2.2. Inflammatory signaling

A growing literature demonstrates that methamphetamine exposure and activation of microglia and astrocytes (as well as other cell types) alters peripheral and central immune functions (In, Son, Rhee, & Pyo, 2005; In et al., 2004; Liang et al., 2008; Martinez et al., 2009; Ye et al., 2008) and that immune factors such as cytokines (e.g., IL-1β, IL-6, and TNF-α), chemokines [e.g., monocyte chemotactic protein-1 (MCP-1)], and adhesion molecules play a critical role in the development and persistence of methamphetamine-induced neuronal injury and neuropsychiatric impairments (Clark et al., 2013; Loftis et al., 2011; Yamamoto, Moszczynska, & Gudelsky, 2010; Yamamoto & Raudensky, 2008). In an astrocytic cell line, methamphetamine exposure for 3 days increases IL-6 and IL-8 RNA levels by 4.6 ± 0.2 fold and 3.5 ± 0.2 fold, respectively (Shah et al., 2012). Consistent with these findings, mice treated with methamphetamine show brain region-specific increases in the expression of proinflammatory cytokines (e.g., IL-1β) up to 3 weeks after methamphetamine exposure (Loftis et al., 2011). In a rigorous study designed to evaluate whether or not deletion of the TNF-α gene in mice affects addictive-like behavior, including methamphetamine self-administration, motivation to self-administer methamphetamine, and cue-induced reinstatement of methamphetamine-seeking behavior, Yan, Nitta, Koseki, Yamada, and Nabeshima (2012) measured methamphetamine self-administration and reinstatement of drug-seeking behavior in TNF-α knock-out and wild-type mice. The authors observed an upward shift of dose responses to methamphetamine self-administration under a fixed ratio schedule of reinforcement in the TNF-α knockout as compared with wild-type mice, indicating that mice lacking TNF-α administered more methamphetamine than controls. Similarly, TNF-α knock-out mice also had a higher breaking point under a progressive ratio schedule of reinforcement, suggesting that TNF-α can also influence motivation to self-administer drug. Taken together, these findings demonstrate that TNF-α signaling affects methamphetamine self-administration and motivation to obtain the drug. However, TNF-α did not appear to contribute to methamphetamine-associated cue-induced relapsing behavior (Yan et al., 2012).

Interestingly, IFN-γ (another proinflammatory cytokine) injected systemically prior to repeated methamphetamine exposure protects against methamphetamine-induced neurotoxicity (as measured by a reduction in striatal dopamine transporters) and hyperthermia, putatively through intracerebralmolecular pathways (Hozumi et al., 2008). Thus, of the altered immune factors, some cytokines appear to facilitate or promote methamphetamine-induced toxicities but others may slow or prevent the development of adverse drug effects. Taken together, these observations describe a critical role for CNS immune signaling in methamphetamine neurotoxicity and dependence. More research is needed to elucidate the specific signaling pathways [e.g., STAT3, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (Wires et al., 2012)] and cell types (e.g., microglia, astrocytes, and vascular endothelial cells) that induce and perpetuate these neuroinflammatory processes—particularly because these immune effects can impact addictive and related behavioral responses.

5.2. Neuroimmune-based and other anti-inflammatory treatment strategies

Ibudilast (AV-411 or MN-166) is a nonspecific phosphodiesterase inhibitor which suppresses glial cell activation and causes other anti-inflammatory effects. Prior to its development as a potential substance abuse treatment (e.g., for methamphetamine, alcohol, and opioid dependence), ibudilast had been used clinically for asthma, pulmonary, and cardiovascular diseases. Preclinically, administration of ibudilast following exposure to methamphetamine reduces: (1) the acute, chronic, and sensitization effects of the drug’s locomotor activity, (2) stress-induced methamphetamine relapse, and (3) methamphetamine self-administration—suggesting that glial cell activity can modulate methamphetamine’s behavioral effects (Beardsley, Shelton, Hendrick, & Johnson, 2010; Snider, Hendrick, & Beardsley, 2013; Snider et al., 2012). To date, a Phase I clinical trial of ibudilast with methamphetamine dependence has been completed. This initial human study was done in order to test the safety of the drug taken in combination with methamphetamine. Results from the Phase I safety interaction trial of ibudilast with methamphetamine are not yet publicly available (https://ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01217970","term_id":"NCT01217970"}}NCT01217970). Currently, the research is into its second phase, and results from the 12-week Phase II clinical trial are expected to be released in early 2015 (https://ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01860807","term_id":"NCT01860807"}}NCT01860807).

In addition to the development of therapeutic strategies for preventing and reducing methamphetamine use, interventions that target immune mechanisms for repairing persistent methamphetamine-induced CNS injury and neuropsychiatric impairments may also help reduce relapse rates and improve treatment outcomes in adults recovering from methamphetamine dependence and other substance use disorders. Given that a partial major histocompatibility complex (MHC)/neuroantigen peptide construct [pI-A^b/mMOG-35–55; a.k.a. recombinant T-cell receptor ligand (RTL)] effectively reduces the inflammatory and behavioral effects of experimental models of multiple sclerosis and stroke (Sinha et al., 2007; Subramanian et al., 2009; Vandenbark et al., 2003; Wang et al., 2006), it is possible that partial MHC/neuroantigen constructs could also effectively address the neuropsychiatric effects of chronic methamphetamine addiction. In a preclinical study, RTL-containing MHC coupled to myelin peptide [mouse myelin oligodendrocyte glycoprotein (mMOG)] improves the learning and memory impairments and CNS inflammation induced by repeated methamphetamine exposure in mouse models of chronic methamphetamine addiction (Loftis, Wilhelm, Vandenbark, & Huckans, 2013).

In addition to vaccine and neuroimmune-based strategies (e.g., ibudilast and partial MHC/neuroantigen peptide constructs), pharmacotherapies that regulate and reduce inflammation and oxidative stress are also under investigation. For example, minocycline (a broad-spectrum tetracycline antibiotic) has anti-inflammatory and antioxidant properties and has demonstrated some efficacy in the treatment of psychiatric disorders and neuropsychiatric symptoms. Preclinically, minocycline improves deficits in novel object recognition (a measure of cognitive function) induced by phencyclidine and methamphetamine treatment in mice (Fujita et al., 2008; Mizoguchi et al., 2008) and reduces the behavioral sensitization induced by methamphetamine and cocaine (Chen, Uz, & Manev, 2009; Zhang et al., 2006). In clinical studies, the results vary, with findings supporting the use of minocycline in schizophrenia, but showing less benefit for nicotine dependence (reviewed in Dean, Data-Franco, Giorlando, & Berk, 2012). Nonsteroidal anti-inflammatory drugs [(e.g., ketoprofen), traditional and selective inhibitors of cyclooxygenase (COX)-2] have also been evaluated for the treatment of psychiatric illness (Berk et al., 2013). For example, in one preclinical study, ketoprofen pretreatment (but not aspirin) dose-dependently attenuated methamphetamine-induced neuroxicity, as measured by reduction of dopamine transporters and accumulation of microglial cells in the striatum (Asanuma, Tsuji, Miyazaki, Miyoshi, & Ogawa, 2003).

Taken together, these preclinical and initial clinical findings indicate that immunotherapeutic strategies which target specific inflammatory pathways, reduce neurotoxicity, promote neuronal repair, and improve neuropsychiatric function may have potential as treatments for methamphetamine dependence and other substances of abuse.

This work was in part supported by National Institutes of Health Grant DA018165 to the Methamphetamine Abuse Research Center (MARC) in Portland, Oregon. This material is the result of work supported with resources and the use of facilities at the Portland Veterans Affairs Medical Center and Oregon Health & Science University. Jennifer M. Loftis, Ph.D., and Aaron Janowsky, Ph.D., are Research Scientists at the Portland Veterans Affairs Medical Center. The authors would like to thank Jason A. Laramie, Certified Medical Illustrator, for help in preparing Fig. 7.1. The authors acknowledge Elsevier for the use of Table 7.1, a version of which was previously published in Pharmacology & Therapeutics (i.e., Loftis and Huckans, 2013).

The Department of Veterans Affairs and Oregon Health & Science University own a technology referenced in this review (a partial MHC/neuroantigen peptide construct). The Department of Veterans Affairs, OHSU, and Dr. Loftis have rights to the royalties from the licensing agreement with Artielle (the company that has licensed the technology).