Neuroscience Letters 482 (2010) 117–122

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Neuroscience Letters
journal homepage: www.elsevier.com/locate/neulet

Increased dopaminergic activity in socially isolated rats:

An electrophysiological study
Katrine Fabricius a,b , Lone Helboe a , Anders Fink-Jensen b,c , Gitta Wörtwein b,c ,
Björn Steiniger-Brach a , Florence Sotty a,∗
a
Discovery Pharmacology Research, H. Lundbeck A/S, Ottiliavej 7-9, 2500 Valby, Denmark
b
Faculty of health science, University of Copenhagen, Denmark
c
Laboratory of Neuropsychiatry, Mental Health Services Copenhagen. The Capital Region of Denmark, University of Copenhagen, Denmark

a r t i c l e i n f o a b s t r a c t

Article history: The development of animal models mimicking symptoms associated with schizophrenia has been a crit-
Received 13 April 2010 ical step in understanding the neurobiological mechanisms underlying the disease. Long-term social
Received in revised form 7 June 2010 isolation from weaning in rodents, a model based on the neurodevelopmental hypothesis of schizophre-
Accepted 8 July 2010
nia, has been suggested to mimic some of the deficits seen in schizophrenic patients. We confirm in the
present study that socially isolated rats display an increase in both spontaneous and d-amphetamine-
Keywords:
induced locomotor activity, as well as deficits in sensorimotor gating as assessed in a pre-pulse inhibition
Social isolation
paradigm. In addition, in vivo electrophysiological studies revealed changes in dopaminergic cell firing
Mesolimbic dopamine system
Schizophrenia
activity in the ventral tegmental area of isolated rats when compared to group-housed controls. These
Animal model alterations include an increase in the number of spontaneously active dopaminergic neurons, and a
In vivo electrophysiology change of firing activity towards a more irregular and bursting firing pattern. Taken together, our find-
ings suggest that the behavioral phenotype induced by social isolation may be driven by an overactive
dopamine system.
© 2010 Elsevier Ireland Ltd. All rights reserved.

Symptoms associated with schizophrenia have been categorized
into positive symptoms (e.g. delusions and hallucinations), nega-
tive symptoms (e.g. blunting of affect, social withdrawal), cognitive
deficits (e.g. impairment in memory and executive function)
and affective (e.g. depressive) symptoms. Preclinical research has
focused on the development of animal models mimicking these
symptoms as an attempt to elucidate the underlying neurobiolog-
ical mechanisms, as well as to develop new pharmacotherapies.
Based on the neurodevelopmental hypothesis of schizophrenia,
it has been reported that social isolation of rats immediately
after weaning induces an “isolation syndrome” involving sev-
eral neurochemical and behavioral changes believed to resemble
some of the core symptoms observed in schizophrenic patients
[6,9,15]. For instance, novelty and psychostimulant-induced loco-
motor hyperactivity [28] and deficits in sensorimotor gating [3,29]
and a range of cognitive deficits [1,18,22] have been encoun-
tered and linked to positive and cognitive symptoms associated
with schizophrenia. Besides, neurochemical studies have revealed
alterations in the reactivity of the dopaminergic system to psy-
chostimulants in socially isolated rats [12,15,28]. In addition,
∗ Corresponding author at: H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Den-
mark. Tel.: +45 3643 3647; fax: +45 3643 8232.
E-mail address: FSOT@lundbeck.com (F. Sotty).
morphologic alterations including reduced dendritic spine den-
sity in the prefrontal cortex and hippocampus of isolated rats have
been reported [23], further strengthening the neurodevelopmen-
tal nature of the changes induced by social isolation. Moreover,
the critical role of stress in the isolation syndrome is of impor-
tance since stress in early life has been implicated in the later
development of schizophrenia [4,17]. Thus, isolation rearing of rats
immediately after weaning seems to produce some changes in
behavior related to core defects associated to schizophrenia, and
may therefore represent an animal model suitable for investigat-
ing the neurobiological mechanisms underlying deficits associated
with schizophrenia, as well as to identify possible novel pharma-
cotherapies for this disease [6,15].
Sensitization of the mesoaccumbal dopaminergic pathway has
been suggested to be responsible for some of the behavioral
changes induced by social isolation [15]. It was further proposed
that these behavioral alterations may result from changes in
presynaptic dopamine function, including alterations in autore-
ceptor regulation, uptake efficiency, synthesis efficiency, and firing
activity.
Since abnormal regulation of dopaminergic neurons in the ven-
tral tegmental area (VTA) is believed to be involved in the etiology
of psychotic symptoms [7], we investigated whether social isola-
tion of rats post-weaning had an influence on the firing activity
of dopamine neurons recorded from the VTA in vivo. In addition,

0304-3940/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.neulet.2010.07.014
118 K. Fabricius et al. / Neuroscience Letters 482 (2010) 117–122

Fig. 1. Behavioral phenotype of 12 weeks SI and GH rats. (A) Amphetamine-induced locomotor hyperactivity. Mean activity count ± SEM (total beam breaks within a 5 min
epoch) revealed a significant difference between GH (n = 6, closed symbols) and SI rats (n = 9, open symbols) after d-amphetamine challenge. *p < 0.05; ***p < 0.001. (B) Pre-
pulse inhibition. Left: Mean % PPI ± SEM at pre-pulse (pp) intensities of 74–82 dB indicates a significant % PPI deficit in SI (n = 17) compared to GH (n = 15) rats *p < 0.05,
***p < 0.001. Right: Mean habituation of the startle response ± SEM to 8 + 8 startle-pulses before an after the testing paradigm *p < 0.05.

the influence of social isolation on dopamine-dependent behav-
iors, e.g. spontaneous and d-amphetamine-evoked hyperlocomotor
activities, as well as pre-pulse inhibition (PPI) of the acoustic
startle, were also evaluated to validate our procedure of social
isolation.
All experiments were carried out in accordance with the Euro-
pean Communities Council Directive (86/609/EEC) for the care and
use of laboratory animals and the Danish legislation regulating
animal experiments. The Danish Animal Experiments Inspectorate
approved the protocols (journal no. 2004/561-798).
Female Lister Hooded rats (Harlan, Netherlands) arrived at the
in-house facilities at postnatal day (PND) 8–9 with foster mothers
[11 pups each which were cross-fostered randomly at birth]. At
arrival, dams and pups were left undisturbed until PND 25 where
the pups where randomly assigned to be singly housed (Social
Isolation rats, SI) or in groups of five (Group-housed controls, GH).
Housing consisted of a transparent high grid lid macrolon cage type
III or IV and wood chip bedding (type IV GH; type III, SI). All animals
were housed in controlled temperature (22 ± 1.5 ◦ C) and humidity
conditions (55–65%) and kept in a 12:12 hour light/dark cycle
(lights on at 06:00 h). Handling and noise were kept to a minimum,
and cages were cleaned twice a week for GH and once a week for
SI. Food (altromin pills, and water were supplied ad libitum. SI and
GH animals were kept in the same room facility and could smell,
hear and see each other). All behavioral testing took place in the
light phase between 09:00 a.m. and 5:00 p.m., after 12 weeks of
isolation.
All cohorts were tested for spontaneous locomotor activity.
For acclimation, all rats were brought to the laboratory one day
prior to the test. On the test day, animals were placed in indi-
vidual test cages and left undisturbed for 2 h (120 min). Each test
cage, (macrolon type III), was placed in a U-frame equipped with
two rows of four infrared light sources and photocells. Record-
ing of a motility count required the interruption of adjacent light
beams in the lower row, thus avoiding counts induced by station-
ary movements of the rat. Registration and timing of locomotor and
rearing activity were fully automated (custom-designed hardware
and software by Ellegaard Systems A/S, Faaborg, Denmark).
The effect of 0.5 mg/kg base d-amphetamine on locomotor activ-
ity was tested in the abovementioned photo beam set-up. The
testing paradigm was divided into three phases: (1) Locomotor
activity was measured for 60 min (habituation). (2) Subsequent to
the habituation, all animals received a saline injection (1 ml/kg, s.c.)
and returned immediately to the test cages. (3) After 60 min ani-
mals were administered d-amphetamine and locomotor activity
recording continued for another 60 min.
A group of rats was further tested for 3 consecutive days in a
PPI paradigm. PPI testing was performed using the Startle Monitor
System (Kinder Scientific), which consisted of 8 sound-attenuated
startle chambers, all calibrated to the same sensitivity, and design
based computer software. The PPI regime consisted of a 5-min accli-
mation period with white background noise (70 dB), followed by
randomized trials that consisted of: no pulse, startle-pulse alone
(120 dB, 40 ms duration), pre-pulse (4, 8 or 12 dB above background
30 ms duration) + startle-pulse, or finally pre-pulse (high) alone.
Inter-stimulus interval was set at 100 ms, whereas the inter-trial
interval varied between 9 and 15 s.
In order to insure that the pre-pulses did not induce a star-
tle by themselves, 11 pre-pulse alone trials were included in the
trial protocol, but were not used in the calculations of PPI. To esti-
mate the habituation to startle each trial session started and ended
with 8 startle-pulse alone which were calculated as percent change
from first 8 startle-pulses and 8 last pulses. Startle magnitude was
calculated as an average of “startle-pulse alone” trials.
 K. Fabricius et al. / Neuroscience Letters 482 (2010) 117–122
Fig. 2. Electrophysiological characteristics of dopaminergic neurons in the VTA of GH and SI rats. (A) mean locomotor activity count (±SEM) of GH and SI rats used for
electrophysiological recordings. The number of spontaneously active dopamine neurons in the VTA (B), percentage of spikes in burst (C) and CV ISI (D) were significantly
increased in SI compared to GH rats (n = 4–6 animals, 24–25 neurons in each group).
PPI was calculated as % PPI for each pre-pulse intensity
as: [100 × (startle-pulse − pre-pulse + startle-pulse)/startle-pulse].
A low percentage score indicates a deficit in PPI.
For electrophysiology experiments, animals were anaes-
thetized with an initial intraperitoneal injection of chloral
hydrate (400 mg/kg). An intraperitoneal catheter then enabled
continuous anesthetic infusion (120 mg/kg/h). Animals were
mounted in a stereotaxic frame, the skull was exposed, and a
hole (0.5 cm × 0.5 cm) was drilled above the VTA (see coordinates
below). Extracellular single-cell recordings were performed using
electrodes pulled from glass capillaries and filled with 2% Pon-
tamine Sky Blue in 0.5 M sodium acetate (impedance 2.0–8.0 M
at 135 Hz). The electrode was lowered to the dorsal border of the
VTA, and advanced at a slow (1–3 ␮m/s), uniform speed using
a hydraulic microdrive. The number of spontaneously active
dopamine neurons was determined in 6–9 stereotaxic descents
[2,30] separated from each other by 200 ␮m, which sequence
was kept constant from animal to animal. Descents were made
in a stereotaxically defined block of tissue within the VTA area
at the following coordinates: 5.6–5.2 mm posterior to bregma,
0.5–0.9 mm lateral to the midline, and 6.5–8.5 mm ventral to the
cortical surface, according to Paxinos and Watson [20]. Extracellu-
lar action potentials were amplified, discriminated and monitored
on an oscilloscope and an audiomonitor. Presumed dopaminergic
neurons were characterized by (1) a slow and irregular firing
pattern (0.5–10 Hz), and (2) triphasic action potentials with a
predominant positive component, a negative component followed
by a minor positive component, with an overall duration >2.5 ms
[8]. Each spontaneously active dopamine neurons was counted
and further recorded for 2–5 min for offline analysis of (i) their
basal firing rate, (ii) the proportion of action potentials occurring
in bursts (defined as the occurrence of two consecutive spikes with
an interspike interval (ISI) of less than 80 ms, and the termination
of a burst defined as the occurrence of an ISI exceeding 160 ms)
[8], and (iii) the coefficient of variation of the ISI (CV ISI) defined
as the ratio between the average ISI and the standard deviation of
the ISI × 100. In addition, autocorrelograms were constructed from
spike trains consisting of at least 300 consecutive spikes using a bin
width of 10 ms for intervals up to 2000 ms and were used to quali-
tatively classify neurons as firing in the regular, irregular, or bursty
firing pattern [26]. Autocorrelograms showing 3 or more regularly
119
occurring peaks were characteristic of the regular firing pattern.
An initial trough that rose smoothly to a steady state was classified
as irregular firing pattern while an initial peak followed by decay
to a steady state was classified as bursty firing pattern (Fig. 3).
d-Amphetamine was obtained from Nomeco A/S (Nomeco A/S,
Copenhagen, Denmark), dissolved in saline, and administered at
a volume of 1 ml/kg. Doses are expressed in base concentrations.
Chloral hydrate was purchased from Sigma (Sigma–Aldrich Dan-
mark A/S, Brøndby, Denmark).
All data are expressed as mean ± SEM. A two-way repeated
measures (RM) analysis of variance (ANOVA) was applied to inves-
tigate statistical differences in the median values among SI and GH
animals in spontaneous and d-amphetamine-induced locomotor
activity, as well as in percent PPI. Time and pre-pulse intensities
were used as the repeated measurement factor, and housing as
the between subject factor. Mean locomotor activity for all cohorts
was tested with a two-way ANOVA with housing and cohort as
between subject factors. If a significant difference was observed, a
multiple comparisons design (Fishers LSD) was used to investigate
statistical significance between SI and GH groups. Acoustic startle
and habituation to the acoustic startle in PPI were analyzed with a
Student’s t-test and paired t-test, respectively. Electrophysiological
data were analyzed using a one-way ANOVA, except for the distri-
bution of firing patterns which was analyzed using the Chi-square
test. For all tests, a p value ≤0.05 was considered significant. Sta-
tistical analysis was performed with SigmaStat (ver 3.0.1 Systat® ,
USA).
SI rats showed consistently increased spontaneous locomo-
tor activity as compared to GH controls in a novel test cage
(F(1,71) = 58.39, p < 0.001). Overall, the mean locomotor activity
count was 1460 ± 73 and 789 ± 50 in SI and GH rats, respectively.
A two-way RM ANOVA revealed a significant effect of housing
(F(1,13) = 13.33, p = 0.003) and time (F(15,455) = 23.06, p < 0.001) with
a significant interaction between housing and time (F(35,455) = 2.82,
p < 0.001). Further analysis showed that SI animals were signif-
icantly more active than GH controls in the habituation period
(F(1,455) = 13.49, p = 0.002), but all animals habituated to the test
cage over time (F(1,455) = 34.3, p < 0.001). Further, SI animals exhib-
ited a significantly higher locomotor activity in response to
d-amphetamine as compared to GH (F(1,455) = 10.49, p < 0.001)
(Fig. 1A).
120 K. Fabricius et al. / Neuroscience Letters 482 (2010) 117–122

Fig. 3. Distribution of firing patterns of dopaminergic neurons in the VTA of GH and SI rats. Autocorrelograms of dopaminergic neurons in the VTA were constructed (A, B
and C, right panel) from spike trains (A, B and C, left panel) and allowed the classification of their firing pattern into regular (A), irregular (B) and bursty (C). The distribution
of these firing patterns was significantly different in SI when compared to GH rats, with a higher population of bursty neurons in SI rats (D).

In the PPI paradigm, increasing the pre-pulse volume signifi-
cantly increased the % PPI of the acoustic startle in both GH and SI
rats (F(2,59) = 455, p < 0.001). However, SI animals exhibited a sig-
nificant PPI deficit when compared to GH controls (F(1,30) = 18.52,
p < 0.001). Further, Fig. 1B analysis revealed that SI animals demon-
strated significantly reduced habituation of the startle response
to the startle-pulse (p = 0.02, paired t-test), but no difference was
observed in startle amplitude between SI and GH animals (p = 0.66,
t-test, data not shown).
All SI rats used in the electrophysiological studies exhibited a
significant increase in locomotor activity in response to a novel test
cage compared to GH rats (F(1,8) = 80.26, p < 0.001; Fig. 2A). SI ani-
mals showed a significant increase in the number of spontaneously
active dopamine neurons recorded from the VTA when compared
to GH animals (1.11 ± 0.12 vs. 0.69 ± 0.05 in SI and GH rats, respec-
tively, F(1,8) = 14.31, p = 0.005; Fig. 2B). Analysis of the firing rate of
all recorded dopamine neurons did not show any significant differ-
ence between SI and GH rats (3.44 ± 0.46 Hz vs. 3.70 ± 0.41 Hz in SI
and GH rats, respectively, F(1,45) = 0.18, p = 0.67; not shown). Anal-
ysis of the percentage of spikes in bursts of all recorded neurons
revealed a significant increase in SI rats when compared to GH rats
(33.2 ± 5.4% vs. 19.9 ± 5.8% in SI and GH rats, respectively, q = 3.97,
p = 0.005; Fig. 2C). A significant increase in the coefficient of varia-
tion of the ISI was also found in SI compared to GH rats (94 ± 7.7%
vs. 68 ± 7.4% in SI and GH rats, respectively, F(1,44) = 6.12, p = 0.017;
Fig. 2D). Construction of autocorrelograms for all recorded neurons
allowed their classification into regular (Fig. 3A), irregular (Fig. 3B)
or bursty (Fig. 3C). A significant change in the distribution of firing
patterns was found in SI compared to GH rats (2 = 11.35, df = 2,
p = 0.003; Fig. 3D), e.g. a lower proportion of neurons exhibiting
 K. Fabricius et al. / Neuroscience Letters 482 (2010) 117–122
regular firing in SI (12%) compared to GH (42%), and a higher pro-
portion of neurons exhibiting burst firing was found in SI (56%)
compared to GH (12%).
The aim of the present study was to investigate whether social
isolation of rats post-weaning had an influence on the firing activ-
ity of dopamine neurons recorded from the VTA in vivo. In addition,
we confirmed that socially isolated rats exhibited an increased
locomotor activity in response to a novel environment, as well as
to d-amphetamine, and a deficit in pre-pulse inhibition as earlier
reported [3,12,21] further validating our social isolation procedure.
Locomotor hyperactivity in response to a novel environment
has been consistently reported to be enhanced as a consequence
of social isolation [6], a finding also observed in the present study.
In addition, an enhanced locomotor response to d-amphetamine
was also observed in our study, in agreement with reports from
the literature [12,24]. Locomotor hyperactivity in response to a
novel environment and to psychostimulants has been suggested to
be dependent on the mesolimbic dopaminergic system [13]. More
precisely, the enhanced locomotor response observed in socially
isolated rats has been suggested to be driven by a sensitization
of the mesolimbic dopaminergic pathway [15]. In support of this
assumption, the locomotor response to intra-accumbal adminis-
tration of amphetamine was enhanced by isolation rearing [12].
In addition, we confirmed in our study that socially isolated rats
displayed deficits in PPI as well as in habituation of the acous-
tic startle response, both of which also reported to be sensitive
to dopaminergic modulation [10,14,21]. For instance, PPI deficits
induced by social isolation were reversed by 6-hydroxydopamine-
induced dopamine depletion in the nucleus accumbens [21] further
supporting a dysfunctional mesolimbic dopaminergic transmission
as a consequence of isolation rearing. Thus far, whether the alter-
ation in presynaptic dopamine function originates from changes in
autoreceptor regulation, uptake efficiency, synthesis efficiency, or
firing activity, has not been clearly established.
In the present study, we found for the first time an increased
number of spontaneously active dopamine neurons recorded from
the VTA in socially isolated rats. It is noteworthy that a some-
what low number of active dopamine neurons were encountered
in control rats in the present study. Even though higher neuronal
counts have generally been reported in the literature, none of
these studies have used Lister Hooded rats. Interestingly, differ-
ences in locomotor activity as well as sensitivity to dopaminergic
drugs have been reported in Lister Hooded compared to other rat
strains [11,27], and may rely on a different spontaneous activity
of dopamine neurons. The increase in the VTA population activity
observed in socially isolated rats is in agreement with findings in
another neurodevelopmental model of schizophrenia, the methy-
lazoxymethanol (MAM) model [16]. In these studies, a hyperactive
state of glutamatergic neurons in the ventral hippocampus was
described and suggested to be responsible for the increased pop-
ulation activity in the VTA via disinhibition of the indirect ventral
striatopallidal pathway. We also found that spontaneously active
dopamine neurons exhibited an exacerbated burst firing activity,
as supported by an overall increased percentage of spikes in bursts
and an increased CV of the interspike interval. Further classification
of the neurons according to their firing pattern revealed a higher
proportion of neurons firing in a burst mode in socially isolated
rats compared to group-housed rats, without affecting their over-
all firing rate. These findings are of particular interest since burst
firing in dopaminergic neurons has been suggested to be more
potent to release dopamine at the terminal level than regular, tonic
firing activity [25]. Surprisingly, microdialysis studies have gen-
erally reported unchanged basal dopamine levels in the nucleus
accumbens of socially isolated rats [31]. As a possible explana-
tion for this apparent inconsistency, it was reported that increasing
burst firing in dopamine neurons from the VTA did not significantly
121
enhance accumbal dopamine levels as measured by microdialy-
sis, unless dopamine reuptake mechanisms were blocked [5]. Since
burst firing activity in dopaminergic neurons is highly dependent
on excitatory inputs [19,25], it would be essential to investigate
whether glutamatergic transmission is also affected by social iso-
lation.
In conclusion, our in vivo electrophysiological recordings from
dopaminergic neurons in the VTA revealed for the first time an
increase in the number of spontaneously active neurons and a
higher proportion of dopamine neurons firing in bursts in socially
isolated rats compared to group-housed rats. Together with the
assumption that an exacerbated burst firing activity in dopamine
neurons underlies the hyperresponsive state of the mesolimbic
dopaminergic system thought to be associated with schizophre-
nia [7], our electrophysiological findings further strengthen the
usefulness of social isolation as a model for studying the patho-
physiological mechanisms underlying the disease.
Acknowledgement
Technician Vibeke Nielsen is thanked for performing the
amphetamine locomotor study.
References
[1] M. Bianchi, K.F. Fone, N. Azmi, C.A. Heidbreder, J.J. Hagan, C.A. Mars-
den, Isolation rearing induces recognition memory deficits accompanied by
cytoskeletal alterations in rat hippocampus, Eur. J. Neurosci. 24 (2006) 2894–
2902.
[2] L.A. Chiodo, B.S. Bunney, Typical and atypical neuroleptics: differential effects
of chronic administration on the activity of A9 and A10 midbrain dopaminergic
neurons, J. Neurosci. 3 (1983) 1607–1619.
[3] J. Cilia, P.D. Hatcher, C. Reavill, D.N. Jones, Long-term evaluation of
isolation-rearing induced prepulse inhibition deficits in rats: an update, Psy-
chopharmacology (Berl.) 180 (2005) 57–62.
[4] C. Corcoran, E. Walker, R. Huot, V. Mittal, K. Tessner, L. Kestler, D. Malaspina,
The stress cascade and schizophrenia: etiology and onset, Schizophr. Bull. 29
(2003) 671–692.
[5] S.B. Floresco, A.R. West, B. Ash, H. Moore, A.A. Grace, Afferent modulation of
dopamine neuron firing differentially regulates tonic and phasic dopamine
transmission, Nat. Neurosci. 6 (2003) 968–973.
[6] K.C. Fone, M.V. Porkess, Behavioural and neurochemical effects of post-weaning
social isolation in rodents—relevance to developmental neuropsychiatric dis-
orders, Neurosci. Biobehav. Rev. 32 (2008) 1087–1102.
[7] A.A. Grace, Phasic versus tonic dopamine release and the modulation of
dopamine system responsivity: a hypothesis for the etiology of schizophrenia,
Neuroscience 41 (1991) 1–24.
[8] A.A. Grace, B.S. Bunney, Intracellular and extracellular electrophysiology of
nigral dopaminergic neurons. 1. Identification and characterization, Neuro-
science 10 (1983) 301–315.
[9] C.A. Heidbreder, I.C. Weiss, A.M. Domeney, C. Pryce, J. Homberg, G. Hedou, J.
Feldon, M.C. Moran, P. Nelson, Behavioral, neurochemical and endocrinologi-
cal characterization of the early social isolation syndrome, Neuroscience 100
(2000) 749–768.
[10] T Humby, L.S. Wilkinson, T.W. Robbins, M.A. Geyer, Prepulses inhibit startle-
induced reductions of extracellular dopamine in the nucleus accumbens of rat,
J. Neurosci. 16 (1996) 2149–2156.
[11] T.T. Iyaniwura, A.E. Wright, D.J. Balfour, Evidence that mesoaccumbens
dopamine and locomotor responses to nicotine in the rat are influenced by
pretreatment dose and strain, Psychopharmacology (Berl.) 158 (2001) 73–79.
[12] G.H. Jones, C.A. Marsden, T.W. Robbins, Increased sensitivity to amphetamine
and reward-related stimuli following social isolation in rats: possible dis-
ruption of dopamine-dependent mechanisms of the nucleus accumbens,
Psychopharmacology (Berl.) 102 (1990) 364–372.
[13] P.H. Kelly, P.W. Seviour, S.D. Iversen, Amphetamine and apomorphine
responses in the rat following 6-OHDA lesions of the nucleus accumbens septi
and corpus striatum, Brain Res. 94 (1975) 507–522.
[14] B.D. Kretschmer, M. Koch, The ventral pallidum mediates disruption of prepulse
inhibition of the acoustic startle response induced by dopamine agonists, but
not by NMDA antagonists, Brain Res. 798 (1998) 204–210.
[15] M.D Lapiz, A. Fulford, S. Muchimapura, R. Mason, T. Parker, C.A. Marsden,
Influence of postweaning social isolation in the rat on brain development, con-
ditioned behavior, and neurotransmission, Neurosci. Behav. Physiol. 33 (2003)
13–29.
[16] D.J. Lodge, A.A. Grace, Aberrant hippocampal activity underlies the dopamine
dysregulation in an animal model of schizophrenia, J. Neurosci. 27 (2007)
11424–11430.
122 K. Fabricius et al. / Neuroscience Letters 482 (2010) 117–122
[17] J.L. Lukkes, M.V. Mokin, J.L. Scholl, G.L. Forster, Adult rats exposed to early-life
social isolation exhibit increased anxiety and conditioned fear behavior, and
altered hormonal stress responses, Horm. Behav. 55 (2009) 248–256.
[18] S McLean, B. Grayson, M. Harris, C. Protheroe, S. Bate, M. Woolley, J. Neill,
Isolation rearing impairs novel object recognition and attentional set shifting
performance in female rats, J. Psychopharmacol. (2008) 57–63.
[19] P.G. Overton, D. Clark, Burst firing in midbrain dopaminergic neurons, Brain
Res. Brain Res. Rev. 25 (1997) 312–334.
[20] G. Paxinos, C. Watson, The Rat Brain in Stereotaxic Coordinates, Academic Press,
New York, 1998.
[21] S.B. Powell, M.A. Geyer, M.A. Preece, L.K. Pitcher, G.P. Reynolds, N.R. Swerd-
low, Dopamine depletion of the nucleus accumbens reverses isolation-induced
deficits in prepulse inhibition in rats, Neuroscience 119 (2003) 233–240.
[22] N.C. Schrijver, H. Wurbel, Early social deprivation disrupts attentional, but not
affective, shifts in rats, Behav. Neurosci. 115 (2001) 437–442.
[23] A.B Silva-Gomez, D. Rojas, I. Juarez, G. Flores, Decreased dendritic spine den-
sity on prefrontal cortical and hippocampal pyramidal neurons in postweaning
social isolation rats, Brain Res. 983 (2003) 128–136.
[24] J.K. Smith, J.C. Neill, B. Costall, Post-weaning housing conditions influence
the behavioural effects of cocaine and d-amphetamine, Psychopharmacology
(Berl.) 131 (1997) 23–33.
[25] M.F. Suaud-Chagny, K. Chergui, G. Chouvet, F. Gonon, Relationship between
dopamine release in the rat nucleus accumbens and the discharge activity of
dopaminergic neurons during local in vivo application of amino acids in the
ventral tegmental area, Neuroscience 49 (1992) 63–72.
[26] J.M. Tepper, L.P. Martin, D.R. Anderson, GABAA receptor-mediated inhibition
of rat substantia nigra dopaminergic neurons by pars reticulata projection
neurons, J. Neurosci. 15 (1995) 3092–3103.
[27] I.C. Weiss, I.L. Di, J. Feldon, A.M. Domeney, Strain differences in the isolation-
induced effects on prepulse inhibition of the acoustic startle response and on
locomotor activity, Behav. Neurosci. 114 (2000) 364–373.
[28] I.C. Weiss, A.M. Domeney, C.A. Heidbreder, J.L. Moreau, J. Feldon, Early social
isolation, but not maternal separation, affects behavioral sensitization to
amphetamine in male and female adult rats, Pharmacol. Biochem. Behav. 70
(2001) 397–409.
[29] I.C Weiss, C.R. Pryce, A.L. Jongen-Relo, N.I. Nanz-Bahr, J. Feldon, Effect of social
isolation on stress-related behavioural and neuroendocrine state in the rat,
Behav. Brain Res. 152 (2004) 279–295.
[30] F.J. White, R.Y. Wang, Differential effects of classical and atypical antipsy-
chotic drugs on A9 and A10 dopamine neurons, Science 221 (1983) 1054–
1057.
[31] L.S. Wilkinson, S.S. Killcross, T. Humby, F.S. Hall, M.A. Geyer, T.W. Robbins,
Social isolation in the rat produces developmentally specific deficits in prepulse
inhibition of the acoustic startle response without disrupting latent inhibition,
Neuropsychopharmacology 10 (1994) 61–72.