol Depend 180, 156–170. 10.1016/j.drugalcdep.2017.08.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Banisadr G, Gosselin RD, Mechighel P, Kitabgi P, Rostene W, Parsadaniantz SM, 2005. Highly regionalized neuronal expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) in rat brain: evidence for its colocalization with neurotransmitters and neuropeptides. J Comp Neurol 489, 275–292. 10.1002/cne.20598 [DOI] [PubMed] [Google Scholar]
  5. Beardsley PM, Shelton KL, Hendrick E, Johnson KW, 2010. The glial cell modulator and phosphodiesterase inhibitor, AV411 (ibudilast), attenuates prime- and stress-induced methamphetamine relapse. Eur. J. Pharmacol. 10.1016/j.ejphar.2010.04.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Benedek G, Vandenbark AA, Alkayed NJ, Offner H, 2017. Partial MHC class II constructs as novel immunomodulatory therapy for stroke. Neurochem Int 107, 138–147. 10.1016/j.neuint.2016.10.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Birath JB, Briones M, Amaya S, Shoptaw S, Swanson AN, Tsuang J, Furst B, Heinzerling K, Obermeit L, Maes L, McKay C, Wright MJ, 2017. Ibudilast may improve attention during early abstinence from methamphetamine. Drug Alcohol Depend 178, 386–390. 10.1016/j.drugalcdep.2017.05.016 [DOI] [PubMed] [Google Scholar]
  8. Blednov YA, Bergeson SE, Walker D, Ferreira VMM, Kuziel WA, Harris RA, 2005. Perturbation of chemokine networks by gene deletion alters the reinforcing actions of ethanol. Behav. Brain Res. 10.1016/j.bbr.2005.06.026 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Blednov YA, Mayfield RD, Belknap J, Harris RA, 2012a. Behavioral actions of alcohol: phenotypic relations from multivariate analysis of mutant mouse data. Genes Brain Behav 11, 424–435. 10.1111/j.1601-183X.2012.00780.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Blednov YA, Ponomarev I, Geil C, Bergeson S, Koob GF, Harris RA, 2012b. Neuroimmune regulation of alcohol consumption: behavioral validation of genes obtained from genomic studies. Addict Biol 17, 108–120. 10.1111/j.1369-1600.2010.00284.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Burrows GG, Adlard KL, Bebo BF Jr., Chang JW, Tenditnyy K, Vandenbark AA, Offner H, 2000. Regulation of encephalitogenic T cells with recombinant TCR ligands. J Immunol 164, 6366–6371. [DOI] [PubMed] [Google Scholar]
  12. Camp DM, Browman KE, Robinson TE, 1994. The effects of methamphetamine and cocaine on motor behavior and extracellular dopamine in the ventral striatum of Lewis versus Fischer 344 rats. Brain Res 668, 180–193. [DOI] [PubMed] [Google Scholar]
  13. Crews FT, Zou J, Qin L, 2011. Induction of innate immune genes in brain create the neurobiology of addiction. Brain Behav Immun 25 Suppl 1, S4–S12. 10.1016/j.bbi.2011.03.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dennhardt AA, Yurasek AM, Murphy JG, 2015. Change in delay discounting and substance reward value following a brief alcohol and drug use intervention. J Exp Anal Behav 103, 125–140. 10.1002/jeab.121 [DOI] [PubMed] [Google Scholar]
  15. Freeman K, Brureau A, Vadigepalli R, Staehle MM, Brureau MM, Gonye GE, Hoek JB, Hooper DC, Schwaber JS, 2012. Temporal changes in innate immune signals in a rat model of alcohol withdrawal in emotional and cardiorespiratory homeostatic nuclei. J Neuroinflammation 9, 97 10.1186/1742-2094-9-97 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gregory JL, Morand EF, McKeown SJ, Ralph JA, Hall P, Yang YH, McColl SR, Hickey MJ, 2006. Macrophage Migration Inhibitory Factor Induces Macrophage Recruitment via CC Chemokine Ligand 2. J. Immunol. 10.4049/jimmunol.177.11.8072 [DOI] [PubMed] [Google Scholar]
  17. Guyon A, Skrzydelski D, De Giry I, Rovere C, Conductier G, Trocello JM, Dauge V, Kitabgi P, Rostene W, Nahon JL, Melik Parsadaniantz S, 2009. Long term exposure to the chemokine CCL2 activates the nigrostriatal dopamine system: a novel mechanism for the control of dopamine release. Neuroscience 162, 1072–1080. 10.1016/j.neuroscience.2009.05.048 [DOI] [PubMed] [Google Scholar]
  18. Hoi AY, Hickey MJ, Hall P, Yamana J, O’Sullivan KM, Santos LL, James WG, Kitching AR, Morand EF, 2006. Macrophage Migration Inhibitory Factor Deficiency Attenuates Macrophage Recruitment, Glomerulonephritis, and Lethality in MRL/ lpr Mice. J. Immunol 10.4049/jimmunol.177.8.5687 [DOI] [PubMed] [Google Scholar]
  19. Hulkower K, Brosnan CF, Aquino DA, Cammer W, Kulshrestha S, Guida MP, Rapoport DA, Berman JW, 1993. Expression of CSF-1, c-fms, and MCP-1 in the central nervous system of rats with experimental allergic encephalomyelitis. J Immunol 150, 2525–2533. [PubMed] [Google Scholar]
  20. Hutchinson MR, Watkins LR, 2014. Why is neuroimmunopharmacology crucial for the future of addiction research? Neuropharmacology 76 Pt B, 218–227. 10.1016/j.neuropharm.2013.05.039 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. June HL, Liu J, Warnock KT, Bell KA, Balan I, Bollino D, Puche A, Aurelian L, 2015. CRFamplified neuronal TLR4/MCP-1 signaling regulates alcohol self-administration. Neuropsychopharmacology 40, 1549–1559. 10.1038/npp.2015.4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kruzich PJ, Xi J, 2006. Differences in extinction responding and reinstatement of methamphetamine-seeking behavior between Fischer 344 and Lewis rats. Pharmacol Biochem Behav 83, 391–395. 10.1016/j.pbb.2006.02.021 [DOI] [PubMed] [Google Scholar]
  23. Leng L, Chen L, Fan J, Greven D, Arjona A, Du X, Austin D, Kashgarian M, Yin Z, Huang XR, Lan HY, Lolis E, Nikolic-Paterson D, Bucala R, 2011. A Small-Molecule Macrophage Migration Inhibitory Factor Antagonist Protects against Glomerulonephritis in Lupus-Prone NZB/NZW F1 and MRL/ lpr Mice. J. Immunol 10.4049/jimmunol.1001767 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Loftis JM, Choi D, Hoffman W, Huckans MS, 2011. Methamphetamine causes persistent immune dysregulation: A cross-species, translational report. Neurotox. Res. 20 10.1007/s12640-010-9223-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Loftis JM, Janowsky A, 2014. Neuroimmune basis of methamphetamine toxicity, International Review of Neurobiology. 10.1016/B978-0-12-801284-0.00007-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Loftis JM, Wilhelm CJ, Vandenbark AA, Huckans M, 2013. Partial MHC/Neuroantigen Peptide Constructs: A Potential Neuroimmune-Based Treatment for Methamphetamine Addiction. PLoS One 8 10.1371/journal.pone.0056306 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. London ED, Kohno M, Morales AM, Ballard ME, 2015. Chronic methamphetamine abuse and corticostriatal deficits revealed by neuroimaging. Brain Res 1628, 174–185. 10.1016/j.brainres.2014.10.044 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Martin-Ventura JL, Madrigal-Matute J, Munoz-Garcia B, Blanco-Colio LM, Van Oostrom M, Zalba G, Fortuno A, Gomez-Guerrero C, Ortega L, Ortiz A, Diez J, Egido J, 2009. Increased CD74 expression in human atherosclerotic plaques: contribution to inflammatory responses in vascular cells. Cardiovasc Res 83, 586–594. 10.1093/cvr/cvp141 [DOI] [PubMed] [Google Scholar]
  29. Offner H, Sinha S, Burrows GG, Ferro AJ, Vandenbark AA, 2011. RTL therapy for multiple sclerosis: a Phase I clinical study. J Neuroimmunol 231, 7–14. 10.1016/j.jneuroim.2010.09.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Offner H, Sinha S, Wang C, Burrows GG, Vandenbark AA, 2008. Recombinant T cell receptor ligands: immunomodulatory, neuroprotective and neuroregenerative effects suggest application as therapy for multiple sclerosis. Rev Neurosci 19, 327–39. 10.1515/REVNEURO.2008.19.4-5.327 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pan J, Palmateer J, Schallert T, Hart M, Pandya A, Vandenbark AA, Offner H, Hurn PD, 2014. Novel humanized recombinant T cell receptor ligands protect the female brain after experimental stroke. Transl Stroke Res 5, 577–585. 10.1007/s12975-014-0345-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Pizzimenti CL, Navis TM, Lattal KM, 2017. Persistent effects of acute stress on fear and drug-seeking in a novel model of the comorbidity between post-traumatic stress disorder and addiction. Learn Mem 24, 422–431. 10.1101/lm.044164.116 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Saika F, Kiguchi N, Wakida N, Kobayashi D, Fukazawa Y, Matsuzaki S, Kishioka S, 2018. Upregulation of CCL7 and CCL2 in reward system mediated through dopamine D1 receptor signaling underlies methamphetamine-induced place preference in mice. Neurosci. Lett 10.1016/j.neulet.2017.11.042 [DOI] [PubMed] [Google Scholar]
  34. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A, 2012. Fiji: an open-source platform for biological-image analysis. Nat Methods 9, 676–682. 10.1038/nmeth.2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Schwarz JM, Hutchinson MR, Bilbo SD, 2011. Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression. J Neurosci 31, 17835–17847. 10.1523/JNEUROSCI.3297-11.2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sekine Y, Ouchi Y, Sugihara G, Takei N, Yoshikawa E, Nakamura K, Iwata Y, Tsuchiya KJ, Suda S, Suzuki K, Kawai M, Takebayashi K, Yamamoto S, Matsuzaki H, Ueki T, Mori N, Gold MS, Cadet JL, 2008. Methamphetamine causes microglial activation in the brains of human abusers. J Neurosci 28, 5756–5761. 10.1523/JNEUROSCI.1179-08.2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Semple BD, Kossmann T, Morganti-Kossmann MC, 2010. Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J Cereb Blood Flow Metab 30, 459–473. 10.1038/jcbfm.2009.240 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Shaham Y, Erb S, Leung S, Buczek Y, Stewart J, 1998. CP-154,526, a selective, non-peptide antagonist of the corticotropin-releasing factor1 receptor attenuates stress-induced relapse to drug seeking in cocaine- and heroin-trained rats. Psychopharmacol. 137, 184–190. [DOI] [PubMed] [Google Scholar]
  39. Sinha S, Subramanian S, Emerson-Webber A, Lindner M, Burrows GG, Grafe M, Linington C, Vandenbark AA, Bernard CC, Offner H, 2010. Recombinant TCR ligand reverses clinical signs and CNS damage of EAE induced by recombinant human MOG. J Neuroimmune Pharmacol 5, 231–239. 10.1007/s11481-009-9175-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sinha S, Subramanian S, Miller L, Proctor TM, Roberts C, Burrows GG, Vandenbark AA, Offner H, 2009. Cytokine switch and bystander suppression of autoimmune responses to multiple antigens in experimental autoimmune encephalomyelitis by a single recombinant T-cell receptor ligand. J Neurosci 29, 3816–3823. 10.1523/JNEUROSCI.5812-08.2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Sinha S, Subramanian S, Proctor TM, Kaler LJ, Grafe M, Dahan R, Huan J, Vandenbark AA, Burrows GG, Offner H, 2007. A promising therapeutic approach for multiple sclerosis: recombinant T-cell receptor ligands modulate experimental autoimmune encephalomyelitis by reducing interleukin-17 production and inhibiting migration of encephalitogenic cells into the CNS. J Neurosci 27, 12531–12539. 10.1523/JNEUROSCI.3599-07.2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Snider SE, Hendrick ES, Beardsley PM, 2013. Glial cell modulators attenuate methamphetamine self-administration in therat. Eur. J. Pharmacol. 10.1016/j.ejphar.2013.01.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sriram K, Miller DB, O’Callaghan JP, 2006. Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha. J Neurochem 96, 706–718. 10.1111/j.1471-4159.2005.03566.x [DOI] [PubMed] [Google Scholar]
  44. Stolyarova A, Thompson AB, Barrientos RM, Izquierdo A, 2015. Reductions in frontocortical cytokine levels are associated with long-lasting alterations in reward valuation after methamphetamine. Neuropsychopharmacology 40, 1234–1242. 10.1038/npp.2014.309 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Subramanian S, Zhang B, Kosaka Y, Burrows GG, Grafe MR, Vandenbark AA, Hurn PD, Offner H, 2009. Recombinant T cell receptor ligand treats experimental stroke. Stroke 40, 2539–2545. 10.1161/STROKEAHA.108.543991 [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Vandenbark AA, Meza-Romero R, Benedek G, Andrew S, Huan J, Chou YK, Buenafe AC, Dahan R, Reiter Y, Mooney JL, Offner H, Burrows GG, 2013. A novel regulatory pathway for autoimmune disease: binding of partial MHC class II constructs to monocytes reduces CD74 expression and induces both specific and bystander T-cell tolerance. J Autoimmun 40, 96–110. 10.1016/j.jaut.2012.08.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Vandenbark AA, Rich C, Mooney J, Zamora A, Wang C, Huan J, Fugger L, Offner H, Jones R, Burrows GG, 2003. Recombinant TCR ligand induces tolerance to myelin oligodendrocyte glycoprotein 35–55 peptide and reverses clinical and histological signs of chronic experimental autoimmune encephalomyelitis in HLA-DR2 transgenic mice. J Immunol 171, 127–133. [DOI] [PubMed] [Google Scholar]
  48. Veillat V, Carli C, Metz CN, Al-Abed Y, Naccache PH, Akoum A, 2010. Macrophage migration inhibitory factor elicits an angiogenic phenotype in human ectopic endometrial cells and triggers the production of major angiogenic factors via CD44, CD74, and MAPK signaling pathways. J Clin Endocrinol Metab 95, E403–12. 10.1210/jc.2010-0417 [DOI] [PubMed] [Google Scholar]
  49. Volkow ND, Chang L, Wang GJ, Fowler JS, Franceschi D, Sedler M, Gatley SJ, Miller E, Hitzemann R, Ding YS, Logan J, 2001. Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence. J Neurosci 21, 9414–9418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Wakida Naoki, Kiguchi N., Saika F, Nishiue H, Kobsayashi Y, Kishioka S., 2014. CC-chemokine ligand 2 facilitates conditioned place preference to methamphetamine through the activation of dopamine systems. J. Pharmacol. Sci. 10.1254/jphs.14032FP [DOI] [PubMed] [Google Scholar]
  51. Wakida N, Kiguchi N, Saika F, Nishiue H, Kobayashi Y, Kishioka S, 2014. CC-chemokine ligand 2 facilitates conditioned place preference to methamphetamine through the activation of dopamine systems. J Pharmacol Sci 125, 68–73. [DOI] [PubMed] [Google Scholar]
  52. Wang, Gold ,BG, Kaler LJ, Yu X, Afentoulis ME, Burrows GG, Vandenbark AA, Bourdette DN, Offner H, 2006. Antigen-specific therapy promotes repair of myelin and axonal damage in established EAE. J Neurochem 98, 1817–1827. 10.1111/j.1471-4159.2006.04081.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Worley MJ, Heinzerling KG, Roche DJO, Shoptaw S, 2016. Ibudilast attenuates subjective effects of methamphetamine in a placebo-controlled inpatient study. Drug Alcohol Depend 10.1016/j.drugalcdep.2016.02.036 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Xie J, Yang L, Tian L, Li W, Yang L, Li L, 2016. Macrophage Migration Inhibitor Factor Upregulates MCP-1 Expression in an Autocrine Manner in Hepatocytes during Acute Mouse Liver Injury. Sci Rep 6, 27665 10.1038/srep27665 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Yadav V, Bourdette DN, Bowen JD, Lynch SG, Mattson D, Preiningerova J, Bever CT Jr., Simon J, Goldstein A, Burrows GG, Offner H, Ferro AJ, Vandenbark AA, 2012. Recombinant T-Cell Receptor Ligand (RTL) for Treatment of Multiple Sclerosis: A Double-Blind, Placebo-Controlled, Phase 1, Dose-Escalation Study. Autoimmune Dis 2012, 954739 10.1155/2012/954739 [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Zhang XQ, Cui Y, Cui Y, Chen Y, Na XD, Chen FY, Wei XH, Li YY, Liu XG, Xin WJ, 2012. Activation of p38 signaling in the microglia in the nucleus accumbens contributes to the acquisition and maintenance of morphine-induced conditioned place preference. Brain Behav Immun 26, 318–325. 10.1016/j.bbi.2011.09.017 [DOI] [PubMed] [Google Scholar]
  57. Zhou L, Smith RJ, Do PH, Aston-Jones G, See RE, 2012. Repeated orexin 1 receptor antagonism effects on cocaine seeking in rats. Neuropharmacology 63, 1201–1207. 10.1016/j.neuropharm.2012.07.044 [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Zhuang W, Tang Y, Zhong N, Jiang H, Du J, Wang J, Zhao M, 2016. Persistent Microstructural Deficits of Internal Capsule in One-Year Abstinent Male Methamphetamine Users: a Longitudinal Diffusion Tensor Imaging Study. J Neuroimmune Pharmacol 11, 523–530. 10.1007/s11481-016-9673-x [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1
NIHMS1596193-supplement-1.pdf (281.7KB, pdf)

RESOURCES