Resistance to alcohol withdrawal-induced behaviour in Fyn transgenic mice and its reversal by ifenprodil.
Recent studies suggest that the protein tyrosine kinase Fyn constitutes a determinant of fear and anxiety as well as alcohol sensitivity in mice. We investigated these functions and their relatedness in mice with transgenic over-expression of native or mutated, constitutively active Fyn. Fear- and anxiety-related behaviour of these animals were normal under varying levels of stress, but under withdrawal from alcohol both types of transgenic mice failed to show any increase of anxiety-like behaviour or reduction of exploratory activity as seen in their wild-type littermates. This apparent lack of alcohol withdrawal-induced behavioural effects was associated with increased Fyn activity and tyrosine phosphorylation of several proteins including the NMDA receptor subunit NR2B in the different mutant lines. NR2B phosphorylation itself remained unaffected by the chronic alcohol ingestion and subsequent withdrawal, but challenge with an NR2B antagonist, ifenprodil, restored a normal behavioural response in alcohol-withdrawn fyn mutants. Moreover, both types of transgenic mice showed a reduction of voluntary alcohol consumption compared to their wild-type littermates. Together, these results suggest that Fyn can modulate alcohol consumption and prevent behavioural changes during alcohol withdrawal, possibly via phosphorylation of NR2B.
Stork
Oliver
O
Laboratory of Neurochemistry, National Institute for Physiological Sciences, Nishigonaka 38, Myodaiji, Okazaki 444-8585, Japan. oliver.stork@medizin.uni-magdeburg.de
Kojima
Nobuhiko
N
Stork
Simone
S
Kume
Nobuko
N
Obata
Kunihiko
K
D000374:Aggression / Q000187:drug effects; D020268:Alcohol-Induced Disorders, Nervous System / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D004351:Drug Resistance / Q000235:genetics*; D000431:Ethanol / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D005260:Female; D005838:Genotype; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010880:Piperidines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; 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