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

164 ETHANOL-AFFECTE D DEVELOPMENT
the hypothalamu s to activate the HP A axis, with specific
stimulator y effect s exerte d o n CRH-producin g
neurons (Rivier, 1999).
Ethanol-induced brai n damag e i s closel y re -
lated t o glutamate-induce d exitotoxicity , mediate d
through N-methyl-D-aspartat e (NMDA ) receptors .
Chronic ethano l exposur e increase s NMD A re -
ceptors and Ca 2+ channel activity , event s associated
with seizure s during alcoho l withdrawa l (Lancaster ,
1992). It has also been postulated that chronic prenatal
ethano l exposur e change s glutamate-NMD A
receptor-NOS signal transduction in the developing
guinea pi g brain (Kimura et al., 2000). Kimur a an d
coworkers (Kimur a e t al. , 1996 , 1999 ; Kimur a an d
Brien, 1998 ) reporte d decrease d feta l hippocampa l
NOS activit y and , consequently , decrease d forma -
tion of NO, bu t thos e changes are not accompanied
by a los s o f NOS-containin g neuron s i n th e hip -
pocampal CA I o r CA3 areas or changes in localization
o f hippocampal NO S protei n i n th e near-ter m
guinea pig . The critica l period for prenatal ethanol -
induced los s o f hippocampa l CA I neuron s i n th e
guinea pig brain appears to be between G62 and PI2
(McGoey et al, 2003). Glutamate an d NMDA binding
site s decrease i n th e hippocampu s o f near-term
fetal guinea pigs chronically exposed to ethanol (Abdollah
an d Brien , 1995) . Thus it has been propose d
that chronic prenatal exposure to ethanol suppresses
the function of the glutamate-NMDA receptor-NO
signal transductio n syste m i n th e developin g hip -
pocampus. Furthermore , i t has been postulated tha t
persistent suppressio n o f thi s signalin g syste m dis -
rupts or delays normal neuronal development, which
temporally precede s th e los s o f hippocampa l CA I
pyramidal cells in postnatal lif e (Gibso n e t al., 2000;
Kimura et al, 2000; McGoey et al, 2003). In view of
the importan t role of the hippocampus in HPA feedback,
suc h alteration s coul d underli e th e ethanol -
induced change s i n HP A feedback regulatio n tha t
have been observed.
Changes i n N O synthesi s in FE E animal s may
mediate th e altere d HP A responses t o immun e sig -
nals reporte d i n FE E rat s compare d t o thos e i n
controls. Gottesfel d (1998 ) repor t increased NO formation
i n respons e t o LP S i n FE E rats . Further -
more, blockade of NO synthesis prevents the blunted
sympathetic respons e to LPS or interleukin (IL)- l i n
FEE rat s but no t i n contro l rat s (Gottesfeld, 1998) .
Similarly, changes i n hypothalamic responsivenes s to
NO ma y mediate the increased HPA responsiveness of
FEE animal s to stressors . Intracerebroventricula r in -
jection o f the N O dono r 3-morpholinosydnonimin e
(SIN)-l increase s the ACTH respons e and th e con -
centration o f mRN A fo r th e immediat e earl y gen e
NGFI-B in FEE male s (Lee et al., 2003). Moreover,
blockade o f NO formatio n abolishes difference s be -
tween FE E an d contro l animal s in respons e t o IL- 1
(Rivier, 1995) . In normal (no ethanol exposure ) rats,
SIN-1 als o up-regulate s CRH , AVP , an d CRH-R L
gene expressio n in the PVN . Th e functiona l impor -
tance o f the increase d concentration s o f CRH an d
AVP transcripts is evidenced b y immunoneutraliza -
tion o f endogenous CR H an d AVP , which abolishe s
or blunts, respectively, the ACTH respons e to SIN-1
(Lee e t al. , 1999) . I t woul d b e fascinatin g to stud y
these relationship s in animal s prenatally exposed t o
ethanol.
Altered HPA-HPG Interactions
There ar e bidirectiona l interaction s betwee n th e
stress syste m and the HPG axi s (Fig . 10-3) . Hor -
mones o f th e HP A axi s hav e inhibitor y effects o n
HPG activity . In turn, the gonadal steroids feed back
to activat e (estradiol) or inhibi t (testosterone) HPA
activity. Recen t studie s hav e investigate d a possibl e
role o f ethanol-induce d alteration s i n HPA-HP G
interactions i n mediatin g th e sexuall y dimorphi c
effects o f ethano l o n mal e an d femal e offspring .
Studies hav e examine d th e effect s o f gonadectom y
(GDX), wit h o r without hormon e replacement , o n
concentrations o f the HP A hormones in bot h sexe s
under basal conditions and following stress. Preliminary
data show that FEE male s have higher plasma
ACTH concentration s tha n control s followin g re -
straint stress , an d tha t GD X eliminate s th e dif -
ferences amon g group s (La n e t al. , 2004) . Thus ,
HPA hyperresponsiveness i n FE E male s appear s t o
be mediated , a t leas t i n part , b y ethanol-induce d
changes i n testosteron e regulatio n o r in HP A sensitivity
to testosterone. That is, the suppressiv e effect s
of testosterone and/or the stimulatory effects o f GDX
on stress-induced ACTH release are altered i n FE E
compared t o contro l males . I n contrast , th e rol e of
the gonada l hormone s i n HP A regulation i n FE E
females i s mor e complex . Preliminar y dat a (Ya -
mashita et al., 2004) show that overall, FEE females
are les s responsiv e tha n control s t o th e effect s o f
estradiol o n bot h reproductiv e an d nonreproduc -
tive measures. Furthermore, FEE female s appear to