Locomotor Activity Induced by Noncompetitive NMDA Receptor Antagonists Versus Dopamine Transporter Inhibitors: Opposite Strain Differences in Inbred Long‐Sleep and Short‐Sleep Mice

Abstract

The actions of ethanol in the brain involve multiple neuroreceptor systems, including glutamatergic N-methyl-D-aspartate receptor (NMDAR) channels. In a novel environment, both ethanol and the noncompetitive NMDAR antagonist MK-801 stimulate locomotor activity to a lesser extent in inbred long-sleep (ILS) mice compared with inbred short-sleep (ISS) mice. The behaviorally activating effects of noncompetitive NMDAR antagonists are thought to involve increased monoamine neurotransmission. Thus, in this study, we sought to determine whether: (1) habituation to the behavioral environment alters the differential locomotor-stimulant effects of noncompetitive NMDAR antagonists in ILS and ISS mice and (2) the differential behavioral sensitivity of ILS and ISS mice to noncompetitive NMDAR antagonists is mediated through direct inhibition of the dopamine transporter (DAT). Open field locomotor activity was measured following acute systemic injection of saline or drug. [3H]DA uptake parameters were determined in striatal synaptosomes prepared from drug-naïve mice. Habituation to the testing environment abolished the strain differences in saline-induced locomotor activity. However, ethanol- as well as MK-801-treated ILS mice still exhibited reduced locomotor activity compared with ISS mice, suggesting that a drug-environment interaction is not the primary explanation for the strain differences. The noncompetitive NMDAR antagonists phencyclidine and ketamine also induced significantly lower locomotor activity in ILS than in ISS mice. In contrast, the DAT inhibitors cocaine and GBR 12909 and the DA releaser amphetamine induced greater locomotor activity in ILS than in ISS mice, a strain difference opposite that of the noncompetitive NMDAR antagonists. Furthermore, the differential behavioral effect found with DAT inhibitors was not mediated by differences in the affinity nor number of striatal DATs between ILS and ISS mice. Our results support the conclusion that the differential locomotor-stimulant effects of ethanol and noncompetitive NMDAR antagonists in ILS and ISS mice are not mediated through direct inhibition of DAT.