impact of alcohol and substance abuse on adolescent
TRANSCRIPT
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
1/22
Indian J Phy siol P harmacol 2010; 5 4 (3) : 2132 34
REVIEW ARTICLE
IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
BRAIN : A PRECLINICAL PERSPECTIVE
RAKA J AIN* AND YATAN PAL SINGH BALHARA
National Drug Dependence Treatment Centre,
All India Institute of Medical Sciences,
Ansari Nagar, New Delhi 110 029
( Received on July 29, 2009 )
Abstract : Use of alcohol and addictive substances by human juveniles and
adolescents i s common. Animal models of fe r researchers unique ins ight
into the effects of alcohol and drugs on adolescents. Recent work in rat
indica tes tha t per iadolescent substance use may disrupt normal puber ta l
development and may induce stronger effects on system subserving plasticity
and cognition than in adults. Several processes may influence the adolescent
r isk of neurocogni t ive damage . The bra in goes through var ious dynamic
changes during adolescence and can seriously affect the short term growth
process . The fea tures of the adolescent bra in may in fac t predispose a
youngster to behave in ways that place him or her at particular r isk of
experimenting with alcohol or other drugs. In addition to behavioral andneurochemica l changes , a number of impor tant physiologica l a l te ra t ions
occur during adolescence, including changes in brain regions implicated in
the re inforc ing proper t ies of a lcohol and other drugs of abuse . Damage
during early stages can cause long term damage which is irreversible. The
present review discusses the neurobehaviora l , neurochemica l and
neuroendocrinal effects of alcohol and other drugs of abuse on the adolescent
bra in in ra ts .
Key words : alcohol subs t ance abuse ado lescent bra in
*Corresponding Author : Fax : 91-011-2658866 3, 26588641, Tel . No. : 91-011-265932 36, 26593595;E-mai l : rakajain200 9@gmai l .com
INTRODUCTION
Use of addictive substances and alcoholis a major problem worldwide. Studies done
in recent years suggest r is ing consumption
and progressive fall in age of initiation. Drug
abuse in adolescents ranging from 1112 to
1718 years of age i s l ike ly to s t a r t wi th
tobacco smoking, which can be followed by
mar i juana and/or a lcohol , and eventua l ly
psychostimulants as well as opiate drugs (1).
Therefore, ear ly l i fe exposure with alcoholand psychoact ive compounds appears to be
critical and may predispose an individual to
the development of alcohol and substance use
di sorder .
Before delving into the research in this
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
2/22
214 Ja in and Balhara India n J Phys iol Pharma col 2010; 54 (3)
cont inues to undergo a t remendous amount
of deve lopment throughout adolescent and
into young adulthood while the overall size
of the bra in changes very l i t t l e be tween
chi ldhood and adul thood (8 , 9) . The
adolescent brain is unique and in a state of
t ransi t ion as i t undergoes both progressive
and regressive changes (2). Recent findings
indica te tha t c i rcu i t ry wi th in the bra in i s
actively being refined during adolescence and
most intriguing change occurs in the frontal
lobes (10). The frontal lobes comprise a large
region of the neocortex, evolutionary recent
t i s sue tha t b lanket s the bra in , sur rounding
older s t ruc tures . Fronta l lobe a reas p lay
vi ta l ro les in a var ie ty of impor tant
processes inc luding p lanning and dec i s ion
making , impulse cont ro l , vo luntary
movement , memory, speech product ion, and
a var ie ty of o ther func t ions . There appear
to be profound changes, both organizational
and func t iona l , in the fonta l lobes dur ingadolescence . A subs tant ia l number of
synapses a re e l imina ted or pruned, in the
cortex during adolescence (10, 11) and this
loss of synapses contributes to a decrease in
gray matter volumes in the frontal lobes as
adolescents matures to adults in both human
and ra t s (8) . Overa l l metabol i sm in the
f ronta l lobes decreases dur ing adolescence
(12) , whereas neura l ac t iv i ty dur ing the
per formance of cer ta in t asks become more
focused and efficient (13, 14, 15). It is quitelikely that this shaping of the frontal lobes
raises the possibili ty that drug abuse could
alter the normal development of the frontal
lobes during adolescence. Similar age-related
changes in bra in ac t iva t ion dur ing t ask
per formance have been observed in the
cerebe l lum, as wel l as in the super ior
col l i cu lus , tha lamus , s t r i a tum and par ie ta l
cortex (15, 16).
specific theme, i t is important to define the
stage of development that we casually refer
to as adolescence. Adolescent is not a distinct
stage. In general, adolescence is considered
a transition between childhood and adulthood
which i s assoc ia ted wi th a var ie ty of
developmental challenges. During this period
individual acquires skills necessary to enable
them to l ive independent ly . I t involves
changes at numerous levels, some of which
are defined biologically and some of which
are def ined behavioral ly. In humans, some
have suggested that adolescence encompasses
the entire second decade of l ife (i .e. 1020
years of age), while others suggest that 12
18 is more conservative range (2). In rodents,
adolescence is a difficult period to delineate
precisely. Spear and Brake (3) have defined
tha t pos tna ta l days 28 to 42 encompass a
per iadolescent per iod in the ra t ( i .e . P30-
42) . This per iod i s charac te r ized by
alterations in the behavior and neurobiologicalorganiza t ion , which a re observed in many
spec ies dur ing adolescence . Animals , l ike
the i r human counterpar t s , may show some
signs of adolescence at significantly younger
and o lder ages , wi th male ra t s t ending to
mature more s lowly than females . Indeed ,
age- typica l a l t e ra t ions charac te r i s t i c of
adolescence may begin as early as P28 and
may last in male rats unt i l P55 or so (4) .
P lay behavior in ra t s peaks be tween
postnatal days 30 to 40 (5). Rats also display
peak adrenocor t i co t ropic hormone and
cor t i sone responses to s t ress dur ing th i s
t ime (6) . In monkeys adolescence i s
recognized as occurring in the age range of
2 to 4 years (7).
Brain development
Recent ev idence sugges t s tha t , in
contrast to previous assumptions, the brain
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
3/22
Indian J Physiol Pharmacol 2010; 54(3) Addiction and Adolescent Brain 215
In addition to changes that occur in the
cortex, multiple changes have been observed
in the subcort ical s t ructures . For instance,
in the rat , levels of dopamine receptors in
the nucleus accumbens increase dramatically
between days 2540, an age range that falls
roughly within the window of early adolescent
development (2, 17). Neurobiologically, the rat
periadolescent period is characterized by the
steady increase in the striatal dopamine and
serotonergic transporter levels (18), increasein the chol inerg ic innerva t ions of the
prefrontal cortex (19), and biphasic changes
in the s t r iatal dopamine receptors (17, 18,
19). Nicotinic receptors have been shown to
reach adult levels during adolescence in the
hippocampus of male rats (20) and 3 and
4 nicot inic acetylchol ine receptor subuni t
mRNAs reached adul t levels in most brain
regions during adolescence (21) . Serotonin
t ranspor te r b inding increases cont inuous ly
in to adul thood in the f ronta l cor tex butremains stable in the straitum and midbrain
af ter weaning (22) . Similar constel lat ion of
neurobiological changes has been observed
in human be ings and pr imates dur ing
adolescence (10 , 23 , 24 , 25) , making th i s
age range in the ra t a good model of
adolescence.
As d i scussed , dopamine receptor l eve l s
in the s t r i a tum a l so increase in ear ly
adolescence and then decrease s ignif icant ly
be tween adolescence and young adul thood(17) . This deve lopment in turn inf luences
cogni t ive deve lopment , i .e . a t t en t ion ,
l earn ing and in te l l ec tua l a t t a inment .
Moreover, dopamine receptors in the nucleus
accumbens p lay a major ro le in the
rewarding (euphoric) properties of drugs. As
a consequence of such changes, alcohol, and
perhaps o ther drugs , a f fec t adolescent and
adults differently (2). Furthermore, levels of
type I Gamma - amino butyric acid (GABA)A
receptors increase dramatical ly in a var iety
of subcor t i ca l s t ruc tures dur ing ear ly
adolescence between days 2836, including
the cerebe l lum and media l septa l nuc leus
(26). Maturational changes during adolescence
are a l so ev ident in o ther bra in reg ions
tha t inc lude the h ippocampus (27) and
hypotha lamus (28) . Mos t lobe func t ions
mature and very l i t t l e change i s l ike ly to
take place beyond this per iod.
In addition, as demonstrated in nonhuman
primates, the input from two key chemicals
( i .e . , neurot ransmi t t e r s ) involved in bra in
ce l l communica t ion i .e . the exc i ta tory
neurot ransmi t t e r g lu tamate and the
inhib i tory neurot ransmi t t e r gamma
aminobutyricc acid (GABA) is reduced during
adolescence, whereas the input from another
neurot ransmi t t e r , dopamine , peaks in
prefrontal cor tex during adolescence (7) .
Cur rent ly many gaps ex i s t in our
knowledge of the developmental changes that
occur in the brain during adolescence. Stil l ,
the data that are avai lable suggest that the
prominent a l t e ra t ions occur in mul t ip le
neurochemical systems during the adolescent
period not only in humans but also in other
species as well, ranging from rodents to non-
human pr imates .
Biological basis of addict ion
Over the l as t two decades , dramat ic
advances both in the neurosciences and the
behavioral sciences have revolut ionized our
understanding of drug abuse and addict ion.
Drug addiction is a complex phenomenon. It
i s a bra in d i sease (29) . The pa th to drug
addiction begins with the act of taking drugs.
Al though each drug predominant ly has a
d i s t inc t mechanism of ac t ion , v i r tua l ly a l l
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
4/22
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
5/22
Indian J Physiol Pharmacol 2010; 54(3) Addiction and Adolescent Brain 217
GABA sys tem
Sedative-hypnotic drugs including alcohol,
benzodiazepines and barbi turates have long
been hypothesized to modulate receptors in
GABA systems.
1.0 Alcohol and adolescent brain
The problem of adolescent a lcohol
consumpt ion cont inues to be a s igni f i cant
concern , as ear ly onse t of a lcohol use oro ther drug use i s one of the s t ronges t
predictor of later alcohol dependence (32) .
In other words, the ear l ier a person begins
drinking alcohol, the more likely he or she
i s to become dependent on a lcohol . A
poss ib le explana t ion could be tha t ear ly
exposure to a lcohol or o ther drugs dur ing
adolescence may a l t e r c r i t i ca l ongoing
processes of bra in deve lopment tha t occur
a t tha t t ime, increas ing the l ike l ihood of
problems wi th a lcohol l a te r in l i f e . An
al te rna te in te rpre ta t ion for an ear lyexposure effect is that early use of alcohol
or o ther drugs might s imply serve as a
marker, not as a precursor, for a later drug
abuse disorder (33, 34).
Animal models offer researchers unique
ins ight in to the e f fec t s of a lcohol on the
adolescent and could fur ther he lp in
determining the mechanisms underlying the
poss ib le assoc ia t ion of ear ly exposure and
later alcohol problems.
1.1 Neurobehavioral effects
It has been observed that adolescent rats
are less sensi t ive to effects of intoxicat ion
and less sens i t ive to the hangover tha t
fo l lows use . Adolescent ra t s a re more
sensitive to the social disinhibition induced
by a lcohol use . Adolescent drunk ra t s
perform worse on memory tasks than adul t
drunk ra t s .
Recent work sugges t s tha t there a re
significant long-term effects of developmental
alcohol exposure in rats (35). It was observed
that chronic intermittent exposure treatment
(5.0 g/kg ip, every 48 hrs for 20 days) during
adolescence in te r fe res wi th the normal
increase in sens i t iv i ty to a lcohol - induced
motor impai rments tha t occurs be tween
adolescence and adul thood. Under cont ro l
condi t ions ra t s were more sens i t ive to the
effects of alcohol on postnatal day 65 (youngadulthood) than they had been on postnatal
day 30 (adolescence). These results suggest
that rats become more sensitive to the motor
impairing effects of alcohol as they progress
f rom adolescence to adul thood (36) .
Surpris ingly, animals that received alcohol
during adolescence did not show the normal
pattern of increased sensitivity to alcohol as
they aged into adulthood. In these animals,
the impact of acute a lcohol on motor
coordinat ion remained unchanged before up
to 16 days a f te r chronic in te rmi t t en texposure treatment. In contrast to the effects
of chronic in te rmi t t en t exposure in
adolescent s , chronic in te rmi t t en t exposure
treatment during adulthood had li t t le impact
on the subsequent effects of alcohol on motor
coordina t ion . This sugges t s the poss ib i l i ty
that the chronic exposure during adolescence
may have locked in the adolescent
insens i t iv i ty to a lcohol s seda t ive e f fec t s ,
or a t l eas t s igni f i cant ly de layed the
normal progress ion to grea te r sens i t iv i ty
in adul thood. Us ing a s t andard t ask of
swimming to a platform in a small pool of
water , Swar tzwelder and col leagues (37)
found adolescent rats given alcohol injections
took far longer than adul ts to swim to the
des t ined t a rge t . These f indings ra i se the
possibili ty that repeated exposure to alcohol
dur ing adolescence might a l t e r the normal
brain development in long-last ing and even
permanent ways .
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
6/22
218 Ja in and Balhara India n J Phys iol Pharma col 2010; 54 (3)
Among the mul t i tude of behaviora l
changes produced by e thanol , perhaps the
most sa l i en t a re the e f fec t s of e thanol on
motor act ivi ty as discussed above. Ethanol
d i s rupt s the ab i l i ty to per form tasks tha t
require balance and motor coordination, such
as driving an automobile, walking, and even
s tanding s ta t ionary in an upr ight pos i t ion
(38) . In rodents , the effects of ethanol on
motor coordination often is assessed by using
the ti l t ing plane test . The ti l t ing plane testsuggests that young rats are less vulnerable
than adult ethanol induced motor impairment
(39) . In addi t ion to reac t ing d i f fe rent ly
to the acute or in i t i a l e f fec t s of e thanol ,
adolescent and adul t r a t s appear to be
af fec ted d i f fe rent ly by repea ted e thanol
exposure . For ins tance , adolescent ra t s
a re l ess vulnerable than adul t r a t s to
chemoconvulsant induced se izures a f te r
cessation of repeated ethanol exposure (40).
Fur thermore , adolescent ra t s appear todevelop chronic to le rance to the e f fec t s
of e thanol more rap id ly than adul t s .
Swar tzwelder e t a l . (41) repor ted the
development of chronic to le rance to the
impact of e thanol on body tempera ture in
adolescent and adult subjects. The degree of
hypothermia produced by ethanol on the first
day of treatment did not differ between age
groups . However , over days , adolescent
subjec t s became to le rant to the e f fec t s
of e thanol on body tempera ture a t a
s ignif icant ly faster rate than adul ts .
Long- las t ing cogni t ive def ic i t s have
a l so been observed in rodents exposed to
alcohol repeatedly during adolescence (42) .
Chronic in te rmi t t en t exposure t rea tment
in adolescent ra t s resu l t s in exacerba ted
alcohol-induced learning deficits in adulthood
(43) . Adolescent and adul t r a t s t r ea ted
wi th chronic in te rmi t t en t exposure and
then t rained on a spat ial memory task, on
subsequent examinat ion showed poor
performance for the task in subjects treated
wi th chronic in te rmi t t en t exposure dur ing
adolescence than the other groups (44) .
A s tudy compar ing dr inking be tween
adolescent rhesus monkeys ra i sed by the i r
mothers and monkeys raised only with their
peers noted tha t peer - reared monkeys
displayed more anxiety-related behaviors anddrank more a lcohol than mother - reared
animals (45). However, on being exposed to
a s ignif icant s t ress when the mother-reared
monkeys were i so la ted f rom one another ,
their levels of drinking increased until they
almost matched those of peer-reared animals.
Wi th in each group, the an imals tha t
d i sp layed more anxie ty a l so drank more
alcohol. These findings propose that anxiety
or s i tua t ions tha t produce h igh degrees of
s t ress may t r igger excess ive a lcohol
consumption (45).
Social interact ion in per iadolescent rats
has been considered as a reinforcer in place
preference condi t ioning (46) and maze-
learning (47). Social factors modulate alcohol
se l f -adminis t ra t ion in ra t s . Hous ing
condi t ions as opera t iona l ized through
comple te , par t i a l or nul l soc ia l i so la t ion
exert significant effects upon alcohol intake
(48).
Sht iegman and King, (49) , r epor tedtha t voluntary a lcohol consumpt ion dur ing
adolescence i s assoc ia ied wi th a l a te r
increase aggressive behavior significantly in
male Golden hamsters. As mentioned above,
chronic alcohol exposure in adolescent rats
induces long-lasting alterations in cognitive
func t ioning (42) and d i s rupt puber ty-
assoc ia ted increases in reproduct ive
endocrinology in both males (50) and females
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
7/22
Indian J Physiol Pharmacol 2010; 54(3) Addiction and Adolescent Brain 219
(51) . Findings in rodents showing that pre-
and post-weaning (52) alcohol exposure can
a l so increase the an imal s preference for
alcohol later in life are contrary to findings
f rom other s tudies in th i s regard showing
no increases in l a te r consumpt ion a f te r
per iods of a lcohol exposure a t t imes tha t
include adolescence (53).
Adolescent ra t s d i sp lay two to three
times higher levels of ethanol intake relativeto their body weights than do more mature
animals (54, 55), although ethanol preference
per se does not peak until well into adulthood
around 5 months of age . The e leva ted
consummatory pa t t e rns of adolescence
could cont r ibute to h igh l eve l s of e thanol
intake by these growing animals relative to
their body weight (2) . I t i s suggested that
adolescent s might be ab le to sus ta in
comparat ively large ethanol intakes due to
the i r re la t ive insens i t iv i ty to the seda t ive
and locomotor incoordina t ing e f fec t s of ethanol, which may be in part related to their
grea te r propens i ty to deve lop acute and
functional tolerance relative to more mature
o r gan i s m s .
There is considerable research that shows
tha t adolescent an imals a re more sens i t ive
to chronic a lcohol exposure , wi th more
pronounced alcohol-related memory problems
and bra in damage than adul t an imals . A
recent s tudy has found tha t adolescent
rodents are less sensi t ive to the unpleasant
consequences of an alcohol-related hangover,
as measured by anxie ty . This hangover -
associated suppression of social interactions
i s supposed to be the remini scent of the
suppression in social interactions seen during
withdrawal f rom chronic alcohol . However ,
adolescent ra t s not only d id not exhib i t a
hangover - re la ted suppress ion in soc ia l
in te rac t ions , but they ac tua l ly showed an
increase in an age-spec i f i c form of soc ia l
activity called play fighting. Thus, opposite
to what is seen in adults, adolescents became
more socially responsive during the hangover
phase. Such a lack of aversive effects could
help establish a persisting cycle of drinking
in adolescent s , l eading to fu ture a lcohol -
related problems (56) .
Recently, adolescent alcohol drinking and
i t s long- ranges consequences have been
reported by McBride et al (57). These group
of workers suggested that alcohol dr inking
during periadolescence by alcohol-preferring
ra t s produces long las t ing e f fec t s tha t
increase the acquis i t ion of e thanol se l f -
administration in adulthood, and, in addition,
increase c raving - l ike behavior and the
potent ial for alcohol relapse.
1.2 Neurochemical /Neurobiological effects
There i s now c lear ev idence tha t
adolescence represent s a unique s tage of bra in deve lopment . Changes in bra in
organization and function during adolescence
are widespread, and include intense rewiring
in the frontal lobes and other neorcort ical
reg ions , as wel l as changes in subcor t i ca l
s t ruc tures . Recent research sugges t s tha t
because of these changes in brain function,
drugs l ike a lcohol a f fec t adolescent s and
adul ts different ly.
Recent research indica tes tha t e thanol
af fec t s bra in func t ion and behavior
d i f fe rent ly in adolescent and adul t r a t s .
Depending on the effect measured, adolescent
ra t s may be more or l ess sens i t ive than
adul ts to ethanol induced impairments . For
ins tance , acute e thanol impai r s spa t i a l
l earn ing more potent ly in adolescent ra t s
than in adults (58), and ethanol inhibits the
induction of long-term potentiation (37, 59)
and NMDA receptor -media ted synapt ic
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
8/22
220 Ja in and Balhara India n J Phys iol Pharma col 2010; 54 (3)
potent ia l s more potent ly in h ippocampal
s l i ces f rom adolescent ra t s compared to
those from adults (60). These findings suggest
tha t cogni t ive func t ions , par t i cu la r ly those
re la ted to memory, may be more potent ly
attenuated by ethanol in adolescent rats than
those from adults. Conversely, the onset of
seda t ion a f te r e thanol adminis t ra t ion i s
s lower , and the magni tude of seda t ion i s
smaller in adolescent rats than in adult rats
(26, 41, 61, 62).
Adolescent s have been shown to
di f fe rent ia l ly respond to b inge dr inking .
Binge a lcohol consumpt ion s igni f i cant ly
damaged the bra in of both the adul t s and
the adolescent s (63) . These researchers
repor ted tha t adolescent ra t s exposed to
a lcohol in a four -day b inge pa t t e rn suf fe r
extens ive bra in damage tha t inc ludes
structures that provide the hippocampus with
the informat ion tha t i t needs to form
memor ies . This damage was s igni f i cant lymore extens ive in adolescent subjec t s .
Damage to the h ippocampus fo l lowing
repea ted a lcohol exposure might s t em
from too much ac t iv i ty a t the NMDA
receptor , a par t i cu la r type of receptor for
the neurot ransmi t t e r g lu tamate , dur ing
a lcohol wi thdrawal . Too much ac t iv i ty a t
these receptors could a l low in t race l lu la r
levels of calcium (Ca2+) to become too high,
which can damage and even k i l l a ce l l .
Evidence for this remains indirect, but such
an ef fec t i s cer ta in ly feas ib le based on
research examining the impact of alcohol on
NMDA receptor ac t iv i ty in s l i ces of bra in
and cul tured neurons (64, 65) .
Cognitive impairments following repeated
a lcohol exposure and wi thdrawal in
adolescents may arise from neurotoxicity in
the h ippocampus and re la ted s t ruc tures .
Studies suggest that alcohol effects on the
hippocampus vary with age. Adolescent rats
show much grea te r vulnerabi l i ty to the
ef fec t s of a lcohol than adul t r a t s . Recent
studies in animals indicate that the l imbic
system may be particularly vulnerable to the
effects of alcohol during adolescence. This
area of the bra in p lays a major ro le in
memory formation, par t icular ly the s torage
and reca l l of fac t s , names , and events . I t
has been hypothesized that alcohol wreaks
havoc in the h ippocampus , and impai redhippocampal function appears to be directly
related to impaired memory formation (44).
Taken together, these recent studies indicate
tha t dur ing juveni le and adolescent
development in the rat the neurobehavioral
potency of ethanol varies markedly from that
observed in adul thood.
A number of repor t s sugges t tha t
repeated ethanol exposure might be expected
to produce long lasting changes in adolescent
behavior and bra in func t ion than dur ing
adul thood. Unfor tuna te ly , mos t of these
publ i shed repor t s do not inc lude an adul t
compar i son group, making i t d i f f i cu l t to
discern whether adolescent and adults differ
in their vulnerabi l i ty to the last ing effects
of e thanol . However , pre l iminary evidence
suppor t s tha t e thanol exposure dur ing
adolescence , but not adul thood, enhances
vulnerabi l i ty to e thanol - induced spa t ia l
memory impai rments l a te r in l i f e (43) .
Animal s tudies have a l so shown tha tchronic e thanol induced h ippocampal
damage cor re la tes wi th def ic i t s in spa t i a l
l earn ing and memory. Exposure to e thanol
vapor for 5 or 10 days has recent ly been
repor ted to a l t e r par ie ta l and h ippocampal
electroencephalogram act ivi ty in adolescent
ra t s (66) , whereas the oppor tuni ty to
consume a lcohol voluntar i ly dur ing
adolescence was found to increase l a te r
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
9/22
Indian J Physiol Pharmacol 2010; 54(3) Addiction and Adolescent Brain 221
aggressive behavior in male golden hamsters
(67).
Al though s tudies us ing animal models
have documented tha t adolescent s a re
resis tant to many ethanol effects , they are
converse ly more sens i t ive to cer ta in
res t r i c ted e f fec t s of e thanol - spec i f i ca l ly
ethanol- induced disrupt ions of hippocampal
p las t i c i ty and memory (37 , 68) found tha t
hippocampal slices from preadolescent (PI5-25) rats were more sensitive than adult slices
to e thanol d i s rupt ion of both N-methyl -D-
aspar ta tes (NMDA) media ted exc i ta t ion
as wel l as s t imulus- induced long- te rm
potent ia t ion .
In an imals , i t has been sugges ted tha t
a l lopregnanolone produced in response to
sys temic e thanol adminis t ra t ion could
contribute to several of the effects of ethanol
that are associated with the modulat ion of
GABA A-receptors (69) . Normal ly a lcoholenhances GABA funct ion in adul t s , bu t
adolescent rats injected with alcohol show
a decreased responsiveness to GABA, (37) .
Levels of serotonin have been found to be
assoc ia ted wi th d i f fe rences in a lcohol
preference be tween a lcohol prefer r ing (P)
and alcohol non- preferring (NP) rats. P rats
have been found to have lower sero tonin
leve l s than NP ra t s (70) . Such var ia t ions
sugges t tha t genes tha t cont ro l se ro tonin
act ivi ty may inf luence alcohol preference.
Studies have found functional differences
in the dopamine system (as act ivated by
amphetamine) between the select ively bred
alcohol-preferring and nonpreferring lines of
rats as early as 28 days of age. Given that
the d ivergent dr inking charac te r i s t i cs of
these lines are also evident at this age, it is
possible that hyposensitivity of the dopamine
system may be a potential biological marker
for suscept ib i l i ty to a lcohol abuse . Many
of the neura l sys tems known to undergo
developmenta l changes dur ing adolescence
are ac t iva ted by s t ress which inc ludes
dopamine (DA) pro jec t ions to pref ronta l
cortex or PFC, as well as to mesolimbic brain
regions (71). These areas are thought to be
cr i t i ca l in modula t ing the p leasurable
response tha t fo l lows a lcohol use (31) .
Important receptors for the s t ress hormone
cor t i cos te rone have been ident i f i ed in ra t son DA cel l bodies in the ventral tegmental
area and substantia nigra as well as in DA
termina l reg ions , inc luding the nuc leus
accumbens and the PFC (72, 73). Increase in
cor t i cos te rone may p lay a c r i t i ca l ro le in
act ivat ing DA transmission. These f indings
suggest that s t ress- induced increases in the
s t ress hormones may in te rac t wi th
mesocorticolimbic brain regions to facili tate
alcohol-use behavior . Using the adolescent
rat as a model, adolescents have been shown
to accommodate more rapidly to the presence
of alcohol in their system (so-called acute
to le rance) than adul t r a t s do , thereby
reducing adolescent relative sensitivity to the
motor impair ing and sedat ive consequences
of alcohol (62). This insensitivity to alcohol
impairment may permit adolescents to drink
relatively large amounts when compared with
the i r more mature counterpar t s . Research
wi th rodents has shown tha t th i s exposure
has more adverse effects on hippocampal ly
re la ted memory processes in adolescent sthan in adults (58, 60).
Fetal effects
Animal models of fetal alcohol syndrome
(FAS) and alcohol- related neurodevelopmental
d i sorder (ARND) demons t ra te widespread
damage to the brain following relatively high
prena ta l exposure to a lcohol , as wel l as
significant brain changes following moderate
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
10/22
222 Ja in and Balhara India n J Phys iol Pharma col 2010; 54 (3)
a lcohol exposure , l eading to ce l l loss in
several areas of the brain and affecting the
synapt ic connec t ions . In genera l , a lcohol -
exposed ra t s have smal le r and l ighter
brains. Specific brain structures affected by
prenatal exposure include the basal gangl ia
and the cerebellum, which are small in cases
of exposure. Moreover, increase in the size
of the fluid-fil led cavities in the brain (i .e.
the ventr icles) also has been observed (74,
75) . Other s tudies have reported an overal lreduct ion in the number of ce l l s in the
cerebral cortex, damage to a particular type
of ce l l ( i .e . ; pyramida l ce l l s ) in the
hippocampus , and damage to the main
pathway for the sense of smell in rats (76).
Furthermore, chronic ethanol intake during
gestation and lactation enhances natural cell
death and induces necrosis ; decreases brain
derived neurotrophic factors (BDNF) levels
and increases the rat io of the t runcated to
full length TrkB mRNA receptors during post
natal developing cerebral cortex. The ethanol
induced a l t e ra t ions in BDNF ava i lab i l i ty
and i t s receptors func t ion might impai r
intracellular signalling pathways involved in
ce l l surv iva l , g rowth and d i f fe rent ia t ion ,
causing enhanced natural cel l death during
cerebra l cor tex deve lopment .
Studies a l so indica te tha t gene t ic
differences in alcohol intake among inbred
l ines of ra t s a re present not only in
adul thood but a l so in adolescence , ra i s ing
the poss ib i l i ty tha t s imi la r gene t ic fac tors
might inf luence not only problem drinking
in adul thood, but a l so the emergence of
alcohol drinking during development (77).
Most recently, effect of alcohol on brain
neuropept ides has been repor ted in
adolescent and adul t rats (66) . The resul ts
of this study indicate that brief exposure to
a lcohol has long- te rm ef fec t s on l eve l s
of neuropept ide Y (NPY-LI) , cor t icotropin-
releasing hormone, substance P (SP-LI) and
neurokinins (NK-LI) . As these effects were
pr imar i ly the resu l t of changes in ra t s
exposed to e thanol dur ing adul thood,
however , they are unl ikely to contr ibute to
the increased susceptibility of adolescents to
the effects of chronic ethanol exposure.
Thus , the causes of the long las t ing
changes during adolescence are sti l l unclear
but might re f l ec t bra in damage in the
t radi t iona l sense . These da ta sugges t tha t
heavy, ep i sodic e thanol exposure dur ing
adolescence might a l t e r bra in deve lopment
in a lasting way.
1.3 Neuroendocrinal effects
The possibi l i ty that alcohol could al ter
neuroendocr ine deve lopment has been
suspected for years. Any effect of alcohol on
puber ty- re la ted hormones a t th i s c r i t i ca l
t ime of growth and deve lopment couldelevate the r isk for developmental def ici ts .
Research with experimental animals suggests
tha t de te rmining the e f fec t s of a lcohol on
endocr ine deve lopment war rant s se r ious
cons idera t ion .
Severa l repor t s have found tha t
adolescent a lcohol exposure reduces
testosterone levels in pubertal animals (50,
78, 79). Studies using rats have shown that
alcohol retards NMDA-tr iggered luteinizing
hormone (LH) release in adolescent femalerats (80) , and also suppresses the basel ine
secre t ions of lu te in iz ing hormone (LH) ,
growth hormone, est radiol , and insul in- l ike
growth factor (51, 81, 82). Moreover, alcohol
a l so de lays vagina l opening and lengthens
the in te rva l f rom vagina l opening to f i r s t
diestrus (83).
Neuros te ro ids have been shown to
be rewarding in rodents (84) . Therefore ,
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
11/22
Indian J Physiol Pharmacol 2010; 54(3) Addiction and Adolescent Brain 223
neuros te ro ids may cont r ibute to the
anxiolytic and rewarding effects of alcohol.
Many animal s tudies have inves t iga ted
the e f fec t of a lcohol on neuros te ro id
concentrat ions (85) .
The l imi ted but s igni f i cant ly expl ic i t
l i t e ra ture on e f fec t of s t ress in l abora tory
animals shows tha t adolescent s a re more
negat ively affected by s t ressful events than
are adults. Adolescent rats have shown more
immobi l i ty under s t ress fu l s i tua t ions , such
as a forced swim test as compared to their
adult counterparts (86). It has been reported
tha t chronic soc ia l s t ress has a grea te r
impact on adolescent than on adult male mice
(87) . The h igher s t ress l eve l s resu l t in
grea te r reduct ions in food in take , body
weight ga in , and t ime spent on the open
arms of a p lus mazean indica tor of
anxie tyin adolescent s than adul t s . Also ,
adolescent s somet imes exhib i t a grea te r
overa l l hormonal response to s t ress
evidenced by the increased product ion of a
key stress-related hormone, corticosterone
compared with younger animals and a more
prolonged increase in s t ress hormones
re la t ive to adul t s (2 , 3) . In addi t ion to
s t ress fu l events , p leasurable exper iences ,
such as drinking alcohol also increase stress
hormone levels in laboratory animals (88) .
In fact, corticosterone itself has been shown
to be reinforcing and is self-administered by
rodents both in t ravenous ly and ora l ly (89 ,90) . In te res t ingly , l i t e ra ture a l so sugges t s
tha t adolescent ra t s exhib i t an a t t enua ted
cor t i cos te rone response to a lcohol as
compared to the adul t r a t s (91 , 92) .
Consider ing that increases in cor t icosterone
cont r ibute to the rewarding aspec t s of
alcohol, adolescents might need to consume
more alcohol to achieve the same effect as
compared to adul ts .
Cor t i cos te rone l eve l s in ra t s have a l so
been pos i t ive ly re la ted to ra tes of se l f -
administration of ethanol and adrenalectomy
has been assoc ia ted wi th suppress ion of
ethanol consumption (93) and stress-induced
eleva t ions in cor t i cos te rone increas ing
ethanol consumption (94). Stressors may also
enhance the ra te of to le rance deve lopment
to e thanol thereby indi rec t ly increas ing
ethanol consumption capaci ty.
2.0 Nicotine and adolescent brain
Tobacco use in adolescence represent s
one of the major cha l lenges to the fu ture
of publ ic hea l th . There i s accumula t ing
evidence tha t adolescence i s a per iod of
he ightened sens i t iv i ty to the e f fec t s of
nicotine. Adolescence appears to be a critical
per iod for the in i t i a t ion of smoking in
h u m a n s .
2.1 Neurobehavioral effects
Despite the increasing use of tobacco by
adolescent s , f ew animal s tudies have
addressed the neurobehavioral consequences
of nicotine exposure during this period. The
acute e f fec t s of n ico t ine enhance ra t
locomotor act ivi ty in ear ly adolescent rats
and suppress it at late ages (95, 96, 97, 98).
Early adolescence also appears to be a period
of increased sens i t iv i ty to the rewarding
effects of nicot ine (96, 98) . Adriani et a l . ,
(99) a l so provide re levant ev idence tha tn icot ine e f fec t s depend on the age of the
animal. They showed that nicotine oral self-
adminis t ra t ion dur ing ear ly adolescence
(pos tna ta l day (P) 2435) increased the
preference for the nicotine solution when the
concent ra t ion was reduced as wel l as the
locomotor response to the drug. These effects
were not observed when nicot ine was self-
administrated by either middle (P37P48) or
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
12/22
224 Ja in and Balhara India n J Phys iol Pharma col 2010; 54 (3)
la te (P50P61) adolescent mice.
Other aspects of nicotine effects are also
age d i f fe rent ia ted . Faraday e t a l , (100)
reported that both gender and age interacted
to a f fec t behaviora l reac t ions to n icot ine
dosing. Some age differentiated effects of
nicot ine may actual ly reduce the l ikel ihood
of dependence. Schochet et al., (101) reported
tha t P28-42 ra t s do not exhib i t n ico t ine -
pa i red cue condi t ioning , a l though adul t sdo . Trauth e t a l . , (102) repor ted tha t
per iadolescent n icot ine (P3047.5) induces
expression of p53 genes consistent with cell
damage in severa l bra in reg ions , and
sugges ted tha t adolescence i s a t ime of
continuing susceptibility to neurotoxic effects
of n icot ine . Females were more sens i t ive
than males to this effect , and hippocampus
was a relat ively sensi t ive s t ructure. Trauth
e t a l . , (103) a l so repor ted tha t adolescent
n icot ine exposure causes upregula t ion of
nicot inic chol inergic receptors to a greater
extent than in adul t an imals , and the
upregula t ion pers i s t s for a t l eas t 1 month
af te r t e rmina t ion of drug exposure .
Dopamine and norepinephr ine were a l so
increased by per iadolescent nicot ine (104) .
These f indings re inforce the concept tha t
deve lopmenta l vulnerabi l i ty to n icot ine
extends in to adolescence , wi th pa t t e rns
of drug e f fec t s d i f fe rent f rom those in
ear l ier or later per iods. The correlat ion of
neurochemica l wi th behaviora l e f fec t s
strengths the connection between adolescent
nicot ine exposure and persis tent funct ional
changes that may influence drug habituation,
l earn ing and memory.
Other workers have conf i rmed tha t
adolescent n icot ine may have pers i s t ing
ef fec t s . Levin and co-workers (105) have
shown tha t female ra t s , aged P54, have
higher rates of nicotine intake than do older
animals. Navarro et al . (106) suggested that
adolescent n icot ine induces pers i s t ing
compromise in immune response suggest ing
that multiple signaling systems are affected
by adolescent n icot ine . Recent ly , S lo tk in
and coworkers (107) a l so rev iewed the
l i t e ra ture on adolescent n icot ine e f fec t s .
Slawecki et a l . (108) s tudied the long-term
neurobehavioral effects of alcohol or nicotine
exposure in adolescent animal models. Thiss tudy suppor ted the hypothes i s tha t
adolescents are uniquely suscept ible to the
effects of chronic alcohol and nicotine use.
Thus, i t is clear that nicotine, l ike alcohol,
can induce last ing neurobehavioral changes
when consumed dur ing the per iadolescent
per iod in animals .
2.2 Neurochemical \Neurobiological effects
Nicot ine al ters var ious neurotransmit ter
systems such as the nicotinic, dopaminergic,
and sero tonergic sys tems in adul t rodent
animal models . I t i s not fu l ly unders tood
whether the e f fec t s of n ico t ine d i f fe r on
spec i f i c neurochemica l pa thways wi th
which i t interacts in adolescents compared
wi th adul t s . Neurochemica l changes in
response to n icot ine adminis te red dur ing
periadolescence have been examined as well.
It has been reported that nicotine injections
for 10 days beginning on pos tna ta l day
34 produced an increase in n icot in ic
ace ty lchol ine receptor gene express ion 5weeks a f te r t r ea tment ended (99) . Fur ther ,
nicotinic acetylcholine receptor binding was
upregula ted a f te r cont inuous infus ion of
nicotine for 17 days beginning in adolescence
(109), and dopamine turnover was increased
at postnatal day 45 after a 17 days nicotine
infusion period that began in preadolescence
(103) . Addi t iona l ly , cont inuous ly infused
nicotine for 17 days in adolescent male rats
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
13/22
Indian J Physiol Pharmacol 2010; 54(3) Addiction and Adolescent Brain 225
produced a reduction in serotonin transporter
densi t ies (110) and a decrease in serotonin
(5-HT) receptor binding (111). However, some
previous s tudies , examined neurochemica l
changes tha t occur red a t t ime poin t s pas t
the per iadolescent per iod . In s tudies
examining the effects of nicot ine exposure
on neurochemica l a l t e ra t ions wi th in the
adolescent per iod, dai ly nicot ine inject ions
for 3 days beginning on postnatal day 30,
decreased serotonin synthesis and tryptophanexpress ion 3 days l a te r (112) . Fur ther
continuous infusion or twice daily injections
of nicotine for 7 days beginning on postnatal
day 30 increased n icot in ic ace ty lchol ine
receptor binding in the midbrain immediately
after treatment ended and persisted at least
a month (113). Collins et al ., (114) studied
the neurochemica l a l t e ra t ions produced by
daily nicotine exposure in periadolescent vs.
adul t r a t s . In th i s s tudy the inves t iga tors
demonstrated the effects of a 7-day treatment
with nicotine on nicotinic, dopaminergic, and
serotonergic neurochemistry. The effect was
examined in the caudate putamen and
nucleus accumbens in per iadolescent vs .
adul t male ra t s . I t was found tha t tha t
n icot ine t rea tment increased dopamine
transporter densities and decreased serotonin
transporter densities in periadolescent
ra t s . There was no change in n icot in ic
acetylcholine receptor densities or dopamine
Dl or D2 receptor dens i t i es in n icot ine-
pre t rea ted per iadolescent ra t s . On thecont ra ry the adul t r a t s pre t rea ted wi th
nicot ine showed increase in n icot ine
ace ty lchol ine dens i t i es and no change
in dopamine t ranspor te r , dopamine Dl or
D2 receptor , or se ro tonin t ranspor te r
densities (114). These findings suggest that
per iadolescent ra t s have neurochemica l
adaptations to nicotine different from adults.
Together these da ta sugges t tha t there a re
neurochemica l a l t e ra t ions occur r ing in
response to adolescent nicotine exposure and
that these changes can last into adul thood.
2.3 Neuroendocrinal effects
Recently, great interest has been devoted
to the interaction between nicotine addiction
and the hypotha lamic -p i tu i t a ry-adrena l
(HPA) axis. Nicotine activates the HPA axis
in adul t r a t s as measured by n icot ine
induced increases in ACTH (115) and
cor t i cos te rone (116) . I t has been repor ted
tha t sys temica l ly adminis te red n icot ine
s t imula tes the hypotha lamus-pi tu i t a ry-
adrena l (HPA) axi s through a cent ra l ly
media ted cor t i co t rophin- re leas ing-hormone
(CRH) dependent mechanism (117) .
Cor t i cos te rone modula t ion of behaviora l
responses to n icot ine appears to be qui te
complex (118) . There is also evidence that
cort icosterone par t icipates in neuroadpat ive
changes underlying conditioned tolerance tonicotine (118). Few studies investigated the
involvement of glucocort icoids on repeated
nicot ine e f fec t on locomotor ac t iv i ty and
sensitization. Shoaib and Shippenberg (119)
have demons t ra ted tha t adrena lec tomy did
not affect the depressant effect of repeated
nicotine but blocked the stimulation induced
by this drug. In addition, Johnson et al. (120)
showed tha t adrena lec tomy di s rupted the
development , but not the express ion of
nicot ine induced locomotor sensi t izat ion.
Despi te the relevance of the interact ion
between drugs and the HPA axis, the effect
of acute or chronic nicotine on the activation
of HPA axis in adolescent s has not been
inves t iga ted . Recent ly , Cruz e t a l . , (121)
repor ted the d i f fe rent ia l behaviora l and
endocr ine e f fec t s of repea ted n icot ine in
adolescent and adult rats. The results of this
s tudy provide evidence that adolescent rats
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
14/22
226 Ja in and Balhara India n J Phys iol Pharma col 2010; 54 (3)
exposed to repeated display behavioral and
neuroendocr ine adapta t ions d i s t inc t f rom
tha t observed in adul t an imals . Also these
resul ts fur ther suggest that cor t icosterone -
activating effect of nicotine did not develop
to le rance in adolescent ra t s as compared
to adul t s . The l ack of to le rance to the
corticosterone-activating effect of nicotine in
adolescent ra t s could be re la ted to the
absence of behaviora l sens i t i za t ion , s ince
in these an imals the h igh l eve l s of cor t i cos te rone fo l lowing repea ted n icot ine
could main ta in the n icot ine chol inerg ic
receptors in the desensitized state. However,
the e f fec t of cor t i cos te rone on n icot ines
action appears to be very complex and thus
the actions of the glucocorticoids may vary
for different nicotinic receptor subtypes and
/or brain regions, as i t has been suggested
for n icot ines ac t ion on i t s own receptors
(109, 122) . Fur ther , s ince cor t i cos te rone
seems to have re inforc ing proper t i es (90) ,the lack of tolerance to the cor t icosterone-
ac t iva t ing e f fec t of n ico t ine in adolescent
rats may increase the reinforcing effect of
n ico t ine and the vulnerabi l i ty to tobacco
addict ion during adolescence. Furthermore,
invest igat ion on the role of glucocort icoids
on the e f fec t s of n ico t ine may provide
re levant knowledge to the deve lopment of
therapeut ic agents for the t rea tment of
nicot ine addict ion.
During late chi ldhood and adolescence,neurobiological systems are sti l l undergoing
impor tant deve lopmenta l rear rangements .
Thus, several mechanisms could account for
age differences in nicotines behavioral and
neuroendocrine actions. Understanding these
di f fe rences in n icot ine e f fec t s be tween
adolescent s and adul t s may lead to age
spec i f i c s t ra teg ies of prevent ion and
treatment . Therefore, i t wi l l be interest ing
in fu ture s tudies to de te rmine which
neurochemica l and molecular mechanisms
may contribute to the differential effects of
nicot ine in adul ts and adolescents .
3 .0 Substance abuse and adole scent bra in
As ment ioned above, drug abuse among
humans of ten begins during adolescence, a
per iod of ontogeny in which indiv idua l s
exhibit age-specific behavioral characteristics,
such as r i sk t ak ing and novel ty seeking ,
which could d i spose them to in i t i a te drug
use (2).
3.2 Neurobehavioral effects
The per iadolescent per iod in the ra t i s
character ized by changes in the behavioral
respons iveness to many drugs of abuse .
These a l t e ra t ions may be predic t ive of
al terat ions in the reward value of drugs of
abuse . Campbel l e t a l . , (123) s tudied the
coca ine and morphine - induced p lacecondi t ioning in adolescent and adul t r a t s .
These workers suggested that adolescent and
adult rats exhibited similar sensitivity to the
rewarding effects of morphine and cocaine.
No differences was found between adolescent
and adul t s in the magni tude of p lace
condi t ioning expressed for morphine or
cocaine.
Persis tent effects of adolescent cocaine
have been reported in a few recent studies.
Smith et al ., (124) reported that 10 mg/kg/day adolescent cocaine modified the pattern
of cocaine stimulated upon field activity in
adul t s and a l so resu l ted in improved
per formance in DLR 20-s t ask . Pepin and
Smi th (125) found tha t 20 mg/kg/day
adolescent cocaine reduced adult consumption
of a cocaine solution in a schedule induced
polydipsia task. Smith et al . , (126) showed
tha t 5 or 20 mg/kg/day coca ine dur ing
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
15/22
Indian J Physiol Pharmacol 2010; 54(3) Addiction and Adolescent Brain 227
adolescent or preadolescent dosing with one
drug can induce changes in reac t ion to
another drug la te r in l i f e . I t i s now c lear
tha t poss ib le cont r ibut ions of b io logica l
factors to adolescent drug progression needs
fur ther s tudy.
3.3 Neurochetnical \Neurobiological effects
Very few published reports are available
on the neurochemica l and neurobio logica l
effects of abusable drugs in adolescent rats.
Recent work on animals have indicated that
adolescent subs tance abuse may have long
las t ing consequences , inc luding bra in
damage , changes in cogni t ive capabi l i t i es ,
changes in electrophysiology, and hormonal
ef fec t s tha t may a l t e r sexual matura t ion .
Riddle et al . (135) have reported that four
10 mg/kg in jec t ions of methamphetamine ,
which induced reduct ions in DA persis t ing
for a t l eas t 7 days in adul t r a t s , induced
only short-term effects in 40-day-old rats. Foramphetamines , Lavio la e t a l . , (136) have
recent ly repor ted tha t adolescent mice
exhib i t d i f fe rent reac t ions than do adul t
mice . The s tudy showed tha t e f fec t s of
adolescent dosing include enhanced s t r iatal
DA response amphetamine cha l lenge , but
adul t dos ing does not produce the same
ef fec t . Other e f fec t s inc lude a marked
sens i t i za t ion of explora tory behavior in
response to amphetamine challenge in adults
but not adolescent s . To unders tand ef fec t sof abusable substances on adolescents, i t is
necessary to s tudy adolescent s . This
conclusion is supported by work of Kosofsky
et a l . , (137) . These workers found tha t
cocaine administration at each of four ages
(P8, PI5 , P28, and adul t ) r esu l ted in
dis t inct ively different pat terns of induct ion
of immedia te ear ly genes a t each age . At
the gene express ion l eve l , adminis t ra t ion
adolescent a l t e red per formance in a
coca ine condi t ioned p lace preference t ask .
Interestingly, 5 mg/kg/day cocaine increased
place conditioning only when the conditioning
chamber had hor izonta l b lack and whi te
s t r ipes whi le 20 mg/kg/day increased
condi t ioning only in a ver t i ca l ly s t r ipped
chamber . This f inding i s sugges t ive of
modi f ica t ion of some aspec t s of v i sua l
functioning by adolescent cocaine. Morin et
al., (127) reported the binge regimen affects
adul t cocaine condi t ioned place preference.
Sensitization to cocaine has been reported
to develop in periadolescent much as it does
in adults (128, 129). Some studies have also
repor ted tha t sens i t i za t ion to coca ine
develops differently in preadolescent animals
than in adults. Synder et al . (130) reported
tha t sens i t i za t ion in preweanl ing ra t s was
especially long- lasting, suggesting that there
may be ontogenetic changes in the substances
for sensitization. Zavala et al. (131) showed
that sensitization to the locomotor effects of
coca ine pers i s ted for a longer per iod in
preadolescent ra t s than in adul t an imals ,
implying that the substrate for sensitization
are somehow di f fe rent depending upon the
age of the subject . Col l ins and Izenwasser
(132) , on the o ther hand, found tha t
per iadolescent ra t s were not sens i t i zed to
cocaine over a 7-day regimen from P 28-35,
while adults were sensitized. More recently,
Melnick and Dow-Edward (133) found thatprepuber ta l coca ine (P-20) reduced the
development of amphetamine sensitization in
older (>6 months) rats. Brandon et al., (134)
repor ted tha t adolescent dos ing wi th
methylphenida te increased responding
for in t ravenous coca ine on a progress ive
ra t io schedule in adul t s . Thus , there a re
now repor t s for four drugs (a lcohol ,
nicotine, cocaine, and methylphenidate) that
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
16/22
228 Ja in and Balhara India n J Phys iol Pharma col 2010; 54 (3)
Groups of prepubescent male ra t s (2527
days of age) were implanted with morphine-
or p lacebo-pe l le t s . When the acute and
chronic effects of morphine on reproductive
endocr ine parameters had d i ss ipa ted and
the i r fe r t i l i ty and the deve lopment of the
male and female progeny was character ized
the resul ts showed that morphine exposure
dur ing adolescence l ed to a pronounced
inhibition of a number of indices of sexual
matura t ion (e .g . se rum tes tos te rone and
lu te in iz ing hormone leve l s and reduced
weights of the testes and seminal vesicles).
Breeding morphine- and p lacebo- implanted
male rats with drug-naive females resul ted
in smal le r l i t t e r s der ived f rom morphine-
t reated fathers when compared to controls ,
but in a l l o ther respec t s the deve lopment
of the of f spr ing in the two groups were
equiva lent . However , upon reaching
adul thood, a number of select ive endocrine
di f fe rences were de tec ted in morphine-derived offspring when compared to controls
(50). Byrnes et al., (141) studied the effects
of chronic morphine exposure during puberty
on pos tpar tum behavior and pro lac t in
secret ion in female rats (141) . The s tudied
showed that per ipubertal morphine delayed
vaginal opening and significantly attenuated
later lactat ion in female rats . The lactat ion
def ic i t s were accompanied by def ic ien t
suckling-induced prolactin release. They also
reported that the offspring of mothers dosed
per ipuber ta l ly wi th morphine were de layed
in vagina l opening , presumably resu l t ing
f rom a l t e ra t ions in materna l hormones .
Adolescent coca ine use (20 mg/kg/day)
reduces es t rous cyc l ing both dur ing and
fol lowing dos ing (Raap e t a l . , 2000) . In
female mice, cocaine can delay the puberty-
acce le ra t ing e f fec t s of exposure to male
pheromones (83) .
of cocaine to early adolescent rats (P28) is
biologically different than adult administration,
and it should not be surprising if other effects
of such administration also differ.
More recently, concerns about subtle long
las t ing neurobio logica l changes tha t might
be t r iggered by exposure to cannabis
exposure derivatives, especially in a crit ical
phase of brain maturat ion, such as puberty
has been ra i sed (138) . The mesol imbicdopamine (DA) sys tem, involved in the
processing of drug induced reward, is a locus
of action of cannabinoid and endocannabinoids
(139). These investigators suggested that an
enduring form of neuronal adaptation occurs
in DA neurons after sub chronic cannabinoid
intake at a young age, affecting subsequent
responses to drug of abuse.
There i s insuf f ic ien t da ta to draw rea l
conclusions. It is speculated that effects of
abusable substances on adolescents and their
behavior with respect to these drugs could
be on account of combinat ion of cont inued
plasticity of the CNS during late maturation.
Moreover , some spec i f i c adolescent adul t
differences in reactions to drugs may perhaps
due to ontogenet ic or exper ience- induced
differences in receptor expression or other
aspects of neurotransmit ter system or other
behavior cont ro l sys tems such as l a te
maturation of frontal lobes etc. (140). More
work i s needed to fu l ly unders tand theneurochemical and neurobiological substrates
of this par t icular age group.
3.4 Neuroendocrinal effects
The ef fec t s of adolescent morphine
exposure on the sexual maturat ion of male
ra t s , the i r reproduct ive capac i ty and the
development of the i r progeny have been
examined by var ious groups of au thors .
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
17/22
Indian J Physiol Pharmacol 2010; 54(3) Addiction and Adolescent Brain 229
amount of ev idence tha t adolescent
consumpt ion of severa l drugs by animals
subjec t s may resul t in res idua l e f fec t s on
neurobehaviora l func t ioning . In some
s tudies , d i rec t compar i sons wi th adul t s
indicated that the adolescent brain is more
sens i t ive to l as t ing e f fec t s of a lcohol and
abusable drugs than i s the adul t s CNS. In
many o ther s tudies , there a re no adul t
comparision groups. However, at this point,
there a re suf f i c ien t da ta to sugges t tha t
consumpt ion of a lcohol , n ico t ine and
abusable drugs by adolescents poses a real
r i sk of l as t ing CNS changes , as re f l ec ted
in par t by cogni t ive changes . Moreover ,
these f indings have he lped in the be t t e r
understanding of the issue and have provided
subs t ra te for the c l in ica l appl ica t ion . But
stil l a lot remains to be answered regarding
impact of a lcohol and subs tance abuse on
adolescent brain. Future s tudies wil l prove
useful to understand the biological substratesof subs tance abuse by th i s par t i cu la r age
group.
Thus, i t is clear that periadolescent use
of abusable substances may alter aspects of
neuroendocr ine cont ro l and assoc ia ted
indices of sexual matura t ion . Fur ther ,
functional consequences for adult reproductive
func t ioning , and poss ib le cont r ibut ions of
a l t e red endocr ine s ta tus to per iadolescent
CNS development , remain to be def ined.
C o n c l u s i o n
The adolescent bra in i s not mere ly a
miniature adult brain rather it is structurally
and developmentally different from its adult
counterpar t . This difference is seen in the
s t ruc tures involved in the use of a lcohol ,
n icot ine and o ther abusable drugs i .e .
stressor-sensitive, mesocorticolimbic dopamine
project ions that are cr i t ical for modulat ing
the perceived value of reinforcing s t imuli .
Moreover, since it is still developing it means
tha t the impact i t suf fe r s would have
consequences for adul t l i f e func t ioning aswel l . Al though signif icant quest ions remain
to be answered, there is now a considerable
REFERENCES
1 . Wi t t chen HU, Behrendt S , Hol l e r M, Perkon i ggA, Lieb R, Buhringer G, Beesdo K. What are thehigh r i sk per iods for incident substance use andtransit ions to abuse and dependence ? Implicationsfor ear ly in tervent ion and prevent ion. In t J M et hods Psych i a t r Res 2008; 17: S16S29.
2 . Spear LP. The adol escen t b ra i n and age- r e l a t edbehav i o ra l man i fes t a t i ons . Neurosc i B i obehav
Rev 2000; 24: 417463.
3 . S p e a r L P , B r a ke S . P e r i a d o le s c e nc e : a g e -dependen t behav i o r and psychopharmaco l og i ca lr espons i v i t y i n r a t s . Dev Psychob i o l 1983; 16:83109 .
4 . Oj eda SR , Urbansk i HF. Puber t y i n t he r a t . I n :Knob i l E , Nei l l JD ed i t o r s . The phys i o l ogy o f r ep roduct i on 2nd ed . New York : Raven PressLtd. , 1999; p . 363409.
5 . Var l i n skaya El, Spear LP , Spear NE. Soci a lbehavior and social motivation in adolescent rats:role of housing condit ions and partners activity.Physiol Behav 1999; 67: 475482.
6 . R i v i er C . Ef fec t i f the age o f ra t on and t heduration of of the st imulus stress- induced ACTHsecre t i on . In Wei ner H F l o r i n R Mur i son RHel l hammer D ed i t o r s . Fron t i ers o f S ressResearch. Toronto: Hans Huber Publ i shers , 1989,pp. 223232.
7 . Lewi s DA. Devel opmen t o f t he p ref ron t a lco r t ex du r i ng ado l escence : In s i gh t s i n t o
vu l nerab l e neu ra l c i r cu i t s i n sch i zophren i a .Neuropsychopharmaco l ogy 1997; 16: 385398.
8 . M e n t L R , K e s l e r S , V o h r B , K a t z K H ,Baumgar t ner H , Schnei der KC, Del ancy S ,S i l bere i s J , Duncan CC, Cons t ab l e RT, MakuchRW, Rei ss AL. Long i t ud i na l b ra i n vo l umechanges i n p re t e rm and t e rm con t ro l sub j ec t sduring late childhood and adolescence. Pediatrics2009; 123: 503511.
9 . Rapopor t JL , Cas t e ll anos FX, Gogat e N , JansonK, Koh l er S , Nel son P . Imag i ng no rmal andabnormal b ra i n devel opmen t : new per spec t i vesfor child psychiatry. Aust N Z J Psychiatry 2001;35: 272281.
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
18/22
230 Ja in and Balhara India n J Phys iol Pharma col 2010; 54 (3)
10 . L i dow MS, Go l dman- Rak i c PS , Rak i c P .Synchronizedd overproduction of neurotransmitterr ecep t o r s i n d i ver se r eg i ons o f t he p r i mat ecereb ra l co r t ex . Proc Na t l Acad Sc i USA 1991 ;88: 1021810221.
11. Blows WT. Chi ld brain development. Nurs Times2003; 99: 2831.
12. Chugani HT. Biological basis of emot ions: Brainsystems and brain development . Pediatr ics 1998;102: 12251229.
13 . Casey BJ . Images i n neu rosc i ence . B ra i ndevelopment XII : maturat ion in brain act ivat ion.Am J Psych i a t ry 1999; 156: 504.
14 . Rub i a K , Overmeyer S , Tay l o r E , Brammer M,Wil l iams SC, Simmons A, Andrew C, Bul lmoreET. Funct ional f rontal i sat ion wi th age: mappingneurodevel opmen t a l t r a j ec t o r i es wi t h fMRI .Neurosc i B i obehav Rev 2000; 24: 1319.
15 . Luna B , Thu l bo rn KR, Munoz DP, Mer r i am EP,Garver KE, Mi nshew NJ , Keshavan MS,Genovese CR, Eddy WF, Sweeney JA.Maturat ion of widely dis t r ibuted brain funct ionsubserves cogn i t i ve devel opmen t . Neuro Image2001; 13: 786793.
16 . Karacay B , Li S , Bon t h i us DJ . Mat u ra t i on -dependen t a l coho l r es i s t ance i n t he devel op i ngmouse : cerebe l l a r neu ronal l o ss and geneexpress i on du r i ng a l coho l -vu l nerab l e and -r es i s t an t per i ods . Al coho l C l i n Exp Res 2008 ;32: 14391450.
17 . Ki mmel HL, Joyce AR, Car ro l l F I , Kuhar MJ .Dopami ne D1 and D2 recep t o r s i n f l uencedopamine transporter synthesis and degradationin the rat . J Pharmacol Exp 2001; 298: 129140.
18 . Taraz i F I , Tomas i n i EC , Bal dessar i n i RJ .Pos t na t a l deve l opmen t o f dopami ne andsero t on i n t r anspor t e r s i n r a t caudat e-pu t amenand nucl eus accumbens sep t i . Neurosc i Le t t 1998; 254: 2124.
19 . Shen HW, Hag i no Y, Kobayash i H , Sh i nohara-Tanaka K, Ikeda K, Yamamoto H, Yamamoto T,Lesch KP, Murphy DL, Hall FS, Uhl GR, Sora I.Reg i onal d i f f e rences i n ex t r ace l l u l a r dopami neand sero t on i n assessed by i n v i vo mi crod i a l ys i sin mice lacking dopamine and/or serotonint r anspor t e r s . Neuropsychopharmaco l ogy 2004 ;29: 17901799.
20 . Adams CE, Bro i de RS, Chen Y, Wi nzer -SerhanUH, Hender son TA, Les l i e FM, Freedman R .Development of the 7 nicot in ic chol inergicrecep t o r i n r a t h i ppocampal fo rmat i on . DevBrain Res 2002; 139: 175187.
21 . OLeary KT, Lough l i n SE, Chen Y, Les l i e FM.Ni co t i n i c ace t y l cho l i ne r ecep t o r subun i t mRNAexpression in adul t and developing rat medul laryca t echo l ami ne neu rons . J Comp Neuro l 2008 ;510: 655672.
22 . Mol l GH, Mehner t C , Wi cker M, Bock N,Ro t henberger A , Ru t her E , Huct her G . Age
associated changes in the densit ies of presynapticmonoami ne t r anspor t e r s i n d i f f e ren t r eg i ons o f t he r a t b ra i n f rom ear l y j uven i l e l i f e t o l a t eadu l t hood . Dev Bra i n Res 2000; 119: 251257.
23. De Bell is MD, Clark DBN, Beers SR, Soloff PH:Bor i ng AM, Hal l J , Ker sh A , Keshvan MS.Hippocampal volume in adolescent onset alcoholuse disorders. Am J Psychiatry 2000; 157: 737744.
24 . Gl an t z LA, Gi l more JH, Hamer RM, Li ebermanJA, Jarskog LF. Synaptophysin and postsynapt icdensi ty protein 95 in the human prefrontalcor tex f rom mid-gestat ion in to ear ly adul thood.Neurosc i ence 2007; 149: 582591.
25. Sowel l ER, Trauner DA, Gamst A, Jernigan TL.Devel opmen t o f co r t i ca l and subcor t i ca l b ra i ns t ruc t u res i n ch i l dhood and ado l escence : ast ructural MRI study 2002; 44: 416.
26 . Moy SS , Duncan GE, Knapp DJ , Breese GR.Sensit ivity to ethanol across development in rats:comparison to (3H) zolpidem binding. Al coho lCl in Exp Res 1998; 22: 14851492.
27 . Dumas TC, Fos t er TC . Lat e devel opmen t a lchanges in the abi l i ty of adenosine Al receptorst o r egu l a t e synap t i c t r ansmi ss i on i n t hehippocampus. Dev Brain Res 1998; 105: 137139.
28 . Lauder JM, Wi l k i e MB, Wu C , S i ngh S .Expression of 5-HT(2A), 5-HT(2B) and 5-HT(2C)recep t o r s i n t he mouse embryo . In t J DevNeurosci 2000; 18: 653662.
29 . Tamrakar SM, Ko i ra l a NR. Lat es t advances i nde-add i c t i on s t r a t eg i es . Kathmandu Univ Med J(KUMJ) 2007; 5 : 124128.
30 . Wi se RA. Drug - ac t i va t i on o f b ra i n r ewardpathways. Drug Alcohol Depend 1998; 51: 122.
31 . Koob GF. Dynami cs o f neu ronal c i r cu i t s i nadd i c t i on : r eward , an t i r eward , and emot i onalmemory . Pharmacopsych i a t ry 2009; 42 Suppl 1 :832841 .
32 . Gran t GF. The i mpact o f f ami l y h i s t o ry o f a l choho l i sm on t he r e l a t i onsh i p be t ween age a tonse t o f a l coho l u se and DSM-IV a l coho ldependence: Resul t s of the Nat ional Longi tudinalAlcohol Epidemiologic Survey. Alcohol Heal th &Research World 1998; 22: 144147.
33 . E l k i ns I J , K i ng SM, McGue M, I acono WG.Per sonal i t y t r a i t s and t he devel opmen t o f n icot ine, alcohol , and i l l ici t drug disorders:p rospec t i ve l i nks f rom ado l escence t o youngadul thood. J Abnorm Psychol 2006; 115: 2639.
34 . Hi ndel ang RL, Dwyer WO, Leemi ng FC . .Adolescent r i sk- taking behavior : a review of therole of parental involvement . Curr Probl Pediatr 2001; 31: 6383.
35 . Barb i er E , P i er r e f i che O , Vaudry D, Vaudry H,Daoust M, Naassi la M. Long-term al terat ions invulnerabi l i ty to addict ion to drugs of abuse andin brain gene expression af ter ear ly l i fe ethanolexposure. Neuropharmacoloey 2008; 55: 11991211.
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
19/22
Indian J Physiol Pharmacol 2010; 54(3) Addiction and Adolescent Brain 231
Gol den Hamst er s El eva t es B l ood Tes t os t e roneand Increases Aggress i on i n Ear l y Adu l t hood .Pos t er p resen t ed a t t he meet i ng o f t he Soci e t yfo r Neurosc i ence i n New Or l eans i n 1997 .
50 . C i cero TJ , Adams ML, OConnor L , Meyer ER,Wozn i ak D. In f l uence o f ch ron i c a l coho l onrep resen t a t i ve i nd i ces o f puber t y and sexualmaturat ion in mule rats and the development of thei r progeny. J Pharmacol Exp Ther 1990; 225:707715 .
51 . Juarez J , Bar r i o s De Tomas i E , Vazquez C .Al coho l t r ea t men t du r i ng l ac t a t i on p roduces anadvance i n t he onse t o f puber t y i n f emal e r a t s .Alcohol 2000; 21: 181185.
52 . Hayash i T , Tadokoro S . Learn i ng r e t a rda t i onand enhanced e t hano l p reference p roduced bypos t na t a l p re t r ea t men t s wi t h e t hano l i n adu l tr a t s . Japanese Journa l o f Pharmaco l ogy 1985 ;37: 269276.
53 . Rodd-Henr i cks ZA, Bel l RL, Kuc KA, MurphyJM, McBr i de WJ , Lumeng L, L i TK. Ef fec t s o f e t hano l exposu re on subsequen t acqu i s i t i on andex t i nc t i on o f e t hano l se l f - admi n i s t r a t i on andexpress i on o f a l coho l - seek i ng behav i o r i n adu l talcohol-preferring (P) rats: I. Periadolescent exposure.Alcohol Clin Exp Res 2002; 26: 16321641.
54 . Brunel l SC , Raj endran P , Spear LP . Et hano li n t ake and s t r ess adap t a t i on i n ado l escen t andadult rats. Soc Neurosci Abstr 2001; 27: 877882.
55. Fat tore L, Al tea S, Frat ta W. Sex di f ferences in
drug addiction: a review of animal and human studies.Womens Heal th (Lond Engl ) 2008; 4 : 5165.
56 . Var l i n skaya El , Spear LP . Acu t e e t hano lwi t hd rawal (hangover ) and soc i a l behav i o r i nado l escen t and adu l t mal e and f emal e sp rague-dawley rats. Alcohol i sm: Cl in ical & ExperimentalResearch 2004; 28: 4051.
57 . McBr i de WJ , Bel l RL, Rodd ZA, S t ro t her WN,Murphy JM. Adolescent alcohol dr inking and i t sl ong- range consequences . S t ud i es wi t h an i malmodels . Recen t Dev Al coho l 2005; 17: 123142.
58 . Raj endran P , Spear LP . The ef f ec t s o f e t hano lon spa t i a l and nonspat i a l memory i n ado l escen tand adu l t r a t s s t ud i ed us i ng an appet i t i veparadigm. Ann N Y Acad Sci 2004; 1021: 441444.
59. Pyapli GK, Turner DA, Wilson WA, SwartzwelderHS. Age and dose-dependen t e f f ec t s o f e t hano lon the induct ion of h ippocampal long- termpo t en t i a t i on . Al coho l 1999; 19: 107111.
60 . Swar t zwel der HS, Wi l son WA, Tayyeb MI .Di f f eren t i a l sens i t i v i t y o f NMDA recep t o r -med i a t ed synap t i c po t en t i a l s t o e t hano l i ni mmat u re ver sus mat u re h i ppocampus . Al coho lCl in J Exp Re 1995b; 19: 320323.
61. Wil l s TA, Knapp DJ, Overst reet DH, Breese GR.Di f f eren t i a l d i e t a ry e t hano l i n t ake and b l oodethanol levels in adolescent and adult rats: effectson anx i e t y - l i ke behav i o r and se i zu re t h resho l ds .Al coho l C l i n Exp Res 2008; 32: 13501360.
36 . Whi t e AM, Bae JG, Truesda l e MC, Ahmad S ,Wi l son WA, Swar t zwel der HS. Chron i c-intermittent ethanol exposure during adolescencepreven t s no rmal devel opmen t a l changes i nsensit ivity to ethanol-induced motor impairments.Al coho l C l i n Exp Res 2002; 26: 960968.
37. Swartzwelder HS, Wilson WA, Tayyeb MI. Age-dependent inhibi t ion of long- term potent iat ionby ethanol in immature versus mature hippocampus.Al coho l Cl i n Exp Res 1995; 19: 14801485.
38 . L i guor i AD, Agnos t i no RB J r , Dwork i n SI ,Edwards D , Rob i nson JH. Al coho l e f f ec t s onmood equi l ibr ium and simulated dr iv ing. AlcoholCl in Exp Res 1999; 23: 815821.
39. White AM, Montoya D, Wilson WA, SwartzwelderHS. Di f f e rences i n Et OH- i nduced mot o rimpai rments and EtOH metabol i sm in adolescentand adu l t r a t s . Al coho l C l i n Exp Res (Supp l )2001; 25: 109A.
40 . Acheson SK, R i chardson R , Swar t zwel der HS.Devel opmen t a l changes i n se i zu re suscep t i b i l i t yduring ethanol withdrawal. Alcohol 1999; 18: 2326.
41 . Swar t zwel der HS, R i chardson RC, Markwi ese-Foerch B , Wi l son WA, Li t t l e PJ . Devel opmen td i f f e rences i n t he acqu i s i t i on o f t o l e rance t oethanol . Al coho l 1998; 15: 311414.
42 . Dursun I , Jakubowska-Dogru E , Uzbay T .Ef fec t s o f p rena t a l exposu re t o a l coho l onac t i v i t y , anx i e t y , mo t o r coo rd i na t i on , andmemory i n young adu l t Wi s t a r r a t s . Pharmaco l
Bi ochem Behav 2006; 85: 345355.
43 . Mayock DE, Ngai AC, Mondares RL, Gl easonCA. Ef fec t s o f b i nge a l coho l exposu re i n t hesecond t r i mes t er on i n t r acereb ra l a r t e r i o l a rfunct i on i n t h i rd t r i mes t er f e t a l sheep . Bra i nRes 2008; 1226: 111115.
44. Whi te AM, Swartzwelder HS. Age-related effectsof alcohol on memory and memory-related brainfunct i on i n ado l escen t s and adu l t s . Recen t DevAlcohol 2005; 17: 161176.
45 . Hi g l ey JD, Haser t MF, Suomi SJ , L i nno i l a M.j Nonhuman p r i mat e model o f a l coho l abuse :Ef fec t s o f ear l y exper i ence per sonal i t y andstress on alcohol consumption. Proceedings of theNational Academy of Sciences 1991; 88: 72617265.
46 . Cunn i ngham CL, Gremel CM, Grob l ewsk i PA.Drug- i nduced cond i t i oned p l ace p reference andaversion in mice. Nat Protoc 2006; 1: 16621670.
47 . Capone F , Adr i an i W, Shumi l i na M, I zykenovaG, Grans t r em O, Dambi nova S , Lav i o l a G .Autoant ibodies against opioid or g lutamatereceptors are associated with changes in morphinereward and physical dependence in mice.Psychopharmacology (Berl ) 2008; 197: 535548.
48 . Hefner K , Ho l mes A . An i nves t i ga t i on o f t hebehavioral actions of ethanol across adolescence inmice. Psychopharmacology (Berl) 2007; 191: 311322.
49 . Sh t i egman K, Ki ng JA, Fer r i s CF . Vo l un t aryEthanol Consumpt ion During Adolescence in
-
8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT
20/22
232 Ja in and Balhara India n J Phys iol Pharma col 2010; 54 (3)
62 . S i l ver i MM, Spear LP . Decreasea sens i t i v i t y t othe hypnotic effects of ethanol early in ontogeny.Alcohol i sm: Cl in ical and Experimental Research1998; 22: 670676.
63 . Nagy J . A l coho l Rel a t ed Changes i n Regu l a t i onof NMDA Receptor Functions. Curr Neuropharmacol2008; 6: 3954.
64. Snel l LD, Tabakoff B, Hoffman PL. Radiol igandb i nd i ng t o t he N-met hy l -D-aspar t a t e r ecep t o r / i onophore compl ex : a l t e r a t i ons by e t hano l i nv i t ro and by ch ron i c i n v i vo e t hano l i nges t i on .Brain Res 1993; 29: 9198.
65 . Crews FT, Braun CJ , Hop l i gh t B , Swi t zer RC
3rd, Knapp DJ. Binge ethanol consumpt ioncauses d i f f e ren t i a l b ra i n damage i n youngado l escen t r a t s compared wi t h adu l t r a t s . Al csmClin Exp Res 2000; 24: 17121723.
66. Slawecki CJ, Betanc our t M, Cole M, Ehlers CL.Per i ado l escen t a l coho l exposu re has l as t i ngef fec t s on adu l t neu rophys i o l og i ca l func t i on i nra t s . Devel Bra i n Res 2001; 128: 6372.
67 . Fer r i s CF , Sh t i egman K, Ki ng JA. Vo l un t arye t hano l consumpt i on i n mal e ado l escen thamst er s i ncreases t es t o s t e rone and aggress i on .Physiol Behav 1998; 63: 739744.
68 . Pa t enaude C , Chapman CA, Ber t r and S ,Congar P , Laca i l l e JC . GABAB recep t o r - andmet abo t rop i c g l u t amat e r ecep t o r -dependen tcooperat ive long- term potent iat ion of rat
h i ppocampal GABAA synap t i c t r ansmi ss i on .J Phys i o l 2003; 553: 155167.
69 . Mor row AL, VanDoren MJ , Pen l and SN,Matthew DB. The role of GABAergic neuroactivesteroids in ethanol action tolerance and dependence.Bra i n Res Bra i n Res j l ev 2001; 37: 98101.
70. Murphy JM, Wal ler MB, Gat to GJ, McBride WJ,Lumeng L, Li TK. Monoamine uptake inhibi torsat tenuate ethanol in take in alcohol -preferr ing(P) rats . Alcohol 1985; 2 : 349352.
71 . Noguch i T , Yosh i da Y , Ch i ba S . Ef fec t s o f p sycho l og i ca l s t r ess on monoami ne sys t ems i nsubreg i ons o f t he f ron t a l co r t ex and nucl eusaccumbens of the rat. Brain Res 2001; 916: 91100.
72 . Ah i ma RS, Har l an RE. Char t i ng t he t ype I I
glucocor t icoid receptor- l ike immunoreact iv i ty int he r a t cen t r a l nervous sys t em. Neurosc i ence1990; 39: 579604.
73. Cint ra A, Zol i M, Rosen L, Agnat i LF, Okret S,Wikst rom AC, Gustafsson JA, Fuxe K. Mappingand comput er ass i s t ed morphomet ry andmi crodens i t omet ry o f g l ucocor t i co i d r ecep t o ri mmunoreac t i ve neu rons i n t he r a t cen t r a lnervous system. Neuroscience 1994; 62: 843897.
74 . Mat t son SN, R i l ey EP , Jern i gan TL, Garc i a A ,Kaneko WM, Eh l er s CL, Jones KL. A decreasei n t he s i ze o f t he basa l gang l i a fo l l owi ngprenat a l a l coho l exposu re : a p re l i mi nary r epo r t .Neuro t ox i co l Tera t o l 1994; 16: 283289.
75 . Bon t h i us DJ , Bon t h i us NE, Napper RM, As t l eySJ , C l ar r en SK, Wes t JR . Pu rk i n j e ce l l def i c i t si n nonhuman p r i mat es fo l l owi ng week l yexposure to ethanol dur ing gestat ion. Teratology1996; 53: 230236.
76. Savage DD, Queen SA, Sanchez CF, Paxton LL,Mahoney JC , Good l e t t CR, Wes t JR . P rena t a le t hano l exposu re du r i ng t he l as t t h i rd o f ges t a t i on i n r a t r educes h i ppocampal NMDAagon i s t b i nd i ng s i t e dens i t y i n 45 -day -o l doffspr ing. Alcohol 1992; 9 : 3741.
77. McKinzie DL, Mcbride WJ, Murphy JM, LumengL, Li TK. Rat l ines select ively bred for alcoholpreference: A potential animal model of adolescent
a l coho l d r i nk i ng . In : Hann i ngan JH, Spear LP ,Spear NE, Good l e t t CR eds . A l coho l andAl coho l i sm: Ef fec t s on Bra i n and Devel opmen t .Mahwah NJ : Lawrence Er l baum Associ a t es ,1999; p . 135160.
78 . S t e i ner JC , LaPag l i a N , Hansen M, Emanuel eNV, Emanuelc MA. Effect of chronic ethanol onrep roduct i ve and g rowt h ho rmones i n t heper i pubcer t a l mal e r a t . J Endocr i no l 1997 ; 154 :363370 .
79 . Ten t l e r J J , Lapag l i a N , S t e i ner J , Wi l l i ams D,Castel l i M, Kel ley MR, Emanuele NV, EmanueleMA. Ethanol growth hormone and testosterone inperipubertal rats. J Endocrinol 1997; 152: 477487.
80 . Nyberg CL, Sr i vas t ava V , Hi ncy JK, Lara F ,Dees WL. N-Met hy l -D-asp ar t i c ac i d r ecep t o r
messenger r i bonucl e i c ac i d l eve l s and u t i l i z i nghormone release in immature female rats : ef fectsof stage of pigboat development and exposure ina l coho l . Endocrinology 1995; 136: 28742880.
81 . Dees WL, Di ssen GA, Hi ney JK, Lara F , Oj edaSR. Al coho l i nges t i on i nh i b i t s t he i ncreasedsecre t i on o f puber t y - r e l a t ed ho rmones i n t hedeveloping female rhesus monkey. Endocr i no l ogy2000; 141: 13251331.
82 . Dees WL, Skel l ey CW, Hi ney JK, Johns t on CA.Act ions of ethanol on hypothalamic and pi tu i taryhormones i n p repuber t a l f