Publications by authors named "Mark D Namba"

11 Publications

  • Page 1 of 1

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities.

Front Neurosci 2021 15;15:650785. Epub 2021 Apr 15.

School of Life Sciences, Arizona State University, Tempe, AZ, United States.

Recent studies examining the neurobiology of substance abuse have revealed a significant role of neuroimmune signaling as a mechanism through which drugs of abuse induce aberrant changes in synaptic plasticity and contribute to substance abuse-related behaviors. Immune signaling within the brain and the periphery critically regulates homeostasis of the nervous system. Perturbations in immune signaling can induce neuroinflammation or immunosuppression, which dysregulate nervous system function including neural processes associated with substance use disorders (SUDs). In this review, we discuss the literature that demonstrates a role of neuroimmune signaling in regulating learning, memory, and synaptic plasticity, emphasizing specific cytokine signaling within the central nervous system. We then highlight recent preclinical studies, within the last 5 years when possible, that have identified immune mechanisms within the brain and the periphery associated with addiction-related behaviors. Findings thus far underscore the need for future investigations into the clinical potential of immunopharmacology as a novel approach toward treating SUDs. Considering the high prevalence rate of comorbidities among those with SUDs, we also discuss neuroimmune mechanisms of common comorbidities associated with SUDs and highlight potentially novel treatment targets for these comorbid conditions. We argue that immunopharmacology represents a novel frontier in the development of new pharmacotherapies that promote long-term abstinence from drug use and minimize the detrimental impact of SUD comorbidities on patient health and treatment outcomes.
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http://dx.doi.org/10.3389/fnins.2021.650785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082184PMC
April 2021

The Long-Acting D3 Partial Agonist MC-25-41 Attenuates Motivation for Cocaine in Sprague-Dawley Rats.

Biomolecules 2020 07 18;10(7). Epub 2020 Jul 18.

School of Life Sciences, Arizona State University, PO Box 874501, Tempe, AZ 85287-4501, USA.

The dopamine D3 receptor is a prime target for developing treatments for cocaine use disorders (CUDs). In this study, we conducted a pre-clinical investigation of the therapeutic potential of a long-acting, D3 receptor partial agonist, MC-25-41. Male rats were pre-treated with MC-25-41 (vehicle, 1.0, 3.0, 5.6, or 10 mg/kg, intraperitoneal (IP)) five minutes prior to tests of cocaine or sucrose intake on either a progressive ratio schedule of reinforcement or a variable interval 60 s multiple schedule consisting of 4, 15-min components with sucrose or cocaine available in alternating components. A separate cohort of rats was tested on a within-session, dose-reduction procedure to determine the effects of MC-25-41 on demand for cocaine using a behavioral economics analysis. Finally, rats were tested for effects of MC-25-41 on spontaneous and cocaine-induced locomotion. MC-25-41 failed to alter locomotion, but reduced reinforcement rates for both cocaine and sucrose on the low-effort, multiple schedule. However, on the higher-effort, progressive ratio schedule of cocaine reinforcement, MC-25-41 reduced infusions, and active lever presses at doses that did not alter sucrose intake. The behavioral economics analysis showed that MC-25-41 also increased cocaine demand elasticity compared to vehicle, indicating a reduction in consumption as price increases. Together, these results suggest that similar to other D3-selective antagonists and partial agonists, MC-25-41 reduces motivation for cocaine under conditions of high cost but has the added advantage of a long half-life (>10 h). These findings suggest that MC-25-41 may be a suitable pre-clinical lead compound for development of medications to treat CUDs.
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http://dx.doi.org/10.3390/biom10071076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408535PMC
July 2020

Erratum to "Economic demand analysis of within-session dose-reduction during nicotine self-administration" [Drug Alcohol Depend. 201 (2019) 188-196].

Drug Alcohol Depend 2019 Oct 26;203:107. Epub 2019 Jul 26.

Department of Psychology, Arizona State University, 950 McAllister Ave., Psychology Room 203, Tempe, AZ, 85287, USA. Electronic address:

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http://dx.doi.org/10.1016/j.drugalcdep.2019.07.005DOI Listing
October 2019

Accumbens neuroimmune signaling and dysregulation of astrocytic glutamate transport underlie conditioned nicotine-seeking behavior.

Addict Biol 2020 09 22;25(5):e12797. Epub 2019 Jul 22.

Department of Psychology, Arizona State University, Tempe, AZ, USA.

Nicotine self-administration is associated with decreased expression of the glial glutamate transporter (GLT-1) and the cystine-glutamate exchange protein xCT within the nucleus accumbens core (NAcore). N-acetylcysteine (NAC) has been shown to restore these proteins in a rodent model of drug addiction and relapse. However, the specific molecular mechanisms driving its inhibitory effects on cue-induced nicotine reinstatement are unknown. Here, we confirm that extinction of nicotine-seeking behavior is associated with impaired NAcore GLT-1 function and expression and demonstrates that reinstatement of nicotine seeking rapidly enhances membrane fraction GLT-1 expression. Extinction and cue-induced reinstatement of nicotine seeking was also associated with increased tumor necrosis factor alpha (TNFα) and decreased glial fibrillary acidic protein (GFAP) expression in the NAcore. NAC treatment (100 mg/kg/day, i.p., for 5 d) inhibited cue-induced nicotine seeking and suppressed AMPA to NMDA current ratios, suggesting that NAC reduces NAcore postsynaptic excitability. In separate experiments, rats received NAC and an antisense vivo-morpholino to selectively suppress GLT-1 expression in the NAcore during extinction and were subsequently tested for cue-induced reinstatement of nicotine seeking. NAC treatment rescued NAcore GLT-1 expression and attenuated cue-induced nicotine seeking, which was blocked by GLT-1 antisense. NAC also reduced TNFα expression in the NAcore. Viral manipulation of the NF-κB pathway, which is downstream of TNFα, revealed that cue-induced nicotine seeking is regulated by NF-κB pathway signaling in the NAcore independent of GLT-1 expression. Ultimately, these results are the first to show that immunomodulatory mechanisms may regulate known nicotine-induced alterations in glutamatergic plasticity that mediate cue-induced nicotine-seeking behavior.
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http://dx.doi.org/10.1111/adb.12797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323912PMC
September 2020

Economic demand analysis of within-session dose-reduction during nicotine self-administration.

Drug Alcohol Depend 2019 08 20;201:188-196. Epub 2019 Jun 20.

Department of Psychology, Arizona State University, 950 McAllister Ave., Psychology Room 203, Tempe, AZ, 85287 USA. Electronic address:

Background: This study determined if a within-session dose-reduction design sufficiently captures elasticity of demand for nicotine in male and female rats using environmental enrichment to manipulate demand elasticity.

Methods: Male and female Sprague-Dawley rats were trained to self-administer nicotine (60 μg/kg/infusion). In Experiment 1, rats began daily dose-reduction for nine sessions following acquisition. Rats then underwent a minimum of five within-session dose-reduction sessions where each dose was available for 10 min. In Experiment 2, rats were reared in isolated, social, or enriched housing followed by acquisition of nicotine self-administration. Rats then underwent within-session dose-reduction. Housing environments were then switched, followed by additional testing sessions. Consumption was calculated for each dose and exponential demand curves were fit.

Results: No sex differences in acquisition of nicotine self-administration were detected for either experiment. In experiment 1, demand intensity (Q; estimated intake if nicotine were freely available), was higher with between- compared to within-session dose-reduction, although elasticity of demand (α; rate of decline in nicotine intake as a function of increasing unit price), was lower. In Experiment 2, animals reared in enrichment had fewer infusions during acquisition compared to animals in isolation. Enriched males had reduced demand intensity compared to both isolated and social males, whereas isolated females had reduced intensity compared to enriched females.

Conclusions: The within-session dose-reduction procedure for nicotine self-administration replicated effects of environmental enrichment on consumption behaviors. Additionally, this procedure captured differences in nicotine demand due to sex, laying important groundwork for future translational research on mechanisms of nicotine dependence.
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http://dx.doi.org/10.1016/j.drugalcdep.2019.03.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639047PMC
August 2019

N-acetylcysteine yields sex-specific efficacy for cue-induced reinstatement of nicotine seeking.

Addict Biol 2020 01 7;25(1):e12711. Epub 2019 Feb 7.

Department of Psychology, Arizona State University, Tempe, Arizona.

Women report greater craving during certain phases of the menstrual cycle. As well, research indicates that pharmacotherapies for smoking may be less efficacious in women compared with men, which may be due to interactions with natural fluctuations in ovarian hormone levels. N-Acetylcysteine (NAC) is a glutamatergic compound that has shown some efficacy in treating substance use disorders and aids in the prevention of relapse. However, it is unclear whether NAC has sex-specific effectiveness for nicotine relapse treatment. Given that NAC has shown promise to reduce nicotine reinstatement in preclinical models using male rats, the exploration of potential sex differences in the efficacy of NAC is warranted. Using a rat model, we first investigated the ability of NAC treatment (100 mg/kg, ip) during nicotine withdrawal with extinction training to reduce cue-induced nicotine seeking in male and female rats. Next, we assessed whether NAC's effects were estrous cycle-dependent for female rats. Results show that following NAC treatment during extinction, reinstatement of nicotine seeking was significantly decreased in males but not females, indicating a sex-specific effect of NAC. Furthermore, for females, both vehicle- and NAC-treated groups significantly reinstated nicotine-seeking behavior compared with extinction, regardless of estrous cycle phase. These results suggest that NAC is inefficacious in reducing nicotine relapse in females regardless of estrous cycle phase at the dose evaluated here. These collective findings could have important clinical implications for use and efficacy of NAC as a pharmacotherapy for freely cycling women smokers.
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http://dx.doi.org/10.1111/adb.12711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685767PMC
January 2020

Chronic treatment with N-acetylcysteine decreases extinction responding and reduces cue-induced nicotine-seeking.

Physiol Rep 2019 01;7(1):e13958

Department of Psychology, Arizona State University, Tempe, Arizona.

N-acetylcysteine (NAC), a promising glutamatergic therapeutic agent, has shown some clinical efficacy in reducing nicotine use in humans and has been shown to reverse drug-induced changes in glutamatergic neurophysiology. In rats, nicotine-seeking behavior is associated with alterations in glutamatergic plasticity within the nucleus accumbens core (NAcore). Specifically, cue-induced nicotine-seeking is associated with rapid, transient synaptic plasticity (t-SP) in glutamatergic synapses on NAcore medium spiny neurons. The goal of the present study was to determine if NAC reduces nicotine-seeking behavior and reverses reinstatement-associated NAcore glutamatergic alterations. Rats were extinguished from nicotine self-administration, followed by subchronic NAC administration (0 or 100 mg/kg/d) for 4 days prior to cue-induced reinstatement. NAcore synaptic potentiation was measured via dendritic spine morphology and mRNA and protein of relevant glutamatergic genes were quantified. Nicotine-seeking behavior was not reduced by subchronic NAC treatment. Also, NAcore transcript and protein expression of multiple glutamatergic genes, as well as spine morphological measures, were unaffected by subchronic NAC. Finally, chronic NAC treatment (15 days total) during extinction and prior to reinstatement significantly decreased extinction responding and reduced reinstatement of nicotine-seeking compared to vehicle. Together, these results suggest that chronic NAC treatment is necessary for its therapeutic efficacy as a treatment strategy for nicotine addiction and relapse.
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http://dx.doi.org/10.14814/phy2.13958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328917PMC
January 2019

A novel rat model of comorbid PTSD and addiction reveals intersections between stress susceptibility and enhanced cocaine seeking with a role for mGlu5 receptors.

Transl Psychiatry 2018 10 5;8(1):209. Epub 2018 Oct 5.

Psychology Department, University of Florida, Gainesville, FL, 32611, USA.

PTSD is highly comorbid with cocaine use disorder (CUD), and cocaine users with PTSD + CUD are more resistant to treatment. Here we sought to develop a rat model of PTSD + CUD in order to identify the neurobiological changes underlying such comorbidity and screen potential medications for reducing cocaine seeking in the PTSD population. We utilized a predator scent stress model of PTSD, wherein rats received a single exposure to the fox pheromone 2,5-dihydro-2,4,5-trimethylthiazoline (TMT). One week after TMT exposure, stress-susceptible (susceptible), intermediate, and resilient phenotypes were detected and were consistent with behavioral, corticosterone, and gene expression profiles 3 weeks post TMT. We assessed phenotypic differences in cocaine self-administration, extinction, and cue-primed reinstatement. Susceptible rats exhibited deficits in extinction learning and increased cue-primed reinstatement that was not prevented by Ceftriaxone, an antibiotic that consistently attenuates the reinstatement of cocaine seeking. TMT-exposed resilient rats displayed increased mGlu5 gene expression in the amygdala and medial prefrontal cortex and did not display the enhanced cocaine seeking observed in susceptible rats. Combined treatment with the mGlu5 positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1 H-pyrazol-5-yl)benzamide (CDPPB), fear extinction, and ceftriaxone prevented the reinstatement of cocaine seeking in susceptible rats with fear extinction an important mediating condition. These results highlight the need for animal models of PTSD to consider stress-responsivity, as only a subset of trauma-exposed individuals develop PTSD and these individuals likely exhibit distinct neurobiological changes compared with trauma-exposed populations who are resilient to stress. This work further identifies glutamate homeostasis and mGlu5 as a target for treating relapse in comorbid PTSD-cocaine addiction.
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http://dx.doi.org/10.1038/s41398-018-0265-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173705PMC
October 2018

Impairments in reversal learning following short access to cocaine self-administration.

Drug Alcohol Depend 2018 11 25;192:239-244. Epub 2018 Sep 25.

Department of Psychology, University of Florida, 945 Center Dr., Gainesville, FL, 32611, United States.

Background: Cocaine use disorder is characterized by compulsive drug-seeking that persists long into abstinence. Work using rodent models of cocaine addiction has found evidence for reversal learning deficits 21 days after non-contingent cocaine administration and 60 days after self-administration. Here we sought to determine if a deficit in reversal learning is present 3-4 weeks after cessation of cocaine self-administration, when relapse to cocaine-seeking is robust. Conversely, we hypothesized that reversal learning training would protect against relapse, similar to other forms of environmental enrichment.

Methods: Male rats underwent short access (ShA, 2 h/10d) or long access (LgA, 1 h/7d then 6 h/10d) cocaine self-administration, followed by 21-29 days of abstinence. During abstinence, a subset of rats underwent training in a plus-maze that required an egocentric strategy to earn a sucrose reward. Following response acquisition and retention, the ability to reverse the spatial navigation strategy was tested.

Results: Total trials to criteria and total errors made did not differ between the groups during response acquisition, retention, or reversal. On the first reversal test, ShA rats performed better than LgA and control rats. ShA rats' performance worsened over time. There were no effects of cognitive training or length of cocaine access on context-primed relapse of cocaine-seeking.

Conclusions: The present data indicate that perhaps LgA cocaine self-administration does not produce adaptations to regions mediating context-primed relapse as it does for cocaine and cocaine-associated cue-induced reinstatement of drug-seeking. A time-dependent deficit in reversal learning was found only in ShA rats. Reversal learning training did not protect against cocaine relapse.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200584PMC
November 2018

Social Influences on Nicotine-Related Behaviors.

Int Rev Neurobiol 2018 6;140:1-32. Epub 2018 Aug 6.

Department of Psychology, Arizona State University, Tempe, AZ, United States. Electronic address:

Cigarette smoking is the leading preventable cause of death in the United States. The number of new smokers, specifically among adolescents, has risen rapidly in recent years. Thus, understanding the role of social influences on patterns of nicotine and tobacco use is important. Clinical studies have addressed the impact social relationships such as family members and peers have on smoking acquisition and susceptibility. As well, preclinical animal models have examined the impact of social factors on drug intake, acquisition, maintenance, and relapse. For example, environmental enrichment (EE) is a multi-faceted model that includes social factors, exercise, and novelty, among others. This model has elucidated addiction-related neurobehavioral effects of these different factors. However, there is a dearth of literature examining the impact of social partners on nicotine addiction and underlying neural mechanisms. Here we discuss the importance of social factors on nicotine addiction vulnerability, and propose new directions for addiction research that integrate social aspects of nicotine use.
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http://dx.doi.org/10.1016/bs.irn.2018.07.001DOI Listing
March 2019

The Winding Road to Relapse: Forging a New Understanding of Cue-Induced Reinstatement Models and Their Associated Neural Mechanisms.

Front Behav Neurosci 2018 9;12:17. Epub 2018 Feb 9.

Department of Psychology, Arizona State University, Tempe, AZ, United States.

In drug addiction, cues previously associated with drug use can produce craving and frequently trigger the resumption of drug taking in individuals vulnerable to relapse. Environmental stimuli associated with drugs or natural reinforcers can become reliably conditioned to increase behavior that was previously reinforced. In preclinical models of addiction, these cues enhance both drug self-administration and reinstatement of drug seeking. In this review, we will dissociate the roles of conditioned stimuli as reinforcers from their modulatory or discriminative functions in producing drug-seeking behavior. As well, we will examine possible differences in neurobiological encoding underlying these functional differences. Specifically, we will discuss how models of drug addiction and relapse should more systematically evaluate these different types of stimuli to better understand the neurobiology underlying craving and relapse. In this way, behavioral and pharmacotherapeutic interventions may be better tailored to promote drug use cessation outcomes and long-term abstinence.
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http://dx.doi.org/10.3389/fnbeh.2018.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811475PMC
February 2018