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.

• Authors: Marguerite C Camp, Michael Feyder, Jessica Ihne, Benjamin Palachick, Benita Hurd, Rose-Marie Karlsson, Bianca Noronha, Yi-Chyan Chen, Marcelo P Coba, Seth G N Grant, Andrew Holmes
• Journal: Addiction biology (Addict Biol) Vol. 16 Issue 3 Pg. 428-39 (Jul 2011) ISSN: 1369-1600 [Electronic] United States
• PMID: 21309945 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Society for the Study of Addiction. No claim to original US government works.

Chemical References

• Antimanic Agents
• Disks Large Homolog 4 Protein
• Dlg4 protein, mouse
• Excitatory Amino Acid Antagonists
• Membrane Proteins
• Dizocilpine Maleate
• Guanylate Kinases
• Lithium Chloride

Topics

• Alcohol Drinking (genetics)
• Alcoholic Intoxication (genetics, psychology)
• Animals
• Antimanic Agents (pharmacology)
• Association Learning (drug effects)
• Choice Behavior (drug effects)
• Conditioning, Classical (drug effects)
• Disks Large Homolog 4 Protein
• Dizocilpine Maleate (pharmacology)
• Excitatory Amino Acid Antagonists (pharmacology)
• Female
• Guanylate Kinases (genetics)
• Injections, Intraperitoneal
• Lithium Chloride (toxicity)
• Male
• Membrane Proteins (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Signal Transduction (genetics)
• Social Environment
• Taste (drug effects, genetics)