Brain Development: Normal Processes and the Effects of Alcohol ...

162 ETHANOL-AFFECTE D DEVELOPMENT
also reveals significant alterations in gen e expressio n
in FEE animals . Followin g ADX, hypothalamie CRH
mRNA concentrations ar e significantly higher i n FE E
males an d female s than i n their contro l counterparts ,
despite the finding that plasma ACTH concentration s
are elevated only in FEE males . FEE male s also have
blunted AVP mRNA responses to ADX and lower pituitary
CRH-R j mRN A expression overall compared t o
controls, but there are no significant differences amon g
groups in pituitary POMC mRNA levels. In addition,
CORT replacemen t i s les s effectiv e i n normalizin g
ADX-induced alteration s in FEE tha n in control ani -
mals at several levels of the HP A axis, including hip -
pocampal M R mRN A concentrations i n bot h male s
and females , hippocampa l G R an d hypothalami e
AVP mRNA in males, and anterior pituitary CRH-R!
mRNA i n females . The alteration s i n M R an d G R
mRNA concentrations are particularly noteworthy, as
previous studie s have found no ethanol-induce d differences
i n M R an d G R recepto r concentration s o r
binding affinity i n the hippocampu s an d othe r brain
regions amon g FE E an d contro l animal s (Weinber g
and Petersen , 1991 ; Ki m et al, 1999c) . Thes e dat a
are th e firs t t o provid e direc t evidenc e fo r possibl e
deficits i n sensitivit y t o COR T regulatio n o f HP A
feedback i n FEE animals . They suggest an alteration
in th e balanc e betwee n HP A drive and COR T feedback
and exten d previous work supporting alterations
in feedbac k sensitivity in th e intermediat e (Osbor n
et al, 1996) , bu t not the fas t (Hofman n et al, 1999 )
feedback time domain.
An altere d balanc e betwee n HP A drive an d feed -
back in FEE compare d t o control animals is also suggested
b y dat a o n HP A responsivenes s followin g
glucocorticoid recepto r blockade (Zhan g et al, 2005).
Adult female offspring fro m FE E an d contro l groups
were injected with the MR antagonist spironolactone,
the G R antagonis t RU38486 , o r vehicle . Followin g
collection o f basal blood samples, rats were subjected
to a 1 hr restraint stress, and additiona l samples were
collected durin g and followin g stress. Both M R an d
GR blockades increase d basa l ACTH concentration s
in FE E bu t no t control animals , compare d t o vehicle
injection . Furthermore , M R blockad e increase d
ACTH concentration s i n contro l bu t no t FE E fe -
males during restraint, whereas GR blockade increased
ACTH concentration s i n FE E female s durin g re -
straint an d i n contro l female s durin g restrain t an d
recovery, compared t o their vehicle-injected counterparts.
This differential patter n of responses under both
basal an d stres s condition s suggest s tha t prenata l
ethanol exposure enhance s HP A drive and alter s sen -
sitivity to feedback regulatio n b y MR and GR , possi -
bly reflecting an altere d balanc e betwee n HP A drive
and feedback.
In summary, ethanol-exposed animals exhibit HPA
dysregulation unde r basa l conditions , eve n i n th e
face o f similar basal hormone levels , and difference s
are furthe r unmaske d followin g perturbation s of th e
system by stress, ADX, or receptor blockade. Dysregulation
occur s a t multipl e sites , includin g th e hip -
pocampus, hypothalamus, an d pituitary , and reflect s
changes both in HPA drive and CORT feedback reg -
ulation and/or in the balance between driv e and feedback.
Althoug h FE E animal s initiat e compensator y
mechanisms to maintain normal basal hormone con -
centrations under mos t circumstances, perturbations
of the syste m reveal that tonic or basal HPA tone in -
creases an d likel y play s a ke y role i n raisin g the se t
point o f responsiveness following stress. The altere d
CRH-Rj mRN A responses and the lac k of differences
in POM C mRN A concentration s i n FE E animal s
suggest compensator y mechanisms , probabl y a t th e
level o f th e pituitary , suc h tha t th e enhance d ac -
tivation i n th e hypothalamu s doe s no t translat e di -
rectly int o enhance d pituitar y activity. This ma y b e
protective fo r FE E animals , minimizin g enhance d
basal pituitary activity in th e fac e o f enhanced hypo -
thalamie drive. Finally, prenatal ethanol exposure has
sexually dimorphi c effect s o n HP A regulation. Thi s
finding implies a role for the gonadal steroids or possibly
an alteration i n adrenal-gonadal interactions me -
diating thes e effect s o f ethanol o n HP A activity an d
regulation.
Ethanol Effects on Neurotransmitters
Regulating HPA Activity
Fetal ethanol exposur e may alter HPA responsiveness
through effect s o n centra l neurotransmitte r system s
that regulat e HP A function. Data indicat e that CR H
release i s stimulated b y acetylocholine an d epineph -
rine in a dose-dependent manner, by low doses of NE,
and b y serotonin (5-HT) , an d i s inhibited b y |3-EP, yaminobutyric
acid (GABA), dynorphin, and substanc e
P (Assenmache r e t al, 1987 ; Plotsky , 1987) . Prenata l
ethanol exposur e alter s th e developmen t o f centra l
neurotransmitter system s in offsprin g (Druse , 1992) .
Of particular relevance to this review are data demon -
strating long-term change s i n NE, 5-HT , nitri c oxide