Behavioural Brain Research 220 (2011) 126–131
Contents lists available at ScienceDirect
Behavioural Brain Research
journal homepage: www.elsevier.com/locate/bbr
Memantine abolishes the formation of cocaine-induced conditioned place
preference possibly via its IL-6-modulating effect in medial prefrontal cortex
Kuei-Ying Lina, Chianfang G. Cherngb, Fu-Rong Yanga, Li-Ching Linc, Ru-Band Lud, Lung Yua,c,∗
aInstitute of Behavioral Medicine, National Cheng Kung University College of Medicine, Tainan 701, Taiwan, ROC
bDepartment of Health Psychology, Chang Jung Christian University, Tainan 711, Taiwan, ROC
cDepartment of Physiology, National Cheng Kung University College of Medicine, Tainan 701, Taiwan, ROC
dDepartment of Psychiatry, National Cheng Kung University College of Medicine, Tainan 701, Taiwan, ROC
a r t i c l ei n f o
Received 14 July 2010
Received in revised form
15 December 2010
Accepted 19 January 2011
a b s t r a c t
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 condi-
tioning. Systemic pretreatment with memantine (20, 2.0, 0.2, and 0.02mg/kg/injection) 30min before
each cocaine and saline conditioning trial abolished the acquisition of cocaine-induced CPP in mice.
Even a total of 0.12mg/kg memantine pretreatment in three days was effective in diminishing cocaine-
tumor necrosis factor (TNF-?) levels in medial prefrontal cortex (mPFC) and nucleus accumbens (Acb).
Interestingly, pretreatment with memantine at the lowest effective dose (0.02mg/kg/injection) reversed
cocaine conditioning-enhanced IL-6 and -decreased TNF-? levels in these brain regions. Neverthe-
less, such a memantine dosing regimen did not affect dopamine metabolism in mPFC and Acb. Single
memantine (0.02mg/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 (0.02mg/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.
© 2011 Elsevier B.V. All rights reserved.
Accrued evidence supports the notion that glutamatergic neu-
rotransmission plays a significant role in the neurobiology of
cocaine addiction [1–5]. Several glutamate receptor antagonists
have been reported to decrease cocaine-induced behavioral sen-
sitization [6,7]. Memantine, a non-competitive glutamate NMDA
antagonist, has shown a potential therapeutic effect in treat-
ment of cocaine addiction in animal models [8,9]. Specifically,
memantine pretreatment was found to abolish the establish-
ment of cocaine-induced conditioned place preference (CPP) .
∗Corresponding author at: Behavioral Neuropharmacology Laboratory, Institute
of Behavioral Medicine, National Cheng Kung University College of Medicine,
1 University Rd., Tainan 70101, Taiwan, ROC. Tel.: +886 6 2353535x5114x5106;
fax: +886 6 2095616.
E-mail address: email@example.com (L. Yu).
statement following the extinction of cocaine-induced CPP .
Furthermore, memantine was found to attenuate the reinforcing
effect of cocaine-conditioned stimuli in Rhesus monkeys . These
to decrease the hedonic effect of cocaine.
However, conflicting results obtained from other studies com-
promised clinical use of memantine. For example, memantine
altering the choice to self-administer cocaine in six cocaine addicts
. Although memantine was well tolerated by humans and did
not appear to have abuse potential , memantine occasionally
increased levels of cocaine self-administration in Rhesus monkeys
. Paradoxically, these results suggest that subjects afflicted with
cocaine abuse or dependence may not gain beneficial effect on
memantine treatment. More importantly, memantine doses used
effect on cocaine addiction.
Many studies reported the effects of memantine on cocaine
addiction by assuming the antagonistic effect of memantine on
0166-4328/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
K.-Y. Lin et al. / Behavioural Brain Research 220 (2011) 126–131
and Acb. Since tissue DA and DOPAC contents both are indirect
indices of synaptic DA level, whether low-dose memantine can
curb cocaine-stimulated DA release in these regions remains to be
Memantine has been used for treating severely demented
[28,29]. In addition to its effect on decreasing care dependence,
memantine has been claimed to diminish emotional distress in
these patients. In this study, we found that an extremely low dose
of memantine affected cocaine-provoked cytokine concentrations
in central nervous system. These findings prompted us to hypoth-
esize that memantine treatment-associated brain immunological
responses could be involved in its treatment effects in the above-
mentioned clinical observations.
This research is supported by ROC National Science Council
grants 97-2321-B-006-010 and 97-2410-H-006-074-MY3 to L.Y.
 Boudreau AC, Wolf ME. Behavioral sensitization to cocaine is associated with
increased AMPA receptor surface expression in the nucleus accumbens. J Neu-
 Cornish JL, Kalivas PW. Glutamate transmission in the nucleus accumbens
mediates relapse in cocaine addiction. J Neurosci 2000;20:RC89.
 Gass JT, Olive MF. Glutamatergic substrates of drug addiction and alcoholism.
Biochem Pharmacol 2008;75:218–65.
 Uys JD, LaLumiere RT. Glutamate: the new frontier in pharmacother-
apy for cocaine addiction. CNS Neurol Disord Drug Targets 2008;7:
 William JM, Steketee JD. Cocaine increases medial prefrontal cortical gluta-
mate overflow in cocaine-sensitized rats: a time course study. Eur J Neurosci
 Bespalov AY, Dravolina OA, Zvartau EE, Beardsley PM, Balster RL. Effects of
NMDA receptor antagonists on cocaine-conditioned motor activity in rats. Eur
J Pharmacol 2000;390:303–11.
Dizocilpine infusion has a different effect in the development of morphine and
cocaine sensitization: behavioral and neurochemical aspects. Neuroscience
 Maldonado C, Rodríguez-Arias M, Castillo A, Aguilar MA, Mi˜ narro J. Effect of
memantine and CNQX in the acquisition, expression and reinstatement of
cocaine-induced conditioned place preference. Prog Neuropsychopharm Biol
 Newman JL, Beardsley PM. Effects of memantine, haloperidol, and cocaine
on primary and conditioned reinforcement associated with cocaine in rhesus
monkeys. Psychopharmacology (Berl) 2006;185:142–9.
 Collins ED, Vosberg SK, Ward AS, Haney M, Foltin RW. The effects of acute
effects of cocaine in humans. Exp Clin Psychopharmacol 2007;15:228–37.
 Vosburg SK, Hart CL, Haney M, Foltin RW. An evaluation of the reinforcing
effects of memantine in cocaine-dependent humans. Drug Alcohol Depend
 Wu HM, Tzeng NS, Qian L, Wei SJ, Hu X, Chen SH. Novel neuroprotective mech-
anisms of memantine: increase in neurotrophic factor release from astroglia
and anti-inflammation by preventing microglial activation. Neuropsychophar-
 Blanchard AP, Guillemette G, Boulay G. Memantine potentiates agonist-
of central neurotoxicity induced by ketamine followed by methamphetamine.
Toxicol Appl Pharmacol 2008;227:239–47.
 Kuhar MJ, Ritz MC, Boja JW. The dopamine hypothesis of the reinforcing prop-
erties of cocaine. Trends Neurosci 1991;14:299–302.
 Trecki J, Unterwald EM. Modulation of cocaine0induced activity by intracere-
bral administration of CXCL12. Neuroscience 2009;161:13–22.
 Cherng CG, Tsai C-W, Tsai Y-P, Ho M-C, Kao S-F, Yu L. Methamphetamine-
disrupted sensory processing mediates conditioned place preference perfor-
mance. Behav Brain Res 2007;182:103–8.
 Menendez-Gonzalez M, Calatayud MT, Blazquez-Menes B. Exacerbation of
Lewy bodies dementia due to memantine. J Alzheimers Dis 2005;8:289–91.
 Moellentin D, Picone C, Leadbetter E. Memantine-induced myclonus and delir-
ium exacerbated by trimethoprim. Ann Pharmacother 2008;42:443–7.
 Fan H-Y, Cherng CG, Yang F-Y, Cheng L-Y, Tsai C-J, Lin L-C, et al. Systemic treat-
ment with protein synthesis inhibitors attenuates the expression of cocaine
memory. Behav Brain Res 2010;208:522–7.
 Robinson TE, Kolb B. Alterations in the morphology of dentrites and dendritic
spines in the nucleus accumbens and prefrontal cortex following repeated
treatment amphetamine and cocaine. Eur J Neurosci 1999;11:1598–604.
 Nakajima A, Yamada K, Nagai T, Uchiyama T, Miyamoto Y, Mamiya T, et al.
dence and neurotoxicity. J Neurosci 2004;24:2212–25.
rotrophic factor, tumor necrosis factor-alpha, and an inducer of these factors
in drug dependence. J Pharmacol Sci 2007;104:116–21.
sis factor-alpha and its inducer inhibit morphine-induced rewarding effects
and sensitization. Biol Psychiatry 2007;62:658–68.
in the brain after stimulation with LPS in young and old mice. Exp Gerontol
 Biber K, Pinto-Duarte A, Wittendorp MC, Dolga AM, Fernandes CC, von Fri-
jtaq Drabbe Kunzel, et al. Interleukin-6 upregulates neuronal adenosine A1
receptors: implications for neuromodulation and neuroprotection. Neuropsy-
 Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. New York, USA: Cam-
bridge University Press; 2008.
 Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-best
study (benefit and efficacy in severely demented patients during treatment
with memantine. Int J Geriatr Psychiatry 1999;14:135–46.
 Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in
moderate-to-severe Alzheimer’s disease. New Eng J Med 2003;348:1333–41.
293 cells. Cell Physiol Biochem