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The Journal of Neuroscience, June 15, 2001, 21(12):4451-4459

Morphine-Induced Dependence and Sensitization Are Altered in Mice Deficient in AMPA-Type Glutamate Receptor-A Subunits

Olga Y. Vekovischeva^{1, 2}, Daniel Zamanillo³, Oxana Echenko¹, Timo Seppälä⁴, Mikko Uusi-Oukari¹, Aapo Honkanen¹, Peter H. Seeburg³, Rolf Sprengel³, and Esa R. Korpi¹

¹ Department of Pharmacology and Clinical Pharmacology, University of Turku, FIN-20520 Turku, Finland, ² International Graduate School in Neurosciences, University of Tampere Medical School, FIN-33101 Tampere, Finland, ³ Department of Molecular Neurobiology, Max-Planck Institute for Medical Research, D-69120 Heidelberg, Germany, and ⁴ Laboratory of Substance Abuse, National Public Health Institute, FIN-00300 Helsinki, Finland

AMPA-type glutamate receptors have been suggested to be involved in the neurobiological mechanisms of drug addiction. We have made use of two mouse lines, which both have modulated AMPA receptor responses. The first line is entirely deficient in glutamate receptor-A (GluR-A) subunits (A/ knock-out line) and, in the second one, the Q582 residue of GluR-A subunits is replaced by an arginine residue (R/R mutants), which reduces the calcium permeability and channel conductance of the receptors containing this mutated subunit. Mice of both lines are healthy, but they show slightly increased locomotor activity. Acute morphine administration enhanced locomotor activity of the GluR-A/ and GluR-A(R/R) mice, at least as much as that of their wild-type littermates. Only in the GluR-A/ mice did we observe reduced tolerance development in tail-flick antinociception and less severe naloxone-precipitated withdrawal symptoms after treatment with increasing morphine doses, without differences in plasma and brain morphine levels when compared with wild type. Repeated daily morphine administration sensitized the locomotor activity responses in the GluR-A/ and GluR-A(R/R) mice only when given in the measuring cages, whereas the wild-type mice showed slightly increased responses also when the repeated treatment was given in their home cages. Normal or even enhanced context-dependent sensitization was observed also with repeated amphetamine administration in the GluR-A subunit-deficient mice. The results indicate that AMPA receptors are involved in the acute and chronic effects of morphine, including context-independent sensitization, and that the GluR-A subunit itself is important for morphine tolerance and dependence.

Key words: neurobiology of addiction; glutamate receptors; AMPA receptors; transgenic mouse lines; morphine; amphetamine

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21124451-09$05.00/0

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