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

160 ETHANOL-AFFECTE D DEVELOPMENT
In contrast , ADX of the pregnan t female can reverse
the effect s o f prenatal ethanol exposur e o n pituitar y
POMC mRNA concentrations in FE E offsprin g (Re -
dei e t al. , 1993) . Furthermore , Trit t an d colleague s
(1993) have suggested that removal of the adrenal cortex,
but no t the medulla, in the pregnant female prevents
th e growth-retardin g effect s o f prenatal ethano l
and ma y reverse the delay in postpartum weight gain
in FEE offspring . Thu s the advers e effects o f ethanol
on birth weight are mediated at least partially through
the adrenal gland. Further studies must be done to resolve
the rol e of corticosteroids derive d from th e preg -
nant female in mediating the adverse effects o f ethanol
on their offspring. I t is likely, however, that a comple x
interaction betwee n direc t an d indirec t effect s o f
ethanol mediates the adverse consequences of ethanol
consumption durin g pregnancy on fetal developmen t
and programming of fetal HP A activity.
Effects of Prenatal Ethanol Exposure
on HPA Activity in Offspring
The Preweanin g Period. Th e comple x interactio n
of direct and indirec t effect s o f ethanol i s apparent i n
the offsprin g followin g parturition. FE E fetuse s exhibit
decrease d COR T concentration s compare d t o
control fetuses on G19 (Revsko y et al., 1997) . I n con -
trast, a t birth , FE E neonate s hav e elevate d plasm a
and brai n contents of CORT, decrease d CB G bind -
ing capacity, elevated plasma and pituitary concentrations
of p-EP, and reduced pituitary concentrations of
p-EP (Kakihana et al, 1980 ; Taylor et al, 1983; Weinberg
et al., 1986; Angelogianni and Gianoulakis, 1989;
Weinberg, 1989). Throughout the preweaning period,
FEE offsprin g exhibi t blunte d HP A an d p-E P re -
sponses t o a wide range o f stressors, including ether ,
novelty, saline injection, and col d stress (Taylor et al.,
1986; Weinber g e t al, 1986 ; Angelogiann i an d Gi -
anoulakis, 1989 ; Weinberg , 1989) . In addition, prenatal
ethanol exposur e alters the ontogeneti c expressio n
of mRNAs fo r CRH an d POMC , delaying and exag -
gerating the rise in CRH expression in female (but not
male) pups, and suppresses POMC mRNA concentrations
i n mal e (bu t no t female ) pup s throughou t th e
preweaning period (Aird et al, 1997) . The implicatio n
is that sexually dimorphic effects o f prenatal ethanol exposure
on these two important glucocorticoid-regulated
genes contribute to both the immediate and the longterm
effect s o f prenatal ethano l o n stres s responsive -
ness of the offspring .
The significanc e of the reduced hormonal responsiveness
described i n FEE pup s during early development
remain s to be determined . Evidenc e indicate s
that i n additio n t o th e reduce d adrenocortica l re -
sponses to stressors , plasma CBG bindin g capacity is
also reduced in FEE compare d to that in controls, at
least durin g th e firs t wee k o f lif e (Weinberg , 1989) .
Thus it is possible that although th e CORT stress response
i s reduced i n FEE pups , the ratio of bound-tofree
steroid s ma y no t b e altered . Th e reductio n i n
CBG binding capacity may represent a compensatory
response t o maintai n norma l neuroendocrin e func -
tion i n FE E offspring . Thi s possibility remains to be
tested.
Long-Term Effect s o f Prenata l Ethano l Exposure .
Importantly, th e reduce d HP A an d p-E P respon -
siveness i n FE E ra t pup s earl y in lif e i s a transien t
phenomenon. Following weaning, FEE rat s are typically
hyperresponsive to stressors and t o drugs such as
ethanol and morphine (Taylor et al., 1988 ; Weinberg,
1993a, 1993b ; Ki m e t al, 1996 ; Le e e t al, 1990 ,
2000). Simila r result s hav e bee n describe d i n non -
human primate s (Schneide r e t al. , 2004) . I n rhesu s
monkeys, prenatal exposur e to moderate amount s of
ethanol induce d highe r plasm a ACTH an d margin -
ally highe r plasm a cortiso l response s t o th e stres s of
maternal separation.
An interesting findin g fro m roden t model s i s that
the sexua l dimorphis m i n th e effect s o f prenata l
ethanol exposur e see n durin g th e ontogen y o f th e
HPA axis (Aird et al, 1997 ) extend s int o adulthood .
Sex differences i n response s of male an d femal e offspring
compare d t o thos e o f their contro l counter -
parts are often observed an d ma y vary depending o n
the natur e o f the stresso r and th e tim e cours e an d
hormonal en d poin t measure d (Weinberg , 1988 ,
1992a, 1995 ; Halas z e t al, 1993 ; Le e an d Rivier ,
1996). Fo r example , i n adulthood , FE E male s an d
females exhibi t increased CORT , ACTH, and/o r p -
EP response s to stressors , such a s repeated restraint ,
footshock, an d immun e challenge s (Taylo r e t al. ,
1988; Weinberg, 1993b ; Kim et al, 1996 , 1999b ; Lee
and Rivier , 1996 ; Weinber g e t al, 1996 ; Le e et al.,
2000). Bot h male s an d female s sho w increase d ex -
pression o f mRNA s for immediat e earl y genes an d
CRH followin g stressors (Lee e t al., 2000) as well as
deficits i n habituatio n t o repeate d restrain t (Wein -
berg e t al, 1996) . I n contrast , i n respons e t o pro -
longed restrain t o r col d stress , HP A hyperactivity is