The effects of
adulthood olanzapine treatment on cognitive
performance and neurotrophic factor content in
male and female rats neonatally treated with
quinpirole
Thacker SK, Perna MK, Ward JJ, Schaefer TL,
Williams MT, Kostrzewa RM, Brown RW
Department of Psychology,
East Tennessee State University, Johnson City,
USA.
Abstract
Male and female
Sprague-Dawley rats were administered quinpirole (1 mg/kg, i.p.) or
saline once daily from postnatal day (P)1 to P21. This drug treatment
has been shown to produce long-term priming of the D2 receptor.
Beginning on P62, rats were administered the atypical antipsychotic
olanzapine (2.5 mg/kg) or saline twice daily (i.p.) for 28 days. One
day after olanzapine treatment ceased, rats were tested on the place
and match-to-place versions of the Morris water maze (MWM) for seven
consecutive days.
Dopamine D2 receptor priming was verified through a yawning behavioural
test, a D2 receptor-mediated event, before olanzapine was administered
as well as after olanzapine treatment and behavioural testing were
complete. Results showed that neonatal quinpirole treatment induced D2
priming that was eliminated by olanzapine treatment. On the MWM place
version, D2-primed rats demonstrated a significant impairment that was
eliminated by olanzapine treatment, but olanzapine treatment to animals
neonatally treated with saline produced a significant deficit on the
place version of the MWM.
There were no significant deficits on the match-to-place version. Brain
tissue analyses revealed that neonatal quinpirole treatment produced a
significant decrease in hippocampal NGF, BDNF and ChAT that was
eliminated by olanzapine treatment. Neonatal quinpirole treatment
produced a significant decrease in BDNF and ChAT in the frontal cortex
that was unaffected by olanzapine treatment. These results show that
olanzapine eliminates D2 receptor priming and cognitive impairment and
also alleviates decreases in neurotrophins and acetylcholinergic
markers produced by D2 priming in the hippocampus.
Introduction
The drug class of atypical antipsychotics has been shown to be
therapeutically useful for the treatment of schizophrenia. Atypical
antipsychotics have advantages over drugs in the typical class of
antipsychotics because they avoid debilitating side-effects including
extrapyramidal motor effects. One of the most promising and commonly
prescribed atypical antipsychtoic drugs, olanzapine (trade name
Zyprexa), gained FDA approval in the United States in 1996. Like many
atypical antipsychotics, olanzapine acts through antagonism of both the
dopamine D2 receptor and the serotonin 5-HT2A receptor.
Interestingly, olanzapine has also been shown to alleviate cognitive
impairment in schizophrenics tested on a number of cognitive tasks .
However, olanzapine has also been shown to produce weight gain,
increase glycosylated haemoglobin and increase triglycerides, more so
than other atypical and typical antipsychotic medications Previous work
from this laboratory has shown that neonatal quinpirole treatment to
rats given during the first 3 weeks of life results in long-term
increases in sensitivity of the dopamine D2 receptor, a phenomenon
called ‘priming’.
Increased activation of the dopamine D2 receptor has been shown to play
a major role in abnormal behaviours observed in schizophrenia. Thus, it
appears that neonatal D2 receptor priming through neonatal quinpirole
treatment may be a valid rodent model of schizophrenia, although it is
recognized that other neurotransmitter systems also play an important
role in this disorder. This increase in dopamine D2 sensitivity is not
accompanied by an increase in receptor proliferation. Priming of the D2
receptor is verified through an acute quinpirole injection in adulthood
and the number of yawns are counted for 1 h.
Yawning has been shown to be a D2 receptormediated behavioural event.
In a series of recent studies, we have shown that neonatal quinpirole
treatment results in cognitive impairment on the Morris water maze.
Interestingly, neonatal quinpirole treatment results in significant
decreases in the neurotrophins nerve growth factor (NGF) and
brain-derived neurotrophic factor (BDNF), as well as a decrease in
choline acetyltransferase (ChAT) in the hippocampus which was
alleviated by nicotine treatment in adulthood. Both NGF and BDNF are
neurotrophic factors important in the development and maintenance of
neurons and synaptic connectivity, and ChAT is the enzyme that
catalyses acetylcholine formation. All of these proteins have been
shown to be important in cognition and maintenance of the
septohippocampal pathway.
Recent studies have shown that olanzapine treatment produces either
cognitive enhancement or impairment, but these effects appear to be
dependent on administration methodology. Wolff & Leander (2003)
have shown that acute olanzapine treatment improves cognitive function
in normal rats tested on a delayed nonmatching-to-sample task, but
animals tested on the MWM during a drug-free washout period after
chronic olanzapine treatment produced cognitive deficits . Other
studies have shown that olanzapine increases hippocampal NGF and ChAT
in rats after chronic administration of the drug through the
animal’s drinking water.
Neurochemically, acute olanzapine treatment produces a robust increase
in acetylcholine release in the hippocampus of normal adult rats. These
results suggest that olanzapine may be effective in alleviating
cognitive impairment in D2- primed rats, as these animals have altered
neurotrophin and acetylcholinergic systems. This study was designed to
test the hypothesis that subchronic treatment with the atypical
antipsychotic olanzapine in adulthood will alleviate increases in
yawning behaviour, cognitive deficits on the MWM and significant
decreases in hippocampal NGF, BDNF and ChAT produced by neonatal
quinpirole treatment. The rationale for choosing olanzapine was based
on findings that have shown that drugs in the atypical antipsychotic
drug class are superior to typical antipsychotic drugs with regard to
cognitive function in schizophrenia and that olanzapine alleviates
certain types of cognitive impairment in schizophrenia. Olanzapine has
also been shown to alleviate decreases in neurotrophic factors in
rodent models of schizophrenia. These same three proteins were also
analysed in the medial frontal cortex (MFC) and medial cerebellar
cortex because of the importance of the MFC in MWM performance. The
cerebellar cortex was utilized as a control.
Discussion
The results of this study demonstrated several
important findings. Rats neonatally treated with quinpirole
demonstrated a significant increase in yawning in adulthood that was
alleviated by olanzapine treatment, indicating that olanzapine
normalized the effects of neonatal quinpirole treatment on a D2
receptor-mediated behaviour. Interestingly, adulthood olanzapine
treatment alleviated cognitive deficits produced by neonatal quinpirole
treatment on the place version of the MWM. However, neonatal quinpirole
treatment did not produce significant deficits on the match-to-place
version of the MWM. Adulthood olanzapine treatment alleviated decreased
levels of NGF, BDNF and ChAT in the hippocampus of animals treated with
neonatal quinpirole but did not alleviate significant decreases in BDNF
and ChAT in the frontal cortex, nor did it alter levels of either BDNF,
NGF or ChAT in the cerebellum. These results demonstrate that the
effects of olanzapine on neurotrophins and acetylcholine appear to be
specific to the hippocampus. An especially impressive finding in the
current study is that olanzapine alleviated the increase in yawning of
animals neonatally treated with quinpirole, and this effect was
demonstrated after an 8-day washout of olanzapine.
The fact that olanzapine alleviated cognitive deficits as well as D2
priming might suggest that increases in D2 sensitivity are responsible
for cognitive deficits observed on the place version of the MWM.
Increases in dopamine D2 receptor activation have been shown to produce
cognitive impairment in spatial memory tasks, although other studies
have shown that activation of the D2 receptor may enhance spatial
memory.
In general, neonatal treatment with drugs that activate the
dopaminergic system have resulted in cognitive impairment, probably due
to their effects on developing brain systems underlying cognitive
performance (for review, see Walker et al., 1999). We hypothesize that
neonatal quinpirole treatment is probably producing disruption of
hippcampal and frontal cortex development, based on findings that have
shown this treatment results in decreases in NGF, BDNF and ⁄ or
ChAT in the hippocampus and frontal cortex of both young and adult
D2-primed animals. Past studies have shown that olanzapine results in
cognitive deficits when administered to control rats either immediately
before or chronically before behavioural testing on the MWM.
The present study also demonstrated that chronic olanzapine
administered before behavioural testing on the MWM place version
resulted in cognitive impairment, which was apparent in females in
acquisition and in both males and females on the probe trial. It has
been previously hypothesized that, during acquisition of the place
version of the MWM, rats learn a search strategy or search strategies
to locate the platform, whereas the probe trial is measure of the
integration of several different search strategies to correctly
pinpoint the platform location. It appears from these data that females
demonstrate a more robust cognitive impairment on both strategy
acquisition and the use of this strategy on the probe trial.
Importantly, the present study is the only report of the effects of
olanzapine on MWM performance in both male and female rats. Cognitive
impairment produced by neonatal quinpirole treatment appears to be more
specific to tasks in which information remains stable over trials, such
as that which occurs in the place version of the MWM. Results showed no
drug-induced impairment on the match-toplace version of the MWM which,
it has been hypothesized, tests working memory.
Although the hippocampus has been shown to be important for both
reference and working memory, it appears that neonatal quinpirole
treatment primarily affects reference but not working memory, at least
in D2-primed adults. We have recently demonstrated match-to-place
deficits in D2-primed animals tested as early postweanlings from P22 to
P28. Thus, the deficits at the earlier age of testing on the
match-to-place version of the MWM may be due to withdrawal from drug
treatment rather than persistent changes in hippocampal connectivity.
The present study demonstrated that olanzapine alleviated significant
decreases in hippocampal NGF, BDNF and ChAT in D2-primed rats. The
exact mechanism through which olanzapine is working to produce these
neurochemical changes is not known. All of these proteins have been
shown to be important in cognitive performance.
Both NGF TrkA and BDNF TrkB receptors are located on septohippocampal
cholinergic neurons, and olanzapine may be increasing acetylcholinergic
activity through its effects on neurotrophins within this pathway. Past
studies have shown complex effects of olanzapine and its effects on
neurotrophins. Chronic olanzapine has been shown to result in
augmention of NGF but a reduction in BDNF but has also been shown to
result in no changes in BDNF after olanzapine treatment in nontreated
control rats, although olanzapine was able to restore significant
decreases in BDNF produced by the typical antipsychotic haloperidol.
The inconsistency of the effects of olanzapine on controls between this
and past studies is probably due to methodological and research design
differences. The contradiction between the present and past results
points out that issues of dose, route of administration and days of
washout after drug administration may be critical when analysing the
effects of olanzapine on these neurochemical markers.
In the present study, we reported significant correlations for
hippocampal NGF and the MSD score of the MWM place version in Groups
Q-O and S-O, and significant correlations for hippocampal ChAT and MWM
MSD and MZD scores in Groups S-S, Q-O and Q-S, and two significant
negative correlations between frontal cortex ChAT and Groups Q-O and
S-S. We did not find any significant correlations with BDNF and MWM
performance. What this may indicate is that the NGF and ChAT levels in
the hippocampus and, to a lesser extent, the frontal cortex correlate
with MWM performance a bit better than BDNF, and indicate that deficits
in spatial memory may be a direct consequence of alterations in
neurotrophin and ChAT content utilizing certain dependent measures.
However, it is important to note that there are relatively low numbers
of subjects in these conditions, and an increased number may be
required to observe significant correlations with BDNF in other drug
conditions. The finding that neonatal quinpirole treatment produced
significant decreases in NGF, BDNF and ChAT in the adult hippocampus
replicates previous work. Studies have shown that the D2 receptor is
important in regulation of acetylcholine release in the hippocampus
although its precise role is yet to be identified.
The primarily acetylcholinergic septohippocampal pathway has been shown
to play an important role in cognition, and it appears that neonatal
quinpirole treatment may be producing significant neurotrophic factor
and enzymatic changes along this pathway that may result in cognitive
impairment on the MWM. Additionally, this study replicated previous
effects from this laboratory showing that priming of the dopamine D2
receptor results in cognitive deficit and produces significant
decreases in NGF and BDNF. These results help to also validate this as
a rodent model of schizophrenia, as schizophrenics have been shown to
demonstrate cognitive impairment as well as decreases in these same
neurotrophic factors in the brain and bloodstream.
In conclusion, adulthood olanzapine treatment was found in the present
study to alleviate behavioural and neurochemical abnormalities in a
rodent model of dopamine D2 receptor priming. However, also important
is that adulthood olanzapine treatment produced a significant
impairment in MWT performance in control animals, suggesting an
important role of the D2 and 5-H2A receptor in this task. Although
olanzapine did not alleviate all changes produced by neonatal
quinpirole treatment, it is apparent that olanzapine may have
therapeutic potential when particular brain systems underlying
cognition may be compromised.
