Low-dose memantine attenuated morphine addictive behavior through its anti-inflammation and neurotrophic effects in rats.
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.
Department of Psychiatry, College of Medicine and Hospital, Addiction Research Center, National Cheng Kung University, 138 Sheng-Li Road, Tainan, Taiwan.
Shiou-Lan
SL
Chen
Pao-Luh
PL
Tao
Chun-Hsien
CH
Chu
Shih-Heng
SH
Chen
Hsiang-En
HE
Wu
Leon F
LF
Tseng
Jau-Shyong
JS
Hong
Ru-Band
RB
Lu
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D053583:Interleukin-1beta / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology; D009021:Morphine Dependence; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
D000701:Analgesics, Opioid; D000893:Anti-Inflammatory Agents; D019208:Brain-Derived Neurotrophic Factor; D053583:Interleukin-1beta; D015850:Interleukin-6; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D009020:Morphine; D008559:Memantine