Chlordiazepoxide-induced expression of c-Fos in the central extended amygdala and other brain regions of the C57BL/6J and DBA/2J inbred mouse strains: relationships to mechanisms of ethanol action.
BACKGROUND
Previous studies have established an association between the ethanol-induced locomotor response and activation of the central nucleus of the amygdala (CeA) as determined by changes in the number of Fos-like immunoreactive (Fos-li) neurons. The purpose of the current study was to determine if the benzodiazepine chlordiazepoxide (CDP) would produce similar effects to ethanol on behavior and the CeA.


METHODS
In experiment 1, C57BL/6J (B6) and DBA/2J (D2) mice were administered CDP over a dose range of 3 to 30 mg/kg and the effects on locomotor behavior and the number of Fos-li neurons in the extended CeA determined. For experiment 2, B6D2 F2 intercross animals were phenotyped for their locomotor response to ethanol using a test-retest design. The activity responsive and nonresponsive extreme phenotypes were then tested in the same fashion as the inbred strains.


RESULTS
Similar to ethanol, CDP increased locomotor activity in the D2 strain but not the B6 strain; furthermore, the D2 strain was 3 to 10 times more sensitive than the B6 strain in terms of CDP activating the CeA and the associated lateral posterior aspect of the bed nucleus of the stria terminalis (BSTLP). In the shell of the nucleus accumbens (NAc), CDP inhibited the number of Fos-positive neurons in both strains. CDP also discriminated between the responsive and nonresponsive extremes both in terms of behavior and activation of the CeA.


CONCLUSIONS
Overall, these data point to the importance of GABA(A) mediated mechanisms in the ethanol-induced locomotor response. It is suggested that both drugs block the feed-forward inhibition in the CeA, resulting in activation of the GABAergic projection neurons. The overall net effect of CDP or ethanol administration on the output from the CeA will be inhibitory, from which it follows that the locomotor activation response must be associated with the selective inhibition of some behavior or ensembles of behaviors that are known to be mediated by the CeA and reduce locomotor activity (i.e., the "freezing" response).
Hitzemann
B
B
Department of Psychiatry, SUNY at Stony Brook, NY 11794-8101, USA. rhitzemann@mail.psychiatry.sunysb.edu
Hitzemann
R
R
D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D002707:Chlordiazepoxide / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D018757:GABA Modulators / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects* / Q000378:metabolism
D002492:Central Nervous System Depressants; D018757:GABA Modulators; D016760:Proto-Oncogene Proteins c-fos; D000431:Ethanol; D002707:Chlordiazepoxide