Proc. Natl. Acad. Sci. USA
Vol. 92, pp. 8906-8910, September 1995
Genetic variation in vulnerability to the behavioral effects of
neonatal hippocampal damage in rats
(strain specificity/Fischer 344 rats/Lewis rats/mesolimbic dopamine system/animal model)
BARBARA K. LiPsKA AND DANIEL R. WEINBERGER
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Neuroscience Center at
St. Elizabeths, 2700 Martin Luther King Avenue, SE, Washington, DC 20032
Communicated by Seymour S. Kety, National Institutes ofHealth, Bethesda, MD, June 14, 1995 (received for review April 3, 1995)
one genetic (i.e., specific rat strains) and another environ-
mental (i.e., a developmental excitotoxic hippocampal lesion),
contribute to phenotypic variation. Sprague-Dawley (SD),
Fischer 344 (F344), and Lewis rats underwent two grades of
neonatal excitotoxic damage: small and large ventral hip-
pocampal (SVH and LVH) lesions. Locomotion was tested
before puberty [postnatal day 35 (P35)] and after puberty
(P56) following exposure to a novel environment or adminis-
tration of amphetamine. The behavioral effects were strain-
and lesion-specific. As shown previously, SD rats with LVH
lesions displayed enhanced spontaneous and amphetamine-
induced locomotion as compared with controls at P56, but not
at P35. SVH lesions in SD rats had no effect at any age. In F344
rats with LVH lesions, enhanced spontaneous and amphet-
amine-induced locomotion appeared early (P35) and was
exaggerated at P56. SVH lesions in F344 rats resulted in a
pattern of effects analogous to LVH lesions in SD rats-i.e.,
postpubertal onset of hyperlocomotion (P56). In Lewis rats,
LVH lesions had no significant effect on novelty- or amphet-
amine-induced locomotion at any age. These data show that
the degree of genetic predisposition and the extent of early
induced hippocampal defect contribute to the particular
pattern of behavioral outcome. These results may have impli-
cations for modeling interactions of genetic and environmen-
tal factors involved in schizophrenia, a disorder characterized
by phenotypic heterogeneity, genetic predisposition, a devel-
opmental hippocampal abnormality, and vulnerability to en-
We explored how two independent variables.
Genetic factors that affect brain function can be studied in
genetically inbred animal strains. For instance, three strains of
rats-Sprague-Dawley (SD), Lewis, and Fischer 344 (F344)-
differ substantially in a number of respects, including respon-
siveness to stress, predisposition to inflammatory diseases, and
preference for drugs of abuse (1-5). Moreover, it has been
suggested that these differences are associated with differen-
tial responsiveness of the hypothalamic-pituitary-adrenal
(HPA) axis to stressful or inflammatory stimuli (3, 6, 7),
differential interactions between neurotransmitter systems
and the HPA axis (8), and the functional state of the mesolim-
bic dopamine (DA) system (9-12). F344 and Lewis rats appear
to represent two ends of a spectrum of stress responsivity; F344
rats are hyperresponsive to stress whereas Lewis rats are
hyporesponsive to stress as assessed by behavioral and neu-
roendocrine responses to an open field, swim test, restraint,
etc. Outbred SD rats exhibit an intermediate response to stress
compared with these two inbred straiins. Thus, comparisons of
these rat strains may provide insights into how genetic factors
influence stress-related behaviors.
We have demonstrated that SD rats with neonatally induced
excitotoxic lesions of the ventral hippocampal formation ex-
hibit a variety of abnormal behaviors, including enhanced
locomotor hyperresponsiveness to stress, accentuated motoric
changes in response to DA agonists and antagonists, and
deficits in sensorimotor gating (13-15). These lesion-induced
behavioral disturbances in SD rats are detectable only after
puberty and are thought to be linked to excessive DA activity
in the mesolimbic/nigrostriatal systems (16, 17). Moreover,
there is evidence suggesting that the severity of behavioral
changes may be related to the extent of hippocampal damage.
In the present study we sought to determine how these two
factors, one genetic (represented by three strains of rats) and one
environmental (represented by variations in the extent of neo-
natal hippocampal damage), affect patterns of behavioral
changes related to DA function. Because stress appears to play a
role in modulating the effects ofthese lesions,we anticipated that
in animals with genetically determined hyperresponsiveness to
stress-i.e., in F344 rats-the effects of the lesion would be
exaggerated and, conversely, in rats that show relative resistance
to stress-i.e., in Lewis rats-these effects would be attenuated.
We assumed thatSD ratswould exhibit an intermediate response.
By infusing varying amounts of the neurotoxin ibotenic acid, we
intended to vary the extent of the VH lesion and thus alter the
severity of behavioral deficits within strains. The experimental
method chosen for phenotypic evaluation was novelty- and
amphetamine-induced hyperlocomotion tested before and after
puberty in computerized photocell-equipped cages.
MATERIALS AND METHODS
Surgery. Rat pupswere lesioned as described (13). Pregnant
SD (Zivic-Miller), F344 (Charles River Breeding Laborato-
ries), and Lewis (Charles River Breeding Laboratories) rats
obtained at 12-15 days of gestation were housed individually
in breeding cages with a 12-hr light/12-hr dark cycle and fed
ad libitum. On postnatal day 7 (P7), the pups (weight: 15-18
g for SD, 9-13 g for F344, and 12-16 g for Lewis) were
anesthetized by hypothermia (placed on ice for 10-20 min). An
incision was made in the skin overlying the skull and 0.3 ,ul [for
large ventral hippocampal (LVH) lesions] or 0.15 ,ul [for small
ventral hippocampal (SVH) lesions] of ibotenic acid solution
(Sigma; 10 ,ug/,lI) or artificial cerebrospinal fluid (in sham-
operated rats) was infused bilaterally into the ventral hip-
pocampal formation at 0.15 ,ul/min. The injection site was
intended to be identical in all three strains: for SD rats, AP
-3.0 mm, ML ±3.5 mm, VD -5.0 mm; for F344 rats, AP -2.2
mm, ML ±3.0 mm, VD -4.5 mm; and for Lewis rats, AP -2.3
mm, ML ±3.1 mm, VD -4.5 mm (relative to bregma). The
pupswerewarmed and then returned to their mothers. On P25,
animals were weaned and separated according to lesion.
Abbreviations: SD, Sprague-Dawley; F344, Fischer 344; Pn, postnatal
day n; SVH, small ventral hippocampal; LVH, large ventral hippocam-
pal; HPA, hypothalamic-pituitary-adrenal; DA, dopamine.
The publication costs of this article were defrayed in part by page charge
payment. This article must therefore be hereby marked "advertisement" in
accordance with 18 U.S.C. §1734 solely to indicate this fact.
Proc. Natl. Acad. Sci. USA 92 (1995)
Behavioral Testing. Rats were lesioned and tested during
three consecutive weeks, each strain separately every day over
1 week. The same rats were tested at P35 and P56. In addition,
a cohort of F344 rats with sham and ibotenic acid lesions was
tested only at P56 to control for a possible effect of sensiti-
zation due to prior exposure to amphetamine. Because no such
effect was detected (i.e., novelty- or amphetamine-induced
locomotion of rats tested only at P56 did not significantly differ
from that tested at P35 and P56), these data were pooled for
a final overall analysis of locomotion. Numbers of animals
tested were 42 SD rats, 67 F344 rats (of which 44 were tested
twice, and 23 only on P56), and 52 Lewis rats (total n = 161).
On the day of testing, animals were transferred from their
home cages to the testing area and weighed. Rats were then
placed in clear Plexiglas photocell activity monitors (42 cm x
42 cm x 30 cm) [Omnitech (Columbus, OH) model RXYZCM
16], and total distance traveled (cm) was measured during 1 hr.
Rats then received 0.9% NaCl injections (1 ml/kg) and were
monitored for another hour. Finally, (S)-amphetamine sulfate
(RBI) was administered (1.5 mg/kg, i.p.) and locomotion was
measured for 1.5 hr.
After completion of behavioral testing, the brains of rats
were quickly removed, frozen, sectioned, and thionin-stained.
The extent of the lesion, defined as the area of neuronal loss
and/or cavitation, was characterized by light microscopy.
Data Analysis. Because for Lewis rats only two lesioned
groups (sham and LVH) were included in the analysis (see
Results), SVH and LVH groups were combined across strains
for an overall statistical analysis of the data. Moreover, be-
cause some rats were tested only at P56, the age variable was
considered an independent factor. Thus, the data were ana-
lyzed by a four-way ANOVA with lesion status (sham and
lesion), strain (SD, F344, and Lewis), and age (P35 and P56)
as independent factors, testing condition (novelty and amphet-
amine) as a repeated measure, and locomotion as a dependent
variable. Fisher probable least-squares difference (PLSD)
post-hoc tests were performed when the main effects were
significant. In post-hoc comparisons, all three lesion groups
were included (sham, SVH, and LVH).
Verification of the Lesion. Thionin-stained 20-p.m brain
sections of the lesioned rats were examined by low-power light
microscopy. From the area of neuronal loss and/or cavitation
within the boundaries of the ventral hippocampal formation,
the brains were assigned to either a LVH or a SVH lesion
group. The LVH lesion was characterized by neuronal loss
throughout all cytoarchitectural subdivisions (CA1-CA3), in-
cluding parts of the dentate gyrus and subiculum, in the
temporal portions of the hippocampal formation [plates 34-
41, according to the atlas of Paxinos and Watson (18)] (Fig. 1).
Moreover, in all brains with LVH lesions, a large area of
cavitation was observed in the vicinity ofthe injection site. The
LVH lesion corresponds to that previously described by us in
SD rats (13). The SVH lesion was much more restricted and
resulted in neuronal loss at the site of injection, but not in
cavitation. The primary area of neuronal loss included CAl
and CA2 subregions (Fig. 2). No damage was seen in the
dentate gyrus or subiculum.
Due to extrahippocampal damage, 3, 4, and 4 rats were
deleted from further analysis from SD, F344, and Lewis
groups, respectively. All remaining SD rats that were infused
with 3jig(0.3 ,ul) of ibotenic acid were assigned to the LVH
lesion group (n = 16), and those that were infused with 1.5jig
(0.15 ,ul) were assigned to the SVH group (n = 10). Again, as
in SD rats, all remaining F344 rats that received 3 ,ug (0.3 ,ul)
of ibotenic acid had, according to the criteria outlined above,
LVH lesions (n = 11), and those that received 1.5 ,ug (0.15 ptl)
had SVH lesions (n = 21). In the Lewis group, although in the
remaining animalswhich received 3 ,ug (0.3 ,ul) ofibotenic acid
(n = 13) the lesion was confined to the hippocampal forma-
tion, it destroyed almost the whole hippocampus, including
subregions CA1-CA3 in the dorsal portion. The only part
spared was the most dorsal aspect of the dentate gyrus.
Because this lesion greatly exceeded damage in SD and F344
rats, and thus was not comparable to the lesions in these
strains, Lewis rats with total hippocampal lesions were not
included in the analysis ofbehavioral data. Lewis rats thatwere
infused with 1.5 ,ug (0.15 ,ul) of ibotenic acid showed destruc-
tion similar to that obtained with 3 p,g (0.3 ,ul) in SD and F344
rats and thus were assigned to the LVH group (n = 14).
Behavioral Testing. Locomotor activityvaried depending on
the specific strain, on the characteristics of the lesion, on the
age of the animals, and on the testing condition. ANOVA
showed significant main effects of strain (F2,498 = 50.8, P <
0.0001), age (F1,498= 30.2, P < 0.0001), lesion (F1,498= 30.1,
lesions. Coordinates refer to distance (mm) posterior to bregma. Black and striped areas indicate the smallest and largest lesions, respectively.
Lesion boundaries defined as the area of neuronal absence and determined from thionin-stained coronal sections from rats with LVH
8908Neurobiology: Lipska and Weinberger
For details, see Fig. 1.
Lesion boundaries determined in rats with SVH lesions.
P < 0.0001), and testing condition (F1,498 = 859.7,P < 0.0001).
These effects were influenced by one another as indicated by
several significant interactions, including an interaction be-
tween strain and lesion(F2,498= 7.4,P < 0.001), between strain
and testing condition (F2,498 = 56.2, P < 0.0001), between age
and testing condition (F1,498 = 24.5,P < 0.0001), among strain,
age, and testing condition (F1,498 = 3.0, P < 0.05), between
lesion and testing condition (F1,498 = 23.9, P < 0.0001), and
among strain, lesion, and testing condition (F1,498 = 6.2, P <
0.01). There was a trend toward a significant strain-by-age
interaction (F2,498 = 2.5, P = 0.08). All other interactions,
including the interaction among all four factors (strain by age
by lesion by testing condition), were not significant.
Post-hoc comparisons showed that sham-operated rats of all
three strains displayed similar spontaneous locomotor activity
after exposure to a novel environment (Figs. 3 and 4). More-
over, the level of spontaneous activity did not considerably
changewith age. Amphetamine-induced locomotion, however,
differed dramatically across the strains at P35, and for each
strain consistently increased from P35 to P56. At P35, SD rats
displayed the lowest level of amphetamine-induced locomo-
tion (5368 ± 786 cm), F344 rats were significantly more active
(11,096 ± 1412 cm), and Lewis rats showed the highest level
of amphetamine-induced locomotor stimulation (16,494 ±
1278 cm, P < 0.05; Fig. 3). At P56, however, SD controls did
not significantly differ from F344 sham-operated rats (9945 ±
1292 cm vs. 13,091 ± 791 cm, respectively; not significant).
Lewis rats still displayed significantly greater amphetamine-
induced locomotion than SD or F344 rats (24,450 + 1289 cm,
P < 0.05; Fig. 4).
Further post-hoc analysis revealed that within each strain,
the lesions (SVH and LVH) resulted in different behavioral
patterns when compared with the corresponding sham-
SD Rats. At P35 there were no significant effects of either
SVH or LVH lesion on locomotor activity displayed in a novel
environment or after amphetamine (Fig. 3). The SVH-lesion
(P7) control (Sham), SVH, and LVH lesions. *, Significantly different
from sham-operated SD group (P < 0.05); t, significantly different
from sham SD and sham F344 groups (P < 0.05); 4:, significantly
different from sham and SVH groups of the same strain (P < 0.05).
Locomotor activity measured on P35 in rats with neonatal
animals also did not differ from sham-operated controls at
P56. However, rats with LVH lesions were significantly more
active at P56 after exposure to novelty (P < 0.05) and after
amphetamine (P < 0.05) than either the SVH or the sham-
operated group (Fig. 4). This finding of delayed emergence of
hyperactivity in rats with LVH lesions is in accord with our
previous data (13).
F344 Rats. At P35, rats with SVH lesions did not signifi-
cantly differ from sham-operated controls after exposure to
novelty or amphetamine (Fig.3). At P56, however, SVH-lesion
animals expressed increased locomotor activity in response to
both novelty (P < 0.05) and amphetamine (P < 0.05) as
compared with controls (Fig. 4). The pattern of abnormalities
characterized by delayed emergence of hyperlocomotion re-
sembles that observed in SD rats with LVH lesions. F344
animals with LVH lesions showed increased activity in a novel
environment and after amphetamine at both ages as compared
with controls (P < 0.05). They were also more active than
animals with SVH lesions in both testing conditions at P35, as
well as after amphetamine administration at P56 (P < 0.05).
Thus, LVH lesions in F344 rats resulted in an early appearance
of hyperactivity, which was further potentiated at an older age.
Lewis Rats. Lewis rats with LVH lesions did not differ from
sham-operated controls in total distance traveled in the novel
environment or after amphetamine administration at any age
tested (Figs. 3 and 4). Lewis rats seemed thus resistant to the
behavioral effects of this lesion. However, sham-operated
Proc. Natl. Acad. Sci. USA 92(1995)
Proc. Natl. Acad. Sci. USA 92 (1995)
3. t, Significantlydifferent from sham SD and sham F344 groups (P
< 0.05); t, significantly different from sham and SVH groups of the
same strain (P < 0.05); §, significantly different from sham group of
the same strain (P < 0.05).
Locomotor activity measured on P56. For details, see Fig.
Lewis rats exhibited the highest level ofamphetamine-induced
locomotion compared with other strains, suggesting that the
effect of the lesion on amphetamine-induced locomotion
might not be detectable in this strain due to a "ceiling" effect.
Further evaluation of the data revealed, however, that at P56
Lewis rats with almost total hippocampal lesions, which were
not included in the comparisons, showed considerably more
amphetamine-induced locomotor activity than Lewis rats with
LVH lesions or sham-operated animals (47,116 ± 6015 cm vs.
28,222 + 1789 cm vs. 24,450 ± 1289 cm, respectively). This
indicated that, at least under certain circumstances, Lewis rats
were physically capable of traveling a greater distance.
The results demonstrate that SD, F344, and Lewis rats display
different vulnerability to the behavioral effects of neurodevelop-
mental excitotoxic hippocampal damage. Further, the lesion-
induced behavioral effects, in terms of both the severity of
behavioral disturbances and the time at which they appear,
depend on the extent of damage. In other words, both factors-
one genetic and one environmental-contribute to a particular
phenotype associated with neonatal hippocampal damage.
Strain specificity in responsiveness of these rats to other
environmental factors has previously been demonstrated. For
instance, Lewis, F344, and SD rats differ considerably in their
susceptibility to a number ofautoimmune diseases (19,20) and in
their neuroendocrine and behavioral responsiveness to stress (4).
In addition, there may be a causative relationship between these
two phenomena (21). Lewis rats, which are particularly suscep-
tible to inflammatory diseases, appear to be deficient in their
ability to respond to a variety of stressful stimuli. In response to
stress mediators, their activation of the HPA axis, including the
synthesis and secretion of hypothalamic corticotropin-releasing
factor and plasma corticotropin and corticosterone, appears to be
inadequate as compared with other strains (4,21-23). Lewis rats
also show blunted behavioral responses to emotional and physical
stressors, such as less grooming and locomotion in the inner
versus outer areas of an open field (3). Conversely, F344 rats,
which are relatively resistant to inflammatory diseases, exhibit
potentiated corticotropin-releasing factor, corticotropin, and cor-
ticosterone responses to stressful stimuli (24). F344 rats are
considered "hyperexcitable and difficult to handle" and "more
sensitive to external stimuli and highly emotional" (25), as well as
"extremely fearful" and "less able to habituate or adapt to
repeated stress" (24) when compared with SD or Lewis rats. SD
rats, on the other hand, exhibit moderate susceptibility to inflam-
mation and moderate responsiveness to stress when compared
with either Lewis or F344 rats. Rats of these three strains differ
also in their preference for drugs of abuse such as ethanol,
cocaine, morphine, and tetrahydrocannabinol. Lewis rats show
much higher rates of self-administration of opiates, alcohol, and
cocaine and greater intracranial self-stimulation responses to
cannabinoids than the two other strains (12, 26, 27).
In attempts to explain these strain-related differences, numer-
ous neurochemical studies have been undertaken. The results
indicate that there are, indeed, major differences in the function
of DA and serotonin systems between Lewis, SD, and F344 rats.
For example, F344 and Lewis rats express different levels of
tyrosine hydroxylase exclusively in brain areas implicated in
mediating the reinforcing properties of drugs of abuse (10,
12)-i.e.,the mesolimbic but not the nigrostriatal DA pathways
(28-30). Despite a lack of differences in basal levels ofDA, Lewis
rats manifest profound increases in cannabinoid-induced extra-
cellular DA overflow in the nucleus accumbens, as measured by
in vivo microdialysis, compared with SD rats (9). Lewis rats also
express lower levels of frontal cortical and hippocampal 5-HTlA
serotonin receptor mRNA and show reduced density of5-HTlA
binding sites in comparison with SD or F344 rats (31). These
differences, whether primary or secondary to the differential
responsiveness of the HPA axis, may play a role in augmenting
phenotypic responses to stress (31). Interestingly, no differences
were detected in the expression or binding properties of D2 DA
receptors between these three strains (32).
While these data suggest neurochemical differences that
might account for the diversity ofbehavioral responsiveness of
these genetically different strains ofrats to the aforementioned
external stimuli, it is difficult to predict which of these differ-
ences, if any, might play a role in the differential response of
these rats to neonatal hippocampal damage. Nevertheless, the
fact that SD, F344, and Lewis rats show differences in func-
tional characteristics of the mesolimbic DA system and re-
sponsiveness to stress seems of particular interest.
As we have previously suggested, the constellation of be-
havioral phenomena associated with the neurodevelopmental
lesion of the ventral hippocampus in SD rats, which corre-
sponds to the LVH lesion in this study, is primarily indicative
of a hyperfunctional mesolimbic DA system. The possibility of
increased DA tone in rats with the neonatal hippocampal
lesion is further supported by the ability of the antipsychotic
drugs haloperidol and clozapine to block excessive locomotion
in these rats (33). Stress is also known to engage DA systems
by increasing the metabolic activation of the dopaminergic
innervation in the medial prefrontal cortex, nucleus accum-
bens, and striatum (34, 35).
In accord with our hypothesis that stress exaggerates the effects
of this developmental lesion, we now report that F344, the
8910 Download full-text
Neurobiology: Lipska and Weinberger
genetically inbred strain characterized bybehavioral and neuroen-
docrine hyperexcitability to stress, shows uniquely high vulnera-
bility to certain effects of neonatal hippocampal damage. Con-
versely, Lewis rats, which manifest relative hyporesponsiveness to
stressful stimuli, seem to be relatively resistant to the behavioral
consequences of the hippocampal lesion. What are the mecha-
nisms bywhich the lesion-induced effects are either potentiated or
attenuated in these different strains ofrats? Although there are no
data to directly support this, it is tempting to speculate that the
genetic variation in sensitivity of the DA system might play a role
in modulating the effects of the lesion and that it might be related
to the variation in vulnerability to stress. F344 rats would then be
predicted to be more sensitive, in this respect, than Lewis rats, and
SD ratswould display amoderate response. From the current data,
it is impossible to elucidate the geneticmechanisms underlying the
diverse responses to the neonatal ventral hippocampal damage.
Our results demonstrate only that such genetic diversity exists and
that it may have profound consequences for the severity of the
lesion-induced impairments. This approach may represent a step
toward a quantitative trait loci (QTL) analysis of stress vulnera-
bility-i.e., a genetic paradigm used for identifying the chromo-
somal locations of multiple genes which contribute to quantitative
variations in a phenotype (36, 37).
Quite surprisingly, Lewis rats, although hyporesponsive to
stress, are the ones significantly more affected by the mesolim-
bic DA-releasing properties of the cannabinoids (9). It may be
assumed that they would be similarly, as compared to the two
other strains, affected by amphetamine. In fact, the heightened
locomotor activity ofthe sham-operated Lewis rats in response
to amphetamine in our study may support such an assumption.
Our results indicate, however, that the basal responsiveness to
amphetamine is not a good predictor of the lesion-induced
altered response to either amphetamine or novelty. Our data
also indicate that the relative vulnerability to the neurotoxic
effects of ibotenic acid is not such a predictor either. Lewis
rats, which appear to be hypersensitive to the locomotor effects
of amphetamine and which also appear hypersensitive to the
neurotoxic effects of ibotenic acid, are the least behaviorally
affected by ventral hippocampal damage. This apparent par-
adox underscores that lesion sizeperse is not the critical factor
in the strain differences in behavioral effects of the lesion.
We have investigated the effects of this neurodevelopmental
lesion in rats as a model of some aspects of schizophrenia, a
human disorder characterized by many analogous phenomena,
including a developmental structural hippocampal abnormality,
postpubertal onset of the diagnostic phenotype, dysregulation of
limbic dopaminergic activity, frontal cortical dysfunction, deficits
in sensorimotor gating, and vulnerability to stress (38, 39). The
extension of our model to include genetically determined factors
that bear on stress responsivity and that interact with the behav-
ioral effects of environmental injury broadens the scope of this
model in two directions: (i) it may now explain additional clinical
phenomena associated with schizophrenia, in particular, varia-
tions across individuals in apparent genetic loading, in severity of
symptoms, and in age of onset; and (ii) it models important
aspects of the genetic data about schizophrenia that genes appear
to convey susceptibility to illness and possibly a latent trait (40).
We thank Ms. Ingrid Phillips and Mr. Graham Wood for excellent
technical assistance. This work was in part supported by the National
Alliance for Research on Schizophrenia and Depression.
Suzuki, T., George, F. R. & Meisch, R. A. (1988) J. Pharmacol.
Exp. Ther. 245, 164-170.
Suzuki, T., Lu, M. S., Yoshii, T. & Misawa, M. (1992) Pharmacol.
Biochem. Behav. 43, 387-393.
Sternberg, E. M., Glowa, J. R., Smith, M. A., Calogero, A. E.,
Listwak, S. J., Aksentijevich, S., Chrousos, G. P., Wilder, R. L. &
Gold, P. W. (1992) Brain Res. 570, 54-60.
Dhabhar,F. S., McEwen,B. S. &Spencer,R. L.(1993)Brain Res.
Kosten, T. A., Miserendino, M. J., Chi, S. & Nestler, E. J. (1994)
J. Pharmacol. Exp. Ther. 269, 137-144.
Glowa, J. R., Geyer, M. A., Gold, P. W. & Steinberg, E. M.
(1992) Neuroendocrinology 56, 719-723.
Smith, T., Hewson, A. K., Quarrie, L., Leonard, J. P. & Cuzner,
M. L. (1994) Neuroendocrinology 59, 396-405.
Calogero, A. E., Sternberg, E. M., Bagdy, G., Smith, C., Bernar-
dini, R., Aksentijevich, S., Wilder, R. L., Gold, P. W. & Chrous-
tos, G. P. (1992) Neuroendocrinology 55, 600-608.
Chen, J., Paredes, W., Lowinson, J. H. & Gardner, E. L. (1991)
Neurosci. Lett. 129, 136-140.
Beitner-Johnson, D., Guitart, X. & Nestler, E. J. (1991) Brain
Res. 561, 146-150.
Beitner-Johnson, D., Guitart, X. & Nestler, E. J. (1993) J.
Neurochem. 61, 1766-1773.
Guitart, X., Beitner-Johnson, D., Marby, D. W., Kosten, T. A. &
Nestler, E. J. (1992) Synapse 12, 242-253.
Lipska, B. K., Jaskiw, G. E. & Weinberger, D. R. (1993) Neuro-
psychopharmacology 9, 67-75.
Lipska, B. K. & Weinberger, D. R. (1993) Dev. Brain Res. 75,
Lipska, B. K., Swerdlow, N. R., Geyer, M. A., Jaskiw, G. E.,
Braff, D. L. & Weinberger, D. R. Psychopharmacology, in press.
Kelly, P. H., Seviour, P. W. & Iversen, S. D. (1975) Brain Res. 94,
Costall, B. & Naylor, R. J. (1977) Adv. Behav. Bio. 21, 47-76.
Paxinos, G. & Watson, C. (1986) The Rat Brain in Stereotaxic
Coordinates (Academic, New York).
Griffiths, M. M. & De Witt, C. W. (1984) J. Immunol. 132,
Sternberg, E. M., Hill, J. M., Chroustos, G. P., Kamilaris, T.,
Listwak, S. J., Gold, P. W. & Wilder, R. L. (1989) Proc. Nati.
Acad. Sci. USA 86, 2374-2378.
Aksentijevich, S., Whitfield, H. J., Jr., Scott Young, W., III,
Wilder, R. L., Chroustos, G. P., Gold, P. W. & Stemnberg, E. M.
(1992) Dev. Brain Res. 65, 115-118.
Stemnberg, E., Young, W., Barnardini, R., Calogero, A., Chrous-
tos, G., Gold, P. & Wilder, R. (1989) Proc. Natl. Acad. Sci. USA
Griffin, A. C. & Whitacre, C. C. (1991) J. Neuroimmunol. 35,
Rosecrans, J. A., Robinson, S. E., Johnson, J. H., Mokler, D. J. &
Hong, J.-S. (1986) Brain Res. 382, 71-80.
Rosecrans, J. A. & Schechter, M. D. (1972) Physiol. Behav. 8,
George, F. R. & Goldberg, S. R. (1989) Trends Pharmacol. Sci.
Gardner, E. L. & Lowinson, J. H. (1991) Pharmacol. Biochem.
Behav. 40, 571-580.
Fibiger, H. C. (1978) Annu. Rev. Pharm. Toxicol. 18, 37-56.
Bozarth, M. A. (1986) Behav. Brain Res. 22, 107-116.
Koob, G. F. & Bloom, F. E. (1988) Science 242, 715-723.
Burnet, P. W. J., Mefford, I. N., Smith, C. C., Gold, P. W. &
Steinberg, E. M. (1992) J. Neurochem. 59, 1062-1070.
Luedtke, R. R., Artymyshyn, R. P., Monks, B. R. & Molinoff,
P. B. (1992) Brain Res. 584, 45-54.
Lipska, B. K & Weinberger, D. R. (1994) Neuropsychopharma-
cology 10, 199-205.
Abercrombie, E. D., Keefe, K. A., DiFrischia, D. S. & Zigmond,
M. J. (1989) J. Neurochem. 52, 1655-1658.
Deutch, A. Y., Clark, W. A. & Roth, R. H. (1990) Brain Res. 521,
Berrettini, W. H., Ferraro, T. N., Alexander, R. C., Buchberg,
A. M. & Vogel, W. H. (1994) Nat. Genet. 7, 54-58.
Lander, E. S. & Schork, N. J. (1994) Science 265, 2037-2048.
Lipska, B. K. & Weinberger, D. R. (1993) in Limbic Circuits and
Neuropsychiatry, eds. Kalivas, P. W. & Barnes, C. D. (CRC, Boca
Raton, FL), pp. 329-349.
Weinberger, D. R. & Lipska, B. K (1995) Schizophr. Res. 16,
Asheron, P., Mant, R. & McGuffin, P. (1995) in Schizophrenia,
eds. Hirch, S. R. & Weinberger, D. R. (Blackwell, London), pp.
Proc. Natl. Acad. Sci. USA 92(1995)