Role of adrenal glucocorticoid signaling in prefrontal cortex gene expression and acute behavioral responses to ethanol.
BACKGROUND
Glucocorticoid hormones modulate acute and chronic behavioral and molecular responses to drugs of abuse including psychostimulants and opioids. There is growing evidence that glucocorticoids might also modulate behavioral responses to ethanol ( EtOH ). Acute EtOH activates the hypothalamic-pituitary-adrenal axis, causing the release of adrenal glucocorticoid hormones. Our prior genomic studies suggest that glucocorticoids play a role in regulating gene expression in the prefrontal cortex (PFC) of DBA2/J (D2) mice following acute EtOH administration. However, few studies have analyzed the role of glucocorticoid signaling in behavioral responses to acute EtOH . Such work could be significant, given the predictive value for the level of response to acute EtOH in the risk for alcoholism.


METHODS
We studied whether the glucocorticoid receptor (GR) antagonist, RU-486, or adrenalectomy (ADX) altered male D2 mouse behavioral responses to acute (locomotor activation, anxiolysis, or loss-of-righting reflex [LORR]) or repeated (sensitization) EtOH treatment. Whole-genome microarray analysis and bioinformatics approaches were used to identify PFC candidate genes possibly responsible for altered behavioral responses to EtOH following ADX.


RESULTS
ADX and RU-486 both impaired acute EtOH (2 g/kg)-induced locomotor activation in D2 mice without affecting basal locomotor activity. However, neither ADX nor RU-486 altered the initiation of EtOH sensitization (locomotor activation or jump counts), EtOH -induced anxiolysis, or LORR. ADX mice showed microarray gene expression changes in PFC that significantly overlapped with acute EtOH -responsive gene sets derived by our prior microarray studies. Q-rtPCR analysis verified that ADX decreased PFC expression of Fkbp5 while significantly increasing Gpr6 expression. In addition, high-dose RU-486 pretreatment blunted EtOH -induced Fkbp5 expression.


CONCLUSIONS
Our studies suggest that EtOH 's activation of adrenal glucocorticoid release and subsequent GR activation may partially modulate EtOH 's acute locomotor activation in male D2 mice. Furthermore, because adrenal glucocorticoid basal tone regulated PFC gene expression, including a significant set of acute EtOH -responsive genes, this suggests that glucocorticoid-regulated PFC gene expression may be an important factor modulating acute behavioral responses to EtOH .
VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
Blair N
BN
Costin
Aaron R
AR
Wolen
Sylvia
S
Fitting
Keith L
KL
Shelton
Michael F
MF
Miles
D000315:Adrenalectomy; D000428:Alcohol Drinking / Q000523:psychology; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism*; D006727:Hormone Antagonists; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D015735:Mifepristone; D009043:Motor Activity / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D057897:Reflex, Righting / Q000187:drug effects
D002492:Central Nervous System Depressants; D005938:Glucocorticoids; D006727:Hormone Antagonists; D015735:Mifepristone; D000431:Ethanol