Gene transfer of GLT-1, a glutamate transporter, into the nucleus accumbens shell attenuates methamphetamine- and morphine-induced conditioned place preference in rats.
Several lines of evidence have suggested that the glutamatergic system in the nucleus accumbens (NAc) plays an important role in the conditioned rewarding effect of drugs of abuse. In addition, it is recognized that extracellular glutamate is rapidly removed from the synaptic cleft by Na+-dependent glutamate transporters in neurons and glial cells, thereby maintaining physiological levels of glutamate. We previously reported that activation of glutamate uptake by a glutamate transporter activator attenuated the acquisition of conditioned place preference induced by methamphetamine and morphine in mice. In the present study, we examined the effects of gene transfer of a glial glutamate transporter, GLT-1, into the NAc shell by recombinant adenoviruses on methamphetamine- and morphine-induced conditioned place preference in rats. Bilateral infusion of the recombinant adenoviruses into the NAc shell efficiently increased GLT-1 expression surrounding the infusion site, at least during the period 2-8 days after the infusion. In the conditioned place preference paradigm, animals were conditioned with repeated subcutaneous injections of methamphetamine (2 mg/kg) or morphine (3 mg/kg). Intra-NAc shell overexpression of GLT-1 before the conditioning significantly attenuated the conditioned place preference induced by methamphetamine or morphine, when compared with control. However, it had no effect on the somatic signs of naloxone-precipitated morphine withdrawal. These results suggest that GLT-1 within the NAc shell plays an inhibitory role in the conditioned rewarding effects of methamphetamine and morphine but not the physical dependence on morphine.
Fujio
Mayumi
M
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Nakagawa
Takayuki
T
Sekiya
Yumiko
Y
Ozawa
Tohru
T
Suzuki
Yuichi
Y
Minami
Masabumi
M
Satoh
Masamichi
M
Kaneko
Shuji
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics*; D018014:Gene Transfer Techniques; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000235:genetics; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000697:Central Nervous System Stimulants; D027342:Excitatory Amino Acid Transporter 2; D009292:Narcotic Antagonists; D009294:Narcotics; D009270:Naloxone; D008694:Methamphetamine; D009020:Morphine