Normal acute behavioral responses to moderate/high dose ethanol in GABAA receptor alpha 4 subunit knockout mice.
BACKGROUND
gamma-Aminobutyric acid type A receptors (GABA(A)-Rs) have been implicated in mediating some of the behavioral effects of ethanol (EtOH), but the contribution of specific GABA(A)-R subunits is not yet fully understood. The GABA(A)-R alpha 4 subunit often partners with beta2/3 and delta subunits to form extrasynaptic GABA(A)-Rs that mediate tonic inhibition. Several in vitro studies have suggested that these extrasynaptic GABA(A)-Rs may be particularly relevant to the intoxicating effects of low doses of EtOH. In alpha 4 subunit knockout mice, tonic inhibition was greatly reduced, as were the potentiating effects of EtOH. We therefore hypothesized that those behavioral responses to EtOH that are mediated by alpha 4-containing GABA(A)-Rs would be diminished in alpha 4 knockout mice.


METHODS
We investigated behavioral responses to acute administration of moderate/high dose EtOH or pentylenetetrazol in alpha 4 subunit knockout mice. We compared behavioral responses to EtOH in alpha 4 knockout and wild-type littermates in the elevated plus maze (0.0, 1.0 g/kg EtOH), screen test (1.5, 2.0 g/kg), hypothermia (1.5, 2.0 g/kg), fixed speed rotarod (1.5, 2.0, 2.5 g/kg), open field (0.0, 1.0, 2.0 g/kg), radiant tail flick (2.0 g/kg), loss of righting reflex (3.5 g/kg), and EtOH metabolism and clearance assays. Sensitivity to pentylenetetrazol-induced seizures was also analyzed.


RESULTS
No differences were observed between alpha 4 knockout mice and wild-type controls in terms of the baseline behavior in the absence of EtOH treatment or in the behavioral effects of EtOH in the assays tested. In contrast, alpha 4 knockout mice were significantly more sensitive to pentylenetetrazol-induced seizures.


CONCLUSIONS
We conclude that GABA(A)-Rs containing the alpha 4 subunit are not absolutely required for the acute behavioral responses to moderate/high dose EtOH that were assessed with the elevated plus maze, screen test, hypothermia, fixed speed rotarod, open field, radiant tail flick, and loss of right reflex assays. We further suggest that these findings are complicated by the demonstrated compensatory alterations in synaptic GABA(A)-R EtOH sensitivity and function in alpha 4 knockout mice.
Chandra
Dev
D
Departments of Anesthesiology and Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Werner
David F
DF
Liang
Jing
J
Suryanarayanan
Asha
A
Harrison
Neil L
NL
Spigelman
Igor
I
Olsen
Richard W
RW
Homanics
Gregg E
GE
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000378:metabolism / Q000494:pharmacology*; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D058787:GABA-A Receptor Antagonists; D007035:Hypothermia / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010433:Pentylenetetrazole / Q000009:adverse effects; D021122:Protein Subunits / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects; D045442:Rotarod Performance Test; D012640:Seizures / Q000139:chemically induced; D013623:Tail / Q000187:drug effects
D002492:Central Nervous System Depressants; D058787:GABA-A Receptor Antagonists; D021122:Protein Subunits; D011963:Receptors, GABA-A; D000431:Ethanol; D010433:Pentylenetetrazole