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

Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism/NIH, 5625 Fishers Ln., Rockville, MD 20852-1798, USA.
Addiction Biology (Impact Factor: 5.36). 02/2011; 16(3):428-39. DOI: 10.1111/j.1369-1600.2010.00282.x
Source: PubMed


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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    • "Badanich et al [43] suggested that deletion of GluN2B containing NMDARs may have altered the normal network and signal transduction processes that regulate the motor and sedative effects of ethanol thus making these animals hypersensitive to alcohol. A similar enhancement in ethanol sedation was reported for mice lacking PSD-95, a protein highly expressed in glutamatergic synapses [45]. As both GluN2B and PSD-95 are critical regulators of much of the plasticity of glutamatergic synapses, loss of either one of these proteins may destabilize synapses and lead to altered sensitivity to acute ethanol as well as impairments in mechanisms that underlie rapid tolerance to ethanol [46]–[48]. "
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