Current Medicinal Chemistry, 2004, 11, 267-277 267

Schizophrenia: From Dopamine to Glutamate and Back

M.L. Carlsson1,2*, A. Carlsson1,2 and M. Nilsson1,2

1Institute of Clinical Neuroscience, Neuropsychiatric Research Unit, Göteborg University,

Sweden and 2A. Carlsson Research AB, Göteborg, Sweden
Abstract: The first part of the present review describes the exciting journey of
dopamine stabilizers, starting in the early eighties with the development of the partial
dopamine agonist (-)-3-PPP of phenylpiperidine structure, via various compounds with
aminotetraline structure with preferential autoreceptor antagonist properties, and then
back again to phenylpiperidine compounds carrying substituents on the aromatic ring
that transformed them from partial dopamine agonists to partial dopamine receptor
antagonists, such as OSU6162. OSU6162 was brought to the clinic and has in preliminary
trials showed antidyskinetic and antipsychotic efficacy. The second part of this review describes results from a
hypoglutamatergia mouse model for cognitive symptoms of schizophrenia, where we have tested traditional
neuroleptics, new generation antipsychotics with marked 5-HT2 vs dopamine D2 receptor blockade as well as a
dopamine stabilizer belonging to the partial dopamine receptor antagonist category.
Keywords: schizophrenia, dopamine stabilizer, cognition, video tracking, glutamate, MK-801, mouse

INTRODUCTION with respect to vocational and social functioning, and

The most important basis for currently used
antipsychotics is dopamine D2 receptor blockade but
unfortunately this suppression of dopaminergic tone also
entails serious motor and mental side effects. The motor side
effects (extrapyramidal side effects; EPS) can be reduced by
careful dosage, because they occur at somewhat higher
dopamine receptor occupancy than that generally needed for
antipsychotic action. This does not seem to be true of the
mental side effects, however, since they, similarly to the
antipsychotic action, seem to reside largely in the ventral
striatum, which seems to be more sensitive to dopamine
receptor blockade than the dorsal striatum, where the EPS
appear to be located. Some of the mental side effects involve
an interference with the reward system and show up as
anhedonia and dysphoria. Another mental side effect is
impairment of cognition, which may result from D2 receptor
blockade both in the striatum and in the cerebral cortex. The
mental side effects are experienced by many patients as a
high, sometimes too high, price to be paid for the
antipsychotic action.
There is now considerable evidence, mainly from
imaging studies [1-7] that dopaminergic presynaptic tone is
elevated in schizophrenia during the active psychotic state.
However, this may not occur in all patients and may not
involve all dopamine systems. Moreover, it does not seem
to occur, at least not to the same extent, in schizophrenic
patients in remission. From a therapeutic point of view this
is important, because many schizophrenic patients need
antipsychotic medication even in remission in order to
prevent relapse.
Thus, the currently available antipsychotic agents have
serious limitations, in many cases leading to a poor outcome
*Address correspondence to this author at the Göteborg University,
Institute of Clinical Neuroscience, Neuropsychiatric Research Unit,
Guldhedsgatan 19, SE-413 46 Göteborg, Sweden; Tel: +46 73 693 96 22;
E-mail: maria.carlsson@psychiat.gu.se
quality of life. Admittedly the so-called atypical
antipsychotic agents, clozapine being the most convincing
example, can induce an antipsychotic action at a lower
dopamine receptor occupancy than the classical agents, but
they can still cause hypodopaminergia with resultant side
effects. Moreover, the currently used atypical antipsychotic
agents have been found to have other side effects, such as
weight gain and insulin resistance, which may lead to
diabetes.
Dopaminergic stabilizers are antipsychotics with much
less or none of those side effects that are a consequence of
hypodopaminergia, because they can suppress dopamine
functions at most moderately below baseline. They can thus
alleviate abnormal motor and mental hyperactivity with but
slight, if any, risk of attaining activity levels below
baseline. In fact, many of them can stimulate low-baseline
behavior. In other words, a dopamine stabilizer is a
compound that can influence behavior in different directions,
depending on the baseline.
Dopaminergic stabilizers may be divided into two
classes: Partial dopamine receptor agonists and partial
dopamine receptor antagonists.
PARTIAL DOPAMINE RECEPTOR AGONISTS
(-)-3-PPP
The dopamine stabilizer project was originally aimed at
developing dopaminergic agonists with better
pharmacokinetic properties and less side effects than
apomorphine. This goal was never reached, but instead a
compound with unusual properties, i. e. 3-(3-hydroxyphe-
nyl)-N-n-propylpiperidine (3-PPP), emerged [8]. It was
discovered in the seventies that the receptor-mediated
feedback mechanism regulating the activity of dopaminergic
neurons is, at least partly, mediated by receptors located on
the dopaminergic neurons themselves [9]. Stimulation of
these receptors, which later were shown to be almost

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268 Current Medicinal Chemistry, 2004, Vol. 11, No. 3
exclusively of the D2 subtype, causes inhibition of the
dopaminergic neuron with respect to firing, release,
synthesis and metabolism of dopamine. Sometimes these
receptors are called presynaptic, but a preferable term may be
autoreceptors, partly because they are largely located
extrasynaptically, partly because they should be
distinguished from presynaptic heteroreceptors.
In various in-vivo models 3-PPP at first seemed to
behave as a selective dopamine autoreceptor agonist,
inhibiting the synthesis and metabolism of dopamine and
locomotor activity of normal animals, whereas in animals
depleted of dopamine it was unable to stimulate behavior. In
other words, it seemed to stimulate the autoreceptors but be
devoid of stimulating activity on postsynaptic receptors [8].
However, when shortly afterwards the two enantiomers of
3-PPP were separated, the (+)-form was found to behave
more or less like the full classical dopamine receptor agonist
apomorphine, whereas the (-)-form turned out to be a partial
dopamine receptor agonist [10-12]. In low dosage both
enantiomers were found to induce behavioral inhibition,
which was largely due to autoreceptor stimulation. However,
in higher doses they differed in that only the (+)-form was
able to stimulate behavior. When the two enantiomers were
combined, as in the racemate, the (-)-form blocked the
stimulation induced by the (+)-form. That is why the
racemate mistakenly had been interpreted as being a selective
autoreceptor agonist, devoid of activity on the postsynaptic
receptors.
Both enantiomers of 3-PPP, and especially the (-)-form,
have been extensively studied in various animal models.
Electrophysiological as well as biochemical studies
demonstrate their agonist properties on both dopamine
autoreceptors and postsynaptic receptors, the (-)- form being
a partial and the (+)-form a full agonist [11, 12].
In order to understand the pharmacological profile of full
or partial dopamine agonists it is essential to recognize the
different responsiveness of autoreceptors and postsynaptic
receptors. The autoreceptors are to a large extent located
outside the dopaminergic synapses. This is clearly the case
of the autoreceptors located to the dopaminergic cell bodies
and dendrites but may well be true of a major portion of the
terminal autoreceptors as well. It is therefore natural that the
autoreceptors will have to be geared to a lower concentration
of dopamine than the postsynaptic receptors in order to be
functionally active; most, but perhaps not all (see below), of
the latter are probably exposed to the high dopamine levels
in the synaptic cleft.
The varying responsiveness of receptors to agonists is
sometimes described in terms of "receptor reserve". It is true
that a high responsiveness shows up as a high receptor
reserve, but this term is somewhat misleading, because it
tends to indicate that we are dealing with a variation in
receptor number rather than coupling of the receptor
molecule to other components in the receptor complex. The
latter alternative is probably more relevant because the
supersensitivity induced by denervation develops before any
increase in receptor density.
The higher responsiveness of the autoreceptors, as
compared to the postsynaptic receptors, shows up somewhat
differently for a full than for a partial agonist. In the former
Carlsson et al.
case the preferential activation of the autoreceptors presents
as a biphasic response: in low dosage this activation leads to
behavioral inhibition, whereas in higher dosage the
postsynaptic receptor activation takes over resulting in
behavioral stimulation. For a partial agonist there is enough
agonism to stimulate the autoreceptors and induce behavioral
inhibition, but not enough to stimulate the postsynaptic
receptors to the extent of causing behavioral stimulation.
The response to, for example, (-)-3-PPP will thus be
inhibitory and monophasic. However, in contrast to pure
dopamine receptor antagonists, partial agonists are unable to
bring down the behavioral activity to zero and to induce
catalepsy. Their behavioral inhibition will level out, the
extent of inhibition being inversely related to their intrinsic
activity.
From a clinical point of view the pharmacological profile
of a partial agonist such as (-)-3-PPP, as it shows up in
animal models, would seem attractive for two reasons: first
this agent is unable to induce catalepsy, suggesting a low
liability for EPS as well as other signs of dopaminergic
hypoactivity. Secondly, as a partial agonist it is capable of
antagonizing the hyperactivity induced by a full agonist such
as apomorphine, (+)-3-PPP, and dopamine itself. Thus, if
dopaminergic hyperactivity is involved in schizophrenia, a
partial agonist should be able to alleviate psychosis as
effectively as a pure dopamine receptor antagonist, and this
should be achieved without the risk of inducing severe
hypodopaminergia.
(-)-3-PPP, also called preclamol, has undergone trials
mainly in schizophrenic patients, and been found to possess
antipsychotic activity and to be entirely devoid of
extrapyramidal or any other serious side effects. However, its
antipsychotic activity, although pronounced following
treatment for one week, did not last much longer in spite of
continuous treatment [13]. Possibly, this loss of therapeutic
activity is due to a too high intrinsic activity of this
compound resulting in reduced autoreceptor sensitivity. In
support of this hypothesis, Tamminga had earlier found that
even full dopamine receptor agonists such as apomorphine
and its congener NPA possess antipsychotic properties but
that in that case the antipsychotic action was lost within a
few days [13]. A logical conclusion would thus be that a
partial dopamine receptor agonist with an intrinsic activity
lower than (-)-3-PPP should possess a more long-lasting
antipsychotic activity.
In rats (-)-3-PPP has been able to antagonize catalepsy
induced by haloperidol, which supports its partial agonistic
properties [14]. Likewise, in two different clinical studies
this agent has been found to possess a mild anti-Parkinson
action [15, 16]. Thus, even at the clinical level, (-)-3-PPP
appears to fulfil the criteria for a dopaminergic stabilizer,
that is, it will antagonize both hyper- and hypoactivity of
the dopaminergic system.
Aripiprazole
The Japanese drug company Otsuka, in collaboration
with Bristol-Myers Squibb, has developed aripiprazole,
which is a partial dopamine receptor agonist with a lower
intrinsic activity than (-)-3-PPP [17]. Indeed, this agent has
been found to have antipsychotic properties that seem to be
Schizophrenia: From Dopamine to Glutamate and Back
longlasting, apparently at least up to one year, as far as can
be judged by the now available, limited data. The partial
dopamine agonist profile of this agent has been
demonstrated both in vitro, where it has been shown to
possess a high affinity to dopamine D2 receptors, and in
animals [18]. Moreover, imaging studies in humans show
that therapeutic doses of aripiprazole can yield D2-receptor
occupancies clearly higher than 80 percent without any EPS,
except for a certain degree of akathisia at very high levels of
occupancy [19]. This is in contrast to dopamine receptor
antagonists, which are known to cause EPS at occupancies
above 80 percent, and clearly supports the view that
aripiprazole is a partial dopamine receptor agonist also in
humans. This is further supported by this agent's ability to
reduce rather than increase serum prolactin levels [20]. The
clinical pharmacology of aripiprazole has been reviewed in a
recent paper by Keck and McElroy [21], where it was
concluded that aripiprazole has shown antipsychotic efficacy
both in short-term (4 weeks) and long-term (26 and 52
weeks) controlled trials. As indicated above the risk of
aripiprazole causing EPS seems low and prolactin levels are
not elevated; in addition it does not appear to significantly
alter QTc interval or induce weight gain. Aripiprazole has
recently been introduced on the U.S. and European markets
PARTIAL DOPAMINE RECEPTOR ANTAGONISTS
In the early 1980s, the Carlsson research group
discovered several dopamine D2 receptor antagonists, devoid
of intrinsic activity, which also possess the dopaminergic
stabilizer profile; these agents behave as partial dopamine
receptor antagonists. A partial dopamine receptor antagonist
can be defined as a pure antagonist with an affinity for
subpopulations of postsynaptic dopamine receptors that is so
low that it even in high dosage can only partially displace a
"ubiquitous" D2 receptor high-affinity ligand, leading to an
inability to cause severe hypomotility or catalepsy. The first
agents discovered belong chemically to the aminotetralines.
The work started out with the full dopamine receptor agonist
OH
HO
NH2
DOPAMINE
OCH3
N N
(+)-UH23 2 CH3
SO2CH3
H
N ACR16
(-)-OSU6162
Fig. (1). Structures of dopamine stabilizers.
Current Medicinal Chemistry, 2004, Vol. 11, No. 3 269
(-)-5-hydroxy-2-(n-dipropylamino)tetraline. Addition of a
methyl group in position 1 yielded two different cis-
enantiomers. The (-)-form turned out to be a partial
dopamine receptor agonist and the (+)-form an antagonist
devoid of intrinsic activity. The O-methylated derivative of
the latter had a similar profile and was more metabolically
stable. This agent, called (+)-UH232 (Fig (1)), as well as its
monopropyl (N-n-propyl) analog (+)-AJ76, were
characterized pharmacologically and turned out to have a
dopamine-stabilizing profile, that is, they antagonized the
hyperactivity induced by dopaminergic agonists without
changing the behavioral activity level of normal rats
exploring a new environment to any marked extent.
Moreover, they stimulated the behavior of animals with a
low activity level habituated to their environment and were
devoid of cataleptogenic action. Virtual absence of intrinsic
activity was shown after previous dopamine depletion and in
the GBL model used for testing the activity of dopaminergic
autoreceptors. Moreover, dopamine receptor antagonism
showed up as a strong stimulation of dopamine synthesis,
turnover and release, similar to the action of typical
dopamine receptor antagonists like haloperidol and
chlorpromazine. A compound with this profile would be
expected to possess antipsychotic properties without
producing EPS [22, 23, 24].
(+)-UH232 was brought to clinical testing on healthy
volunteers as well as schizophrenic patients, though only
after single doses. In the former group the drug had some
mixed actions with respect to mood and wakefulness.
However, a rather striking effect was some abnormalities in
perception observed in a number of individuals (illusions
with a trend to hallucinations). In some of the schizophrenic
patients the psychotic symptoms worsened. These effects
may be due to 5-HT2-receptor agonist effects of (+)-UH232
[25].
In spite of this disappointing result it was felt that the
pharmacological profile of (+)-UH232 was intriguing and
clearly worthy of further exploration.
OH
H
N
(-)-3-PPP
CN
H
(-)-DS12 1
SO2CH3
N
270 Current Medicinal Chemistry, 2004, Vol. 11, No. 3
Thus, a further step was taken when the chemists of the
Carlsson group switched from the aminotetraline back to the
phenylpiperidine structure in order to find out if also in the
latter it would be possible to convert a partial agonist such
as (-)-3-PPP into an antagonist, and then perhaps with
"stabilizer" properties. Initially Wikström and coworkers
[26] reported that replacing the aromatic ring hydroxyl group
of (-)-3-PPP with CF3 resulted in a compound with weak
dopamine receptor antagonist properties judged from effects
on dopamine turnover. An increase in motor activity was
observed concomitant with the increased dopamine neuronal
activity and the compound was suggested to be a preferential
dopamine autoreceptor antagonist. Subsequently, the
hydroxyl group of (-)-3-PPP was replaced by other electron-
drawing groups, such as CN or SO2 CH 3 (Fig (1)). The
compounds thus synthesised were (-)-DS121 and (-)-
OSU6162 and they too behaved, biochemically and
behaviorally, as preferential dopamine autoreceptor
antagonists, or as we prefer to call them now partial
dopamine receptor antagonists. Thus, it was concluded that
the replacement of a hydrogen bond donor, such as a
hydroxyl group, on the aromatic ring of (-)-3-PPP to an
electron-drawing group, such as CF3, CN or SO2CH, was
important in converting a partial dopamine agonist to an
antagonist [26, 27]. It should be noted that the racemic form
of DS121 had several years previously been observed to lack
intrinsic activity on dopamine receptors [8]. Both (-)-DS121
1
and (-)-OSU6162, and more recently ACR16 , were
characterized pharmacologically and were found to fulfil the
criteria for a dopaminergic stabilizer. In other words, they
have but slight effect on the behavior of actively exploring
rats but antagonize the hyperactivity induced by
dopaminergic agonists; in animals with low motor activity
following habituation to their environment they induce a
clear-cut, though moderate stimulation, and they are devoid
of cataleptogenic activity. (-)-OSU6162 was brought to
clinical testing and was found to have antipsychotic and
antidyskinetic efficacy (sometimes dramatic) in short term
studies. Long-term studies remain to be done [28].
In conventional receptor binding assays, (-)-DS121 and
(-)-OSU6162 show very low ability to displace a dopamine-
receptor blocking ligand but a stronger ability to displace a
dopamine-receptor agonist [29]. This is remarkable, because
generally agonists are more efficient in displacing agonists
than antagonists, whereas antagonists are more efficient in
displacing antagonists than agonists. As mentioned, (-)-
DS121 and (-)-OSU6162 are devoid of intrinsic activity and
are thus pure antagonists but structurally they are derived
from agonists, and this may explain why they behave as
1 with a Ki around a couple of hundred nM (using an agonist
F. Pettersson, N. Waters, E.S. Waters, A. Carlsson, C. Sonesson. The
development of a new class of dopamine stabilizers. Program No. 894.11*.
N. Waters, A. Carlsson, M.L Carlsson, P. Martin, J. Tedroff, J. Kullingsjö,
F. Pettersson, C. Sonesson, E.S. Waters. Pharmacology of ACR16, a
dopamine stabilizer. Program No 894.13*. H. Ponten, A Carlsson, J.
Kullingsjö, C. Sonesson, E.S. Waters, N. Waters, J. Tedroff. The dopamine
stabilizer ACR16 prevents L-DOPA induced sensitization in the 6-OHDA-
lesioned rat. Program No 787.6*. Abstract Viewer online, Society for
Neuroscience*, 2002. Carlsson ML (2002) E x p e r i m e n t a l
hypoglutamatergia model for cognitive deficits of schizophrenia: Effects
of classical neuroleptics, 5-HT2A receptor blocking antipsychotics, the
ampakine CX516 and the dopaminergic stabiliser ACR16. European
Neuropsychopharmacology 12: (suppl 3) 167-168.
Carlsson et al.
such in the binding assays even in the absence of intrinsic
activity.
Although both partial dopamine receptor agonists and
partial dopamine receptor antagonists fulfil the criteria for
dopaminergic stabilizers, they differ in one potentially
important respect: the partial agonists inhibit normal
exploratory behavior, whereas the partial antagonists are, if
anything, slightly activating on this behavior over a large
dose range; higher doses can decrease motor activity to a
certain degree during the early exploratory phase when the
base-line is high. However, this distinction is observed in
rodents after single doses; whether it remains after repeated
dosage and occur in other species is an open question.
It may seem remarkable that compounds with agonistic
and antagonistic properties may have such similar
pharmacological profiles. A plausible hypothetic explanation
may be the following. In partial agonists the stabilizing
properties are inherent in the partial agonism: at high levels
of endogenous agonist (dopamine) a partial agonist will
antagonize the stimulant action of the agonist. At low levels
of endogenous agonist the partial agonist will add to the
agonism. Regardless of whether the endogenous agonist
level is high or low, the partial agonist will bring the
activity towards the level determined by the intrinsic
activity. In principle this should be true regardless of the
responsiveness of the receptor. However, at a high receptor
responsiveness, like in the case of the autoreceptors, a partial
agonist is more likely to act as an agonist. Therefore, the
situation can occur that a partial agonist acts as an agonist
on the autoreceptors and as an antagonist on the postsynaptic
receptors. In such a case the effect on the autoreceptors and
the postsynaptic receptors will influence behavior in the
same direction and cause inhibition.
Since the autoreceptors are in contact with low
endogenous agonist levels, it should be easier for an
antagonist to compete for the autoreceptors than for the
postsynaptic receptors. Antagonists should therefore have a
preferential action on the autoreceptors, showing up in low
dosage as behavioral stimulation. The reason that the
behavioral influence following interaction with the
autoreceptors is so profound, despite the low concentration
of dopamine molecules at the autoreceptors, is probably a
greater impact per dopamine molecule due to a higher
responsiveness of autoreceptors, which in turn is due to
exposure to much lower dopamine concentrations compared
to the postsynaptic receptors of the synapse. Although this
phenomenon has been described after treatment with full
dopaminergic antagonists, it is not always obvious, possibly
because it may occur only in a narrow dose range. However,
if the affinity for D2 receptors comes down to a certain level,
binding assay), such as has been found for e g (-)-DS121 and
(-)-OSU6162 [29], a separation between binding to
autoreceptors and postsynaptic receptors becomes apparent.
In other words, such compounds can be called preferential
dopamine autoreceptor antagonists, a term that we have
previously used, even though now we prefer to call them
partial dopamine receptor antagonists. In support of the latter
term there are data showing that there is an ability of these
agents to displace a dopaminergic agonist from striatal
binding sites, but that this effect is only partial, compared to
Schizophrenia: From Dopamine to Glutamate and Back Current Medicinal Chemistry, 2004, Vol. 11, No. 3 271

a typical dopamine receptor antagonist such as haloperidol
[30].
Our interpretation of the stabilizer profile of the partial
dopamine receptor antagonists is thus the following: In
normal rats exploring a new environment there is no striking
effect of these agents, because the relatively weak
antagonism on the postsynaptic receptors and the ensuing
mild behavioral inhibition, is counter-balanced by a strong
antagonism on the autoreceptors, which acts in a stimulating
direction. The hyperactivity induced by dopaminergic
agonists probably depends on the recruitment of a large
population of postsynaptic receptors. The partial dopamine
receptor antagonists, although being able to block only a
portion of postsynaptic receptors, can nevertheless prevent a
sufficient recruitment of receptors to lead to behavioral
hyperactivity. In habituated rats the effect of these agents on
the autoreceptors will predominate, and thus a moderate
stimulation will ensue.
In the case of amphetamine-induced locomotor
stimulation, which is effectively antagonised by partial
dopamine receptor antagonists, postsynaptic receptors
located outside the synapse may play an important role (see
Fig (2)). These receptors are normally exposed to extremely
low levels of dopamine and will thus display a high

Fig. (2). Dopaminergic synapse at different activity levels. The size of the arrow indicates the degree of firing activity. Red dots
represent dopamine molecules, blue dots represent apomorphine molecules.
272 Current Medicinal Chemistry, 2004, Vol. 11, No. 3
responsiveness, which means that each dopamine molecule
will have a much greater impact following binding to the
receptor than is the case with intrasynaptic receptors with a
lower responsiveness. Following amphetamine
administration a massive dopamine release will ensue,
resulting in diffusion of some dopamine molecules even to
these extrasynaptic receptors on the postsynaptic neuron.
Here the partial dopamine receptor antagonists will have a
chance to compete, though, because the dopamine
concentrations will still be much lower than in the synapse
under normal circumstances and of course after amphetamine
treatment. Since the interaction of dopamine with the
extrasynaptic sites probably is important for the
hyperactivity response, administration of a partial dopamine
receptor antagonist will in this situation, contrary to the
normal situation where intrasynaptic dopamine probably to a
larger extent determines the behavior, have a large behavioral
impact, effectively bringing motor activity down to normal
levels.
An interesting observation with partial dopamine receptor
antagonists is that they appear to more effectively counteract
amphetamine- than apomorphine-induced hyperactivity [e. g.
23]. A reason for this may be that whereas in the
amphetamine situation the concentration of dopamine
molecules reaching strategic extrasynaptic sites is still
relatively modest and thus readily counteracted by partial
dopamine receptor antagonists, apomorphine administration
will result in a ubiquitous increase in agonist concentration
due to an increased agonist concentration in the extracellular
water phase (see Fig. (2)).
Regarding the concentration of endogenous agonist it is
reasonable to assume that it will vary considerably with the
structure of the junction, and that the highest concentration
will occur in the synaptic cleft, while the lowest
concentrations will be in locations where the distance
between the neurotransmitter releasing structure and the
receptor is the largest.
The pharmacological consequences of these varying
distances could be dramatic. Let us assume that that an
exogenous agonist capable of getting into the brain via the
blood-brain barrier will be equally distributed in the
extracellular water phase of the brain, allowing for a period
of equilibration, and that under resting conditions the degree
of receptor activation, expressed as percent of full activation,
for example 25 percent, is about the same in different
locations, and that finally the affinity of either the
endogenous or the exogenous agonist does not vary between
different locations. In other words, the variations in the
responsiveness of receptors at different locations are due to
factors other than affinity. If we now compare a synaptic
with a non-synaptic location, the concentration of the
endogenous agonist should, under the assumptions given
above, be much higher in the synapse than in the non-
synaptic location. Let us, for the sake of the argument,
assume that it is five-fold higher. If we now look at the
action of the exogenous agonist and assume that it will have
an action equivalent to a doubling of the endogenous agonist
at the non-synaptic site, it will then only be expected to be
equivalent to a twenty percent increase in endogenous
agonist in the synaptic site. We may thus have a simple
explanation of the preferential action of an agonist on the
Carlsson et al.
autoreceptors and thus of the biphasic dose-response curve of
a dopaminergic agonist such as apomorphine or (+)-3-PPP.
However, one would expect an array of examples
demonstrating qualitative changes in the pharmacological
profile of a dopaminergic agonist, depending on the dosage.
For example, the emetic action of apomorphine shows up
already in low dosage, which could be due to the absence of
well-developed dopaminergic synapses in the emetic trigger
zone. Another phenomenon might be explained in a similar
way: with increasing doses of apomorphine behavioral
inhibition switches into stimulation, but the picture of
stimulation will undergo changes. In an intermediate dose
range an increase in locomotor activity predominates. In
higher doses stereotypic activity (compulsive gnawing etc.)
takes over at the expense of locomotion. Locomotion is
initiated predominantly from the nucleus accumbens, that is
a part of the ventral striatum, whereas stereotypies are
probably elicited from the dorsal striatum. As mentioned,
the synapses in the ventral striatum are not so well
developed as in the dorsal striatum. This will provide an
explanation of the differences between drugs in regard to the
balance between actions on the "limbic" versus
"extrapyramidal" systems.
If we now turn our attention from agonist to antagonist
pharmacology, the perspective will become even more
interesting. Let us go back to the above example with the
introduction of an exogenous agonist but replace it by an
antagonist. Let us also assume that following a period of
equilibration the antagonist's concentration in the
extracellular water phase of the brain and its affinity for the
receptor are the same in different locations. Under these
assumptions the action of the antagonist will depend on its
ability to compete with the endogenous neurotransmitter.
This competition will be least successful in locations where
the concentration of the neurotransmitter is the highest, that
is, in the well-developed synapses of, for example, the
dorsal striatum. It will be somewhat more successful in the
ventral striatum, and thus the EPS of a dopamine receptor
antagonist will occur after somewhat higher doses than the
antipsychotic action, which presumably resides in the
ventral, "limbic" striatum. Furthermore, the competition
will be even more successful in the non-synaptic areas, such
as the dendritic dopaminergic regions, and the emetic trigger
area. Certainly the antiemetic effects of dopamine receptor
antagonists show up in low dosage, and signs of behavioral
stimulation, among other things an antidepressant effect,
have been described after treatment with antidopaminergic
agents in low dosage.
In this context the profile of the partial dopaminergic
antagonists is interesting. When this group of compounds -
aminotetralines and phenylpiperidines - are examined
together, there is a clear trend for the molecules to shift from
a typical neuroleptic to a stabilizing profile, when they are
modified in the direction of diminishing the affinity to D2
receptors [30].
GLUTAMATE
For several years considerable interest has focused on the
possible role of glutamate in schizophrenia. One reason for
this is the discovery that phencyclidine (PCP, "angel dust"),
Schizophrenia: From Dopamine to Glutamate and Back
which can induce a psychotic condition mimicking
schizophrenia, perhaps even more faithfully than the
amphetamines, is a powerful antagonist on one of the
glutamate receptor subtypes, namely the NMDA receptor.
This receptor is equipped with an ion channel regulating the
penetration of calcium and other cations into the neuron.
PCP binds to a specific site in this channel, thereby
blocking the function of the receptor. Examples of other
NMDA antagonists that bind to this "PCP”-site are
ketamine and MK-801. There are also competitive NMDA
antagonists available, such as D-CPPene and CGS 19755,
which bind to the same site as glutamate. Another way to
modulate NMDA receptor-mediated activity is via the
associated glycine site, where the mixed agonist-antagonist
D-cycloserine binds and where glycine and D-serine serve
agonist functions [for refs see 31]. Another potentially useful
tool to enhance NMDA receptor-associated glycine
transmission is a glycine transporter 1 inhibitor [see 32].
Strengthening NMDA receptor-mediated transmission by
direct or indirect stimulation of the associated glycine
receptor has for several years been discussed as a possible
treatment strategy in schizophrenia.
In the late eighties we set up a hypoglutamatergia model
of schizophrenia in mice, where we as a rule used MK-801
to interfere with central glutamate activity [33, 34, 35], but
we also observed behavioral effects of competitive NMDA
antagonists in this mouse model that were predictive of their
psychotogenic actions in man [see 36]. Furthermore, we
observed psychotomimetic actions of the glycine antagonist
(+)-HA-966 following local administration into the nucleus
accumbens of mice, results that are in consonance with the
psychotogenic effects reported with D-cycloserine in man
[37, 38]. Interestingly, there is some evidence that the
enhanced dopaminergic tone observed in the active psychotic
phase of schizophrenia (see Introduction) is secondary to
deficient glutamate transmission [39].
Brain glutamatergic systems also interact with serotonin
(5-HT). NMDA receptor antagonists stimulate 5-HT turnover
and induce increased responsiveness of 5-HT2 receptors [25,
40, 41]. This is of special interest in view of the effective
counteraction of the selective 5-HT2A antagonist M100907
on the behavioral stimulation induced by NMDA receptor
antagonism [42].
We also compared the effects of the 5-HT2A receptor
antagonist M100907 in different psychosis models using
haloperidol as reference [42]. Two hyperdopaminergia and
two hypoglutamatergia models were used. M100907 was
found to counteract NMDA receptor antagonist induced
hyperactivity whereas spontaneous locomotion and
dopamine agonist induced hyperactivity were not
significantly affected. Haloperidol, on the other hand,
antagonised both NMDA antagonist and dopamine agonist
induced hyperactivity as well as spontaneous locomotion.
Based on these and previous results we concluded that 5-
HT2A receptor antagonists may be particularly effective in
hypoglutamatergic conditions [including e. g. subgroups of
schizophrenia, autism [see 43] and ADHD [see 44]. The
modest effect of M100907 on spontaneous behavior would
predict a low risk for side effects. Indeed, clinical phase III
trials in schizophrenia conducted by Aventis demonstrated
antipsychotic effect of M100907; in addition, this agent was
Current Medicinal Chemistry, 2004, Vol. 11, No. 3 273
virtually without side effects. These clinical data underline
the relevance and predictive value of our experimental MK-
801 model for schizophrenia and are remarkable in that they
showed for the first time that dopamine D2 blockade is not
obligatory for achieving antipsychotic effect.
In schizophrenia, classical antipsychotic compounds
often alleviate positive symptoms like hallucinations and
delusions but are in general less effective in overcoming
negative and cognitive symptoms with severe consequences
for the patients’ quality of life, hampering vocational and
social rehabilitation [45, 46, 47]. Impaired cognitive
functioning was previously thought to be solely secondary
to the psychosis, or a side effect of antipsychotic treatment,
but is today regarded as a core feature of the disease [46, 47,
48] which may even be manifested in childhood and precede
the onset of psychotic symptoms by many years [49].
Administration of a glutamate antagonist like MK-801
causes a marked primitivization of the behavior. An
interesting serendipity observation we made in the
hypoglutamatergic mice treated with haloperidol and
M100907 respectively, was that whereas both compounds
counteracted MK-801-induced hyperactivity, only M100907
improved the quality of the behavior. Mice receiving MK-
801 in combination with haloperidol looked very similar to
those animals treated with MK-801 only, i. e. they
displayed mainly monotonous, forward locomotion
behavior, whereas the hypoglutamatergic mice treated with
M100907 displayed a more varied, control-like behavior,
although the restoration of behavioral quality was far from
complete.
This observation prompted us to set up an automated
video system for characterization and quantification of the
behavioral pattern of hypoglutamatergic animals. We
hypothesised that the MK-801-induced primitivization of
behavior might correspond to cognitive deficits of
schizophrenia and that this might be a good model to screen
for new compounds that could be developed to treat
cognitive symptoms of schizophrenia.
Experimental Hypoglutamatergia Model for Cognitive
Deficits of Schizophrenia
NMDA receptor antagonist-induced hyperactivity in
rodents has become a popular model of schizophrenia, and
there is reason to believe that this hyperactivity may
correspond to the positive symptomatology of this disorder.
As mentioned above, NMDA receptor antagonist treatment
also causes a behavioral primitivization, which may
correspond to cognitive deficits of schizophrenia. Therefore,
we characterize and quantify changes in behavioral pattern
induced by NMDA receptor antagonists, using an automated
video tracking system. Mice are treated with a glutamate
antagonist, e g MK-801, before being introduced into an
unfamiliar, diffusely illuminated arena and video taped from
above. The video tapes are analyzed with the video tracking
system EthoVision from Noldus Information Technologies.
What we then find is that MK-801, apart from causing
hyperactivity, wipes out or markedly weakens other
components of normal mouse behavior. This is reflected in
the behavioral variables we measure as a decreased number of
turnings per cm moved, a reduced number of switches
274 Current Medicinal Chemistry, 2004, Vol. 11, No. 3 Carlsson et al.

between the states "moving"and "stationary”, reduced rearing
(= rising on hind legs) frequency, reduced grooming
behavior and a reduced variation in the digitised video image
of the animals’ body size seen from above. What we see, in
short, in these hypoglutamatergic animals is a severely
impoverished behavioral repertoire.
Effects of Classical Neuroleptics vs Antipsychotics with
Strong 5-HT2A Relative to D2 Receptor Antagonism on
Behavioral Quality in Hypoglutamatergic Mice
In an attempt to validate our model we have compared
traditional neuroleptics with a new generation
antipsychotics, based on the view that while the old
compounds are often either ineffective against or may even
worsen cognitive symptoms [45], the newer agents seem to
cause partial relief [45, 46, 50]. This is obviously an
intensely debated issue, and exceedingly difficult to
penetrate for a number of reasons [see e. g. 51]. The
consensus at present nevertheless seems to be that the new
agents with lower D2 receptor affinity often combined with
substantial 5-HT2 receptor blockade have beneficial, albeit
modest or moderate, effects on cognitive deficits of
schizophrenia, although it should be noted that such
beneficial effects on cognition have also been observed
following low dose haloperidol treatment [52]. It has been
suggested that there may be some specificity in how the
different agents affect various cognitive symptoms [e. g. 45,
49] but needless to say considerably more research is needed
before we can tell if different modern antipsychotics indeed
target specific cognitive symptoms.
In our model, the classical neuroleptics haloperidol,
chlorpromazine and trifluoperazine administered in doses
that reduced hyperactivity in hypoglutamatergic mice to
control levels were unable to restore behavioral diversity.
This is illustrated e. g. by their inability to restore
variability in body area (Fig. (3)) as well as by their
inability to improve the quality of the ethograms in
hypoglutamatergic mice (Fig. (4)); [53]. The body area is
perceived as large by the camera when the animals engage in
forward locomotion and as small when the animals engage
in rearing, grooming and digging and these latter behaviors
are abolished or attenuated by MK-801. In contrast to
conventional neuroleptics, various antipsychotic compounds
with pronounced 5-HT2A receptor-blocking properties, i. e.
compounds with strong serotonin(5-HT)2A receptor
blockade in relation to the dopamine (DA) D2 receptor
blockade, increased behavioral complexity in MK-801-
treated mice in doses that reduced MK-801-induced
hyperactivity to control levels, as evident from the
ethograms seen in Fig. (4 ), but, like the classical
neuroleptics they were unable to restore variability in body
area (Fig. (3)). The compounds tested from this latter
category were clozapine, risperidone, olanzapine, ziprasidone
and the selective 5HT2A receptor antagonist M100907. The

Fig. (3). Effects of haloperidol (0.2, 0.5 mg/kg), chlorpromazine (0.3, 0.9, 1.2 mg/kg), trifluoperazine (0.33, 1, 3 mg/kg), clozapine
(0.05, 0.4, 3.2 mg/kg), risperidone (0.01, 0.03, 0.09 mg/kg), olanzapine (0.083, 0.25, 0.75 mg/kg), ziprasidone (0.33, 1, 3 mg/kg),
M100907 (0.001, 0.01, 0.1 mg/kg) and ACR16 (8, 20, 50 µmol/kg) on the MK-801 (0.2 mg/kg) induced decrease in body area
variation in mice at two different time intervals. *p<0.05 compared to MK-801, +p<0.05 compared to controls (Mann-Whitney U-
test)2 .
Schizophrenia: From Dopamine to Glutamate and Back
reason we chose to compare the different antipsychotic
compounds in doses that restored hyperactivity to control
levels, is that we believe that MK-801-induced hyperactivity
corresponds to positive symptomatology of schizophrenia.
In other words, we wished to see if the different
antipsychotic agents tested, in addition to controlling
"positive symptoms”, could affect cognitive status as
reflected by behavioral complexity level. The antipsychotic
compounds with strong 5-HT2A receptor antagonism in
relation to their DA D2 receptor antagonism increased
behavioral complexity in hypoglutamatergic mice with
respect to horizontal (e. g. spontaneous turning), but not
vertical (rearing) measures. Olanzapine seemed to be
somewhat superior to the other compounds in restoring
behavioral quality, which is interesting in view of a recent
report [50] showing some advantage of olanzapine over both
haloperidol and risperidone with respect to cognitive
functions in schizophrenia.
Current Medicinal Chemistry, 2004, Vol. 11, No. 3 275
Effects of the Dopaminergic Stabilizer ACR16 on
Behavioral Quality in Hypoglutamatergic Mice
The dopaminergic stabilizer ACR16, developed by
Carlsson Research, was also tested in hypoglutamatergic
mice. As described above, dopaminergic stabilizers are
compounds that are able to counteract both hypo- and
hyperdopaminergia, and, in consequence, both hypo- and
hyperactivity. In contrast to currently used antipsychotic
agents, the risk for causing dysphoria and anhedonia is
probably low.
ACR16 counteracted the MK-801-induced
primitivization of the behavior, apparently even more so
than M100907 and the other antipsychotic compounds with
strong 5-HT2A receptor blockade [Figs (3), (4)]. Most
importantly, it influenced aspects of the behavior that were
not restored by the 5-HT2A receptor blocking
antipsychotics. For instance, ACR16 partly restored rearing
in the hypoglutamatergic mice and this is the first time we
276 Current Medicinal Chemistry, 2004, Vol. 11, No. 3 Carlsson et al.

(Fig. 4). contd.....

Fig. (4). Effects of haloperidol, chlorpromazine, trifluoperazine, clozapine, risperidone, olanzapine, ziprasidone, M100907 and
ACR16 on the MK-801 (0.2 mg/kg) induced primitivization of the movement pattern in mice at two different time intervals.
Whenever possible, tracks from mice treated with the test compounds were chosen among individuals having motor activity levels
similar to controls to facilitate comparisons2.

make this observation following administration of an
established or potential antipsychotic agent [54]. Since we
consider explorative rearing as one of the most sophisticated
components of rodent behavior we deem this to be an
important finding.
2 Experimental hypoglutamatergia model for cognitive deficits of
These data have previously been published in/presented at: M. Nilsson,
S. Waters, N. Waters, A. Carlsson, M.L Carlsson: A behavioural pattern
analysis of hypoglutamatergic mice - effects of four different
antipsychotic agents, J Neural Transm. 2001;108(10):1181-96; Stockholm
autism patient association, February 2002; 4th International Conference
on Methods and Techniques in Behavioral Research, Amsterdam, August
2002; First Arvid Carlsson Symposium, Göteborg, September 2002; “The
ACR16 has been found safe in phase I studies on healthy
volunteers. In an open study involving seven patients with
Parkinson’s disease, ACR16 showed efficacy against L-
role of comorbidities in the causation of neurodevelopmental disorders”,
The Novartis Foundation, London, November 2002; Carlsson, M.L.
schizophrenia: Effects of classical neuroleptics, 5-HT2A receptor
blocking antipsychotics, the ampakine CX516 and the dopaminergic
stabiliser ACR16, European Neuropsychopharmacology, 2002, 12 (suppl
3), 167-168/15 t h Congress of the European College of
Neuropsychopharmacology, Barcelona, October 2002.
Schizophrenia: From Dopamine to Glutamate and Back
DOPA-induced dyskinesias. ACR16 is currently undergoing
clinical testing in schizophrenia.
ACKNOWLEDGEMENTS
The present study was supported by grants from the
Swedish Medical Research Council (9067).
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