Morphine-induced dependence and sensitization are altered in mice deficient in AMPA-type glutamate receptor-A subunits

AMPA-type glutamate receptors have been suggested to be involved in the neu robiological mechanisms of drug addiction. We have made use of two mouse li nes, which both have modulated AMPA receptor responses. The first line is e ntirely 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 repla ced by an arginine residue (R/R mutants), which reduces the calcium permeab ility and channel conductance of the receptors containing this mutated subu nit. Mice of both lines are healthy, but they show slightly increased locom otor 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 tolera nce development in tail-flick antinociception and less severe naloxone-prec ipitated withdrawal symptoms after treatment with increasing morphine doses , without differences in plasma and brain morphine levels when compared wit h wild type. Repeated daily morphine administration sensitized the locomoto r 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 increase d 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 mi ce. The results indicate that AMPA receptors are involved in the acute and chronic effects of morphine, including context-independent sensitization, a nd that the GluR-A subunit itself is important for morphine tolerance and d ependence.