A novel role for PSD-95 in mediating ethanol intoxication, drinking and place preference

Abstract

The synaptic signaling mechanisms mediating the behavioral effects of ethanol (EtOH) remain poorly understood. Post-synaptic density 95 (PSD-95, SAP-90, Dlg4) is a key orchestrator of N-methyl-D-aspartate receptors (NMDAR) and glutamatergic synapses, which are known to be major sites of EtOH’s behavioral actions. However, the potential contribution of PSD-95 to EtOH-related behaviors has not been established. Here, we evaluated knockout (KO) mice lacking PSD-95 for multiple measures of sensitivity to the acute intoxicating effects of EtOH (ataxia, hypothermia, sedation/hypnosis), EtOH drinking under conditions of free access and following deprivation, acquisition and long-term retention of EtOH conditioned place preference (CPP) (and lithium chloride-induced conditioned taste aversion), and intoxication-potentiating responses to NMDAR antagonism. PSD-95 KO exhibited increased sensitivity to the sedative/hypnotic, but not ataxic or hypothermic, effects of acute EtOH relative to wild-type controls (WT). PSD-95 KO consumed less EtOH than WT, particularly at higher EtOH concentrations, although increases in KO drinking could be induced by concentration-fading and deprivation. PSD-95 KO showed normal EtOH CPP 1 day after conditioning, but showed significant aversion 2 weeks later. Lithium chloride-induced taste aversion was impaired in PSD-95 KO at both time points. Finally, the EtOH-potentiating effects of the NMDAR antagonist MK-801 were intact in PSD-95 KO at the dose tested. These data reveal a major, novel role for PSD-95 in mediating EtOH behaviors, and add to growing evidence that PSD-95 is a key mediator of the effects of multiple abused drugs.

mTORC1-dependent translation of collapsin response mediator protein-2 drives neuroadaptations underlying excessive alcohol-drinking behaviors

“…58 Furthermore, PSD-95 knockout mice exhibit hypersensitivity to alcohol intoxication and show decreased voluntary alcohol intake. 59 Our findings therefore put forward the possibility that mTORC1, by simultaneously inducing the translation of a group of synaptic proteins, is a molecular gateway responsible for neuroadaptations induced by alcohol drinking.…”

NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism

“…PSD-95 KO mice were generated as previously described and have a constitutive deletion of PSD-95 [43–45]. The mutant line was backcrossed onto a C57BL/6J background for >10 generations.…”

Modulation of behavior by scaffolding proteins of the post-synaptic density

“…Similarly, PSD knockouts exhibit robust impairment of conditioned taste aversion, however in appetitive conditioning with ethanol-induced place preference, these mice normally learn the ethanol-place contingency but develop place avoidance later on (Camp, Feyder, Ihne, Palachick, Hurd et al, 2011). In addition to appetitive learning, PSD-95 also interferes with the function of the reward system by affecting sensitization to psychostimulants.…”