Fyn kinase and NR2B-containing NMDA receptors regulate acute ethanol sensitivity but not ethanol intake or conditioned reward.
BACKGROUND
The tyrosine kinase Fyn previously has been shown to play a key role in mediating acute tolerance to ethanol. Recently, we found that the compartmentalization of Fyn to the NR2B subunit of the NMDA receptor (NMDAR) in the hippocampus regulates Fyn phosphorylation of NR2B in response to ethanol, which mediates the acute tolerance of NMDAR to ethanol inhibition in hippocampal slices. In this study we determined, first, whether acute tolerance to ethanol inhibition is mediated via NR2B-containing NMDARs in vivo and, second, whether the increase in acute sensitivity to ethanol in the Fyn-/- mice influences ethanol consumption or ethanol's conditioned rewarding effects.


METHODS
A loss of righting reflex test was used to study the acute/sedative effects of ethanol after intraperitoneal injections of sedative doses of ethanol. Conditioned place preference was used to study the rewarding properties of ethanol. The two-bottle choice protocol was used to measure oral ethanol self-administration and preference as described previously.


RESULTS
We found that systemic injection of the NR2B-containing NMDAR selective antagonist, ifenprodil, abolished the differences between Fyn+/+ and Fyn-/- mice in sensitivity to the acute sedative effects of ethanol. Moreover, we found that Fyn-/- and Fyn+/+ mice did not differ in their voluntary ethanol consumption or in the rewarding properties of ethanol.


CONCLUSIONS
Our results suggest that the interaction between Fyn and NR2B mediates the acute sedative effects of ethanol, and that alteration in acute ethanol sensitivity does not necessarily correlate with levels of ethanol consumption or the rewarding properties of ethanol.
Yaka
Rami
R
Ernst Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville 94608, USA.
Tang
Ka-Choi
KC
Camarini
Rosana
R
Janak
Patricia H
PH
Ron
Dorit
D
D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010880:Piperidines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D012201:Reward
C121001:NR2B NMDA receptor; D010880:Piperidines; D011518:Proto-Oncogene Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C010739:ifenprodil