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

seen primarily in FEE male s (Weinberg , 1992a ; Kim
et al., 1999a) , wherea s in respons e t o acute restraint
or acut e ethano l o r morphin e challenge , increase d
CORT and ACTH concentrations occur primarily in
FEE female s (Taylo r e t al, 1982 , 1988 ; Weinber g
et al. , 1986 ; Weinberg , 1988) . Similarly , altered re -
sponses i n a consummator y tas k (Weinberg , 1988 )
and t o predictable an d unpredictabl e restrain t stress
(Weinberg, 1992b ) sugges t deficit s i n th e abilit y of
FEE female s but not males to use or respond to environmental
cues.
Possible Mechanisms Mediating
Ethanol-Induced HPA Hyperresponsiveness
The mechanism s underlyin g HP A hyperrespon -
siveness i n FE E offsprin g ar e unknow n a t presen t
but coul d reflec t change s at all levels of the axis . Increased
HP A activit y coul d resul t fro m increase d
secretion o f secretagogues (e.g., POMC, CRH, an d
AVP), increase d pituitar y and/o r adrena l respon -
siveness t o thes e secretagogues , increase d driv e t o
the hypothalamus , deficits in feedback regulation of
HPA activity , and/o r alteration s i n centra l neuro -
transmitters regulatin g th e HP A axis . Indeed , i t i s
likely tha t multipl e mechanism s pla y a role . Fur -
thermore, the finding that prenatal ethano l exposur e
differentially alter s HP A responsivenes s i n male s
and females compared t o that in their control counterparts
suggest s that th e gonada l hormone s o r al -
tered adrenal-gonadal interaction s play a significant
role i n mediatin g prenatal ethano l effect s o n HP A
activity. This chapter focuses on four possible mechanisms
considered importan t i n mediatin g HP A hyperresponsiveness
in FEE animals : (1 ) alterations in
HPA drive, (2 ) alterations i n HP A feedback regula -
tion, (3 ) altered neurotransmitter regulation of HPA
activity, an d (4 ) possibl e interaction s betwee n th e
HPA an d hypothalamic-pituitary-gonada l (HPG )
Altered HPA Drive and/or Feedback
A numbe r o f studie s sho w tha t stimulator y inputs o r
drive to the PVN of the hypothalamus are enhanced by
prenatal ethano l exposure . Weanling FE E mal e an d
female pup s exhibi t increased basal concentrations of
CRH mRN A in the PVN (Lee et al., 1990) , and adul t
FEE male s hav e increase d basa l concentration s o f
both hypothalamic CRH mRNA and pituitary POMC
ETHANOL EFFECTS ON ENDOCRINE AND IMMUNE FUNCTION 16 1
mRNA (Redei et al., 1993 ) compare d t o those of controls.
Not all studies, however, show these alterations in
central HP A regulation o f basal activity. Kim and col -
leagues (1996) reported no differences i n basal CRH or
AVP mRN A concentration s amon g adul t FE E an d
control animals. Lee and colleagues (2000) showed no
differences i n basa l CRH heteronuclea r (hn ) RNA or
in basal CRH and AVP median eminence protein con -
centrations i n FEE rat s compared t o controls. Impor -
tantly, however, the latter investigators also showed that
in respons e to both footshoc k and lipopolysaccharid e
(LPS; an endotoxin used to mimic infection or inflammation)
challenge, FEE animal s exhibit enhanced hypothalamic
neurona l activit y compare d t o tha t i n
controls, reflecte d i n increased mRN A concentration s
of two immediate earl y genes (c-fos an d NGFI-B) , as well
as significantly increased CRH hnRN A content. Thus,
although ther e is some controversy in the literatur e as
to whethe r HP A regulatio n i s altere d i n FE E ani -
mals under basal conditions, the dat a of Lee an d col -
leagues (2000 ) provide the first evidence o f a selective
stress- and cytokine-induce d increas e i n activity of hypothalamic
CR H neuron s in FEE animals , indicating
a potentia l hypothalami c mechanis m throug h whic h
ethanol up-regulates the HPA axis.
Weinberg an d colleague s (Glava s e t al. , 2001 ;
Zhang e t al. , 2005b ) undertoo k studie s t o resolv e
conflicting finding s o n whethe r FE E animal s sho w
changes in centra l HPA regulatio n unde r basa l or
nonstressed conditions . Steady-stat e HP A functio n
and th e rol e of CORT in mediating changes i n HPA
regulation were examined i n ADX rats with or without
COR T replacement . I n additio n t o hormona l
concentrations, thes e investigator s assesse d th e con -
centrations o f mRNA for (a) hypothalamic CR H an d
AVP a s measures o f hypothalamic activity , (b) CR H
type 1 receptor (CRH-R ^ an d POM C a s indices of
pituitary activity, and (c ) hippocampal mineralocorticoid
receptor (MR) and glucocorticoid receptor (GR)
mRNA concentrations a s measures of feedback regulation.
As expected , followin g ADX, animal s exhibi t a n
increase in basal plasma ACTH concentrations com -
pared t o thos e i n sham-operate d animal s (Glava s
et al, 2001, Zhang et al., 2005b). Importantly, ACTH
elevations are greater in FEE male s but no t females,
compared t o thos e i n thei r contro l counterparts .
These dat a sugges t tha t a CORT-independent alter -
ation i n HP A regulation i s unmasked b y remova l o f
the COR T feedbac k signal , a t leas t i n males . ADX