title: 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.affiliation: 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. campmc@mail.nih.gov
authors.forename: Marguerite C
authors.initials: MC
authors.lastname: Camp
authors.forename: Michael
authors.initials: M
authors.lastname: Feyder
authors.forename: Jessica
authors.initials: J
authors.lastname: Ihne
authors.forename: Benjamin
authors.initials: B
authors.lastname: Palachick
authors.forename: Benita
authors.initials: B
authors.lastname: Hurd
authors.forename: Rose-Marie
authors.initials: RM
authors.lastname: Karlsson
authors.forename: Bianca
authors.initials: B
authors.lastname: Noronha
authors.forename: Yi-Chyan
authors.initials: YC
authors.lastname: Chen
authors.forename: Marcelo P
authors.initials: MP
authors.lastname: Coba
authors.forename: Seth G N
authors.initials: SG
authors.lastname: Grant
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D000435:Alcoholic Intoxication / Q000235:genetics* / Q000523:psychology*; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D001245:Association Learning / Q000187:drug effects*; D002755:Choice Behavior / Q000187:drug effects*; D003214:Conditioning, Classical / Q000187:drug effects*; D000076122:Disks Large Homolog 4 Protein; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D051528:Guanylate Kinases / Q000235:genetics*; D007274:Injections, Intraperitoneal; D018021:Lithium Chloride / Q000633:toxicity; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics; D012931:Social Environment; D013649:Taste / Q000187:drug effects / Q000235:genetics
chemical_list: D018692:Antimanic Agents; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D018691:Excitatory Amino Acid Antagonists; D008565:Membrane Proteins; D016291:Dizocilpine Maleate; D051528:Guanylate Kinases; D018021:Lithium Chloride