Memantine abolishes the formation of cocaine-induced conditioned place preference possibly via its IL-6-modulating effect in medial prefrontal cortex

Institute of Behavioral Medicine, National Cheng Kung University College of Medicine, Tainan 701, Taiwan, ROC.
Behavioural brain research (Impact Factor: 3.03). 06/2011; 220(1):126-31. DOI: 10.1016/j.bbr.2011.01.031
Source: PubMed


In this study, we decided to use low doses of memantine pretreatment to examine the roles of the immune function in cocaine-supported conditioning. Cocaine-induced conditioned place preference (CPP) was used to assess the hedonic value and/or reinforcing efficacy of cocaine and cocaine-supported conditioning. Systemic pretreatment with memantine (20, 2.0, 0.2, and 0.02 mg/kg/injection) 30 min before each cocaine and saline conditioning trial abolished the acquisition of cocaine-induced CPP in mice. Even a total of 0.12 mg/kg memantine pretreatment in three days was effective in diminishing cocaine-induced CPP. Three consecutive days of cocaine conditioning increased interleukin-6 (IL-6) but decreased tumor necrosis factor (TNF-α) levels in medial prefrontal cortex (mPFC) and nucleus accumbens (Acb). Interestingly, pretreatment with memantine at the lowest effective dose (0.02 mg/kg/injection) reversed cocaine conditioning-enhanced IL-6 and -decreased TNF-α levels in these brain regions. Nevertheless, such a memantine dosing regimen did not affect dopamine metabolism in mPFC and Acb. Single memantine (0.02 mg/kg) injection did not acutely affect mouse locomotor activity or cocaine-increased locomotor activity. Similar memantine dosing regimen was ineffective to affect the maintenance of cocaine-induced CPP. Finally, intra-mPFC infusion of recombinant IL-6, but not thalidomide, reversed memantine (0.02 mg/kg/injection × 6)-decreased cocaine-induced CPP. These results, taken together, suggest that cocaine conditioning-enhanced IL-6 in mPFC may be, in part, involved in the acquisition of cocaine-induced CPP. Moreover, an extremely low dose of memantine may decrease the acquisition of cocaine-induced CPP by reversing cocaine conditioning-increased IL-6 levels in mPFC.

Full-text preview

Available from:
  • Source
    • "We tested if six consecutive rimonabant injections (SR1, i.p., 3 mg/kg or 1.5 μg bilaterally in the mPFC) administered twice per day at 8 h intervals for 3 days would affect mouse activity levels. Approximately 20 h after the 6th injection of rimonabant, the locomotor activity was monitored for 15 min as previously described (Ho et al. 2009; Lin et al. 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cannabinoid CB1 receptors are implicated in various forms of learning and memory, including acquisition and reinstatement of cocaine-associated memory. However, roles of CB1 receptors in consolidation and extinction processes of cocaine-associated memory and the brain areas potentially involved remain unknown. This study examined the effect of rimonabant, a CB1 receptor antagonist, administered systemically or directly into the medial prefrontal cortex (mPFC) on memory consolidation and extinction of cocaine-induced conditioned place preference (CPP). Male C57BL/6J mice were trained to acquire cocaine-induced CPP. Rimonabant (0.1-3 mg/kg, i.p. or 1.5 μg bilaterally in the mPFC) or vehicle was administered either immediately after each CPP training (consolidation) or forced extinction (extinction) trial. Cocaine-induced CPP was tested after training, extinction, or cocaine priming. Systemic or intra-mPFC administration of rimonabant impaired consolidation of CPP induced by a high dose (20 or 40 mg/kg) of cocaine but facilitated that induced by a low dose (2.5, 5, or 10 mg/kg). Moreover, systemic or intra-mPFC administration of rimonabant enhanced extinction of CPP memory induced by a high-dose (20 mg/kg) cocaine. Our results suggest that antagonism of CB1 receptors in the mPFC bidirectionally modulates consolidation but facilitates extinction of cocaine-induced CPP memory. Therefore, CB1 receptor blockade with the concomitant extinction behavioral procedure may hint important therapeutic intervention strategies for the heavy cocaine addicts in a clinical setting.
    Full-text · Article · Nov 2014 · Psychopharmacology
  • Source
    • "For example, specific lesion of the prelimbic mPFC was sufficient to block cocaine induced CPP [26], [27]. Furthermore, noradrenergic and 5-HT depletion of the PFC could attenuate the preference for cocaine-associated environment [28], [29]. In the present study, we found that cocaine CPP resulted in global DNA hypomethylation in the PFC. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Analysis of global methylation in cells has revealed correlations between overall DNA methylation status and some biological states. Recent studies suggest that epigenetic regulation through DNA methylation could be responsible for neuroadaptations induced by addictive drugs. However, there is no investigation to determine global DNA methylation status following repeated exposure to addictive drugs. Using mice conditioned place preference (CPP) procedure, we measured global DNA methylation level in the nucleus accumbens (NAc) and the prefrontal cortex (PFC) associated with drug rewarding effects. We found that cocaine-, but not morphine- or food-CPP training decreased global DNA methylation in the PFC. Chronic treatment with methionine, a methyl donor, for 25 consecutive days prior to and during CPP training inhibited the establishment of cocaine, but not morphine or food CPP. We also found that both mRNA and protein level of DNMT (DNA methytransferase) 3b in the PFC were downregulated following the establishment of cocaine CPP, and the downregulation could be reversed by repeated administration of methionine. Our study indicates a crucial role of global PFC DNA hypomethylation in the rewarding effects of cocaine. Reversal of global DNA hypomethylation could significantly attenuate the rewarding effects induced by cocaine. Our results suggest that methionine may have become a potential therapeutic target to treat cocaine addiction.
    Full-text · Article · Mar 2012 · PLoS ONE
  • Source
    • "Memantine in higher doses (7.5–20 mg/kg; s.c.) was considered an NMDA receptor antagonist and an inhibitor of morphine-induced tolerance, physical dependence, and drug seeking effects in animal models (Popik and Skolnick 1996; Ribeiro Do Couto et al. 2004). However, we recently showed (Lin et al. 2011) that using a low dose of memantine (0.02–2.0 mg/kg) abolished cocaine-induced CPP behavior in rats via its IL-6-modulating effect in the medial prefrontal cortex. In our clinic, 5 mg (0.1 mg/kg) of oral memantine added to the methadone replacement therapy given to heroin abusers significantly attenuated the methadone replacement dose and the combined heroin use (unpublished data). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Opioid abuse and dependency are international problems. Studies have shown that neuronal inflammation and degeneration might be related to the development of opioid addiction. Thus, using neuroprotective agents might be beneficial for treating opioid addiction. Memantine, an Alzheimer's disease medication, has neuroprotective effects in vitro and in vivo. In this study, we evaluated whether a low dose of memantine prevents opioid-induced drug-seeking behavior in rats and analyzed its mechanism. A conditioned-place-preference test was used to investigate the morphine-induced drug-seeking behaviors in rats. We found that a low-dose (0.2-1 mg/kg) of subcutaneous memantine significantly attenuated the chronic morphine-induced place-preference in rats. To clarify the effects of chronic morphine and low-dose memantine, serum and brain levels of cytokines and brain-derived neurotrophic factor (BDNF) were measured. After 6 days of morphine treatment, cytokine (IL-1β, IL-6) levels had significantly increased in serum; IL-1β and IL-6 mRNA levels had significantly increased in the nucleus accumbens and medial prefrontal cortex, both addiction-related brain areas; and BDNF levels had significantly decreased, both in serum and in addiction-related brain areas. Pretreatment with low-dose memantine significantly attenuated chronic morphine-induced increases in serum and brain cytokines. Low-dose memantine also significantly potentiated serum and brain BDNF levels. We hypothesize that neuronal inflammation and BDNF downregulation are related to the progression of opioid addiction. We hypothesize that the mechanism low-dose memantine uses to attenuate morphine-induced addiction behavior is its anti-inflammatory and neurotrophic effects.
    Full-text · Article · Dec 2011 · Journal of Neuroimmune Pharmacology
Show more