Neonatal
quinpirole treatment enhances locomotor
activation and dopamine release in the nucleus
accumbens core in response to amphetamine
treatment in adulthood
Zackary A. Cope, Kimberly N. Huggins, A.
Brianna Sheppard, Daniel M. Noel1, David S.
Roane, Russell W. Brown
Department of Psychology,
East Tennessee State University
Neonatal quinpirole treatment to rats
produces long-term increases in D2 receptor
sensitivity that persists throughout the
animal's lifetime, a phenomenon referred to as
D2 priming. Male and female Sprague-dawley rats
were administered quinpirole (1mg/kg) or saline
from postnatal days (P)1-11.
At P60, all animals were given an injection
of quinpirole (100 ug/kg), and results showed
that rats neonatally treated with quinpirole
demonstrated enhanced yawning in response to
quinprole, verifying D2 receptor priming because
yawning is a D2 receptor mediated event.
Beginning 1-3 days later, locomotor
sensitization was tested through administration
of d-amphetamine (1mg/kg) or saline every other
day over 14 days, and horizontal activity and
turning behavior were analyzed.
Findings indicated that D2-priming enhanced
horizontal activity in response to amphetamine
in females compared to males at days 1 and 4 of
locomotor sensitization testing, and D2-priming
enhanced turning in response to amphetamine.
Seven to 10 days after sensitization was
complete, microdialysis of the NAcc core was
performed using a cumulative dosing regimen of
amphetamine (0.1 &endash; 3.0 mg/kg). D2- primed
rats administered amphetamine demonstrated a
500% increase in accumbal DA overflow compared
to control rats administered amphetamine.
Additionally, amphetamine produced a
significant increase in NE overflow compared to
controls, but this was unaffected by D2 priming.
These results indicate that D2 receptor priming
as is produced by neonatal quinpirole treatment
robustly enhances behavioral activation and
accumbal DA overflow in response to amphetamine,
which may underlie increases in psychostimulant
use and abuse within the psychotic population
where increased D2 receptor sensitivity is a
hallmark.
Introduction
Past studies have shown that neonatal
quinpirole (a dopamine D2/D3 agonist) treatment
to rats result in a significant increase of
dopamine D2 receptor sensitivity that persists
throughout the animal's lifetime, which is a
phenomenon that has also been referred to as 'D2
priming' (Kostrzewa, et al., 1993;Thacker, et
al., 2006). Interestingly, this change in
receptor sensitivity is independent of a change
in receptor number (Kostrzewa, 1995). Increases
in D2 receptor sensitivity are common in several
behavioral disorders, including schizophrenia,
bipolar disorder, obsessive-compulsive disorder,
and D2 receptor family genetic polymorphisms
have been shown in attention
deficit/hyperactivity disorder (ADHD) (Jimerson
et al. 1987; Seeman et al. 2006; Kieling et al.
2006; Sery et al. 2006). Recently we have shown
that neonatal quinpirole treatment results in a
significant decrease of genetic expression of
Rgs9, a regulator of Gprotein signaling at the
dopamine D2 receptor, in the nucleus accumbens,
striatum, and to a lesser extent, in the frontal
cortex of adult rats (Maple, et al., 2007).
This significant decrease in RGS9 expression
is consistent with post-mortem findings in
psychosis (Seeman, et al., 2007). Additionally,
we have shown that treatment with the
antipsychotic olanzapine alleviates cognitive
impairment and significant decreases of
neurotrophic factor protein produced by neonatal
quinpirole treatment (Thacker, et al., 2006),
also consistent with other preclinical findings
(Fumagalli, et al., 2003; Angelucci, et al.,
2004). In psychotic disorders, a common
comorbidity is a significant 2-5 increase in
psychostimulant abuse compared to the normal
population (LeDuc and Mittleman 1995; Lasser et
al. 2000; Snyder et al. 2006). Psychostimulants,
such as amphetamine and nicotine, are the most
frequently abused drugs in these behavioral
disorders.
Despite these observations no definitive
explanation for the high level of drug abuse in
this population exists, and few investigations
have been done into the neural correlates of
psychostimulant abuse in these populations.
Interestingly, imaging studies in schizophrenics
have shown that treatment with amphetamine
produces a significant increase in striatal
dopamine release, which is most pronounced
during episodes of illness exacerbation
(Laruelle, et al., 1996; Abi Dargham, et al.,
1998). This result suggests that schizophrenics
may be vulnerable to abuse of psychostimulants
due to an increased dopaminergic response to
drugs of addiction, which presumably would
produce increased behavioral activation and
positive reinforcement in response to the drug.
Consistent with this past work, a collaborating
laboratory has shown that acute amphetamine to
rats D2-primed with quinpirole as neonates
resulted in a four-fold increase in striatal
dopamine release compared to controls
administered amphetamine (Nowak, et al.,
2001).
However, this past study did not analyze sex
differences or locomotor sensitization, and
although the dorsal striatum plays a role in
mediating locomotor activation and positive
reinforcement, the nucleus accumbens has been
shown to central to the reinforcement properties
of addictive drugs as well as mediate behavioral
activating aspects of psychostimulants
(DiChiara, 1993). The present study was designed
to analyze amphetamine locomotor sensitization
as well as DA and NE microdialysis in male and
female rats D2-primed as neonates with the D2/D3
agonist quinpirole. Locomotor sensitization has
been prominently used as a behavioral assay to
analyze underlying behavioral mechanisms of
addiction (Robinson and Berridge, 1993; Pierce
and Kalivas, 1995). An additional focus of this
study was to analyze the effects of previous
exposure to amphetamine on dopamine release in
the nucleus accumbens core in animals D2
receptor primed as neonates.
The rationale for choosing the NAcc core is
based on findings that have shown that the core,
but not the NAcc shell, has been implicated in
dopamine release in psychostimulant locomotor
sensitization (Cadoni, et al., 2000; Ito, et
al., 2000), and the NAcc core is preferentially
innervated by nuclei that process motor
information (Heimer, et al., 1991). Finally,
direct injections of dopamine to this region
produce a more robust locomotor response than
the shell of the NAcc (Campbell, et al., 1997).
Based on the focus of this study on locomotor
behavioral senstization and the role of the NAcc
core in locomotor behavior, we chose to focus on
the NAcc core as the brain area for
microdialysis.
Male and female rats were used as subjects,
as several past studies have reported a sex
difference in both the behavioral and
neurochemical response to amphetamine (Becker,
et al., 1999; 2001). Additionally, both dopamine
(DA) and norepinephrine (NE) levels were
analyzed, because although increases in
dopaminergic activity have been shown to be
central to primary drug reinforcement and
locomotor sensitization (for review, see
Vetulani, 2001), amphetamine has also been shown
to increase NE in the NAcc core which may be
related to behavioral effects produced by
amphetamine (McKittrick and Abercrombie, 2007).
Further, several studies have shown alterations
in the NE system in post-mortem analyses of the
nucleus accumbens in psychosis, specifically in
schizophrenia, (Farley, et al., 1978; Bridge, et
al., 1985, for review see Yamamoto &
Hornykiewicz, 2004) but it is unclear whether
this change is an increase or decrease of
noradrenergic functioning within the
accumbens.
In conclusion, there are several
consistencies between the present study and
other nonclinical and clinical literature
analyzing the effects of amphetamine on DA
levels in model of psychosis and in psychotic
individuals. In pre-clinical work, past studies
using the neonatal ventral hippocampal lesion
(NVHL) model of schizophrenia in rats have also
shown hyperresponsiveness to amphetamine both
behaviorally and in enhanced DA release in the
NAcc core. Clinically, both schizophrenics and
schizotypal personality disorder have shown an
enhanced DA response in the dorsal striatum
measured using PET. Moreover, these studies
revealed a correlation between the exaggerated
response of the striatal dopaminergic system to
acute amphetamine and a transient exacerbation
of positive symptoms in patients with
schizophrenia, underscoring the clinical
relevance of this alteration in DA-mediated
transmission.
