Behavioural adaptations to addictive drugs in mice lacking the NMDA receptor ε1 subunit

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Abstract
N-methyl-D-aspartate (NMDA) receptors, a subtype of glutamate receptors (GluRs) formed by assembly of the GluRzeta subunit (called NR1 in rats) with any one of four GluRepsilon subunits (GluRepsilon1-4; NR2A-D), play an important role in excitatory neurotransmission, synaptic plasticity and brain development. Recent pharmacological studies have also indicated a role for NMDA receptors in drug addiction. In the present study, we investigated the behavioural adaptations to addictive drugs such as phencyclidine (PCP), methamphetamine (MAP) and morphine (MOR) in mice lacking the GluRepsilon1 subunit of the NMDA receptor. GluRepsilon1 mutant mice exhibited a malfunction of NMDA receptors, as evidenced by the reduction of [3H]MK-801 binding in an autoradiographic receptor binding assay. GluRepsilon1 mutant mice showed an attenuation of acute PCP- and MAP-induced hyperlocomotion. The development of sensitization by repeated treatment with PCP and MAP at a low, but not high, dose was also suppressed. The development of MOR-induced analgesic tolerance and naloxone-precipitated MOR withdrawal symptoms were attenuated in GluRepsilon1 mutant mice. In the place conditioning test, PCP-induced place aversion in naive mice and place preference in PCP-pretreated mice, as well as MOR-induced place preference, were diminished whereas MAP-induced place preference was not affected in GluRepsilon1 mutant mice. These findings provide genetic evidence that GluRepsilon1 subunit-containing NMDA receptors are involved in certain aspects of drug addiction.