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.
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