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Introduction
(-)Stepholidine (SPD) is one of the active ingredients of the Chinese herb Stephania intermedia and belongs to the tetrahydroprotoberberines
(THPBs)[1], which consist of a four-ring main structural backbone with substituents at the two
benzene rings (Figure 1). SPD is characterized by two _OH in the
C2 and C10 position and two
_OCH3 in the C3 and
C9 position. Receptor binding studies have shown that SPD has a relative high affinity for the
D1 (Ki of 13 nmol/L) and less affinity for the
D2 (Ki of 85 nmol/L)
receptors[2]. Electrophysiological studies have shown that SPD induces depolarization inactivation of
dopaminergic cells in the ventral tegmental area
(A10) but not in the substantia nigra
(A9)[3]. This pattern is characteristic of
some atypical antipsychotics, such as clozapine and
thioridazine[4,5], although the newer antipsychotics such as risperidone
and ziprasidone do not seem to selectively affect the
A10 cell group[6].
Moreover, SPD also shows antipsychotic-like activity
in several behavioral experiments. Thus it reverses apomorphine-induced stereotyped behaviour and induces a weak,
short-lasting catalepsy[7]. In addition, SPD reverses amphetamine-induced or
D2 selective agonist-induced rotations in 6-OHDA
lesioned rats[8] and increases serum prolactin
levels[9]. In an experiment with forskolin-induced stimulation of adenylate
cyclase activity, SPD did not affect the formation of cAMP, but it reversed the dopamine-induced inhibition, which is
mediated via D2 receptors[10]. SPD also reverses the apomorphine-induced inhibition of firing of the
A9 dopaminergic neurons[11] and of
A10[12]. All of these data point to a dopamine
D2 antagonistic effect of SPD.
Interestingly, by itself SPD induces contralateral rotations and enhances the effects of apomorphine in 6-OHDA lesioned
rats, suggesting an agonistic action[8]. In addition, SPD increases the production of cAMP by stimulating the
Gs protein [13], and increases the phosphorylation of
DARPP-32[14]. This strongly suggests that in addition to its
D2 antagonistic properties, SPD is a dopamine
D1 agonist, thus giving it a unique pharmacological profile. Further studies have shown that SPD has
D1 agonistic effects on the firing activity in the medial prefrontal
cortex[15] and D1 agonistic/D2 antagonistic effects in the nucleus
accumbens[16]. Taking into account all of these data, it can be suggested that SPD represents a novel antipsychotic drug.
Indeed preliminary clinical studies seem to underline this
presumption[17].
The aim of the present study was to investigate whether SPD indeed shows antipsychotic-like actions in established
animal models for schizophrenia. Therefore we compared the effects of SPD with those of haloperidol and clozapine in two
different behavioural paradigms: (1) the paw test and (2) drug-induced disruption of prepulse inhibition. The paw test was
developed approximately 20 years ago in an attempt to differentiate between classical and atypical
antipsychotics[18]. In this test, a rat is placed on a platform with its fore- and hindlimbs extended through four holes. The dependent parameters are the
retraction times for the fore- and the hindlimbs. Results from a large series of pharmacological studies show that all
antipsychotics increase the hindlimb retraction time, and only the classical antipsychotics affect the forelimb retraction
time[19_21], thus allowing a differentiation between classical and atypical antipsychotics.
The reversal of a drug-induced prepulse inhibition deficit is an extensively used model for identifying (novel)
antipsychotic compounds. Although many different drugs can disrupt prepulse inhibition, especially the disruption induced by
dopamine agonists or glutamate antagonists has been used in antipsychotic
research[22]. With respect to the former, it has
been shown that all antipsychotics reverse the prepulse inhibition deficit induced by dopamine agonists such as
apomorphine[22,23]. The reversal of glutamate antagonist induced disruption by antipsychotics is less obvious. Thus, whereas most
authors agree that classical antipsychotics are
ineffective[24_28],
some[29_31] but not
all[24,26,32,33] have found that clozapine can
reverse the effects of glutamate antagonists.
Material and methods
Rats and housing Male Wistar rats weighing between 230 and 300 g were used (Central Animal Laboratory, Nijmegen, the
Netherlands). The rats were housed in groups of 2 or 3 rats in standard Macrolon cages until the day prior
to the experiment, in temperature controlled rooms (23±1 oC). The rats were maintained on a standard 12 h light-dark cycle (lights on from 7:00
AM to 7:00 PM), and had free access to food and water, except during the experiment. Animals were only used once
throughout the experiment.
Paw test The paw test was performed using a Perspex platform measuring 30 cm×30 cm, with a height
of 20 cm. The top of the platform had two smaller holes of 4-cm diameter for the forelimbs, two larger holes of 5 cm diameter for the hindlimbs and
a slit for the tail[18]. The paw test was performed 30 min after intraperitoneal administration of the solvent or the drug by taking
the rat behind the forelimbs and carefully lowering the hindlimbs in the holes, followed by the forelimbs. The Forelimb
Retraction Time (FRT) was defined as the time it took the rat to withdraw one forelimb. Likewise, the Hindlimb Retraction Time
(HRT) was defined as the time it took the rat to withdraw one hindlimb. For both FRT and HRT the minimum was set to 1 s and
the maximum to 30 s. The paw test was repeated at 40 and 50 min after the injection. As there were no statistically significant
differences between the scores at 30, 40 and 50 min, the average FRT and HRT was calculated as the mean of the three
measurements.
Startle paradigm The prepulse inhibition experiments were performed in four startle chambers (San Diego Instru-ments,
San Diego, CA, USA). The chambers contained a plexiglass tube (diameter 8.2 cm, length 25 cm) mounted on a plastic frame,
under which a piezoelectric accelerometer was attached. This device recorded and transduced the motion of the tube, which
was then sent to a computer. The whole device was placed inside a sound attenuating chamber. After the rats were placed
in the startle box, they were allowed to habituate to the tube and the background noise (70 dB) for 5 min. After this period they
were subjected to a prepulse inhibition session. In this session, rats received 10 startle trials, 10 no-stimulus trials and 30
prepulse inhibition trials. The startle trials consisted out of a 30 ms 120 dB burst of white noise. The prepulse inhibition trials
consisted of a 30 ms white-noise burst of 73, 75, or 80 dB followed, 100 ms
later, by a 30 ms white noise burst of 120 dB. Each
prepulse intensity was presented 10 times. During the no-stimulus condition only the background noise was presented. The
50 trials were pseudo-randomly presented with different inter-trial intervals (between 10 and 20 s). The resulting movement
of the rat was recorded for 100 ms, starting at the onset of the 120 dB stimulus, with a sampling frequency of 1 kHz. Basal
startle amplitude was calculated as the mean of the 10 startle trials. As there were no prepulse intensity×drugs interaction for
any of the drugs tested (data not shown), we decided to only show the mean prepulse inhibition. This was calculated
according to the formula PPI=100×[1_(PP73+ PP75+PP80)/3×P120], in which PP73, PP75, and PP80 are the startle response of
three different prepulse trials and P120 the startle response of the startle trial.
Drugs SPD (1_16 mg/kg, obtained form the Shanghai Institute of Materia Medica, Chinese Academy of Sciences), and
clozapine (5_40 mg/kg, Sigma, Zwijndrecht, the Nether-lands) were dissolved in a small amount of 1 mol/L HCl, and diluted to
the appropriate concentration with saline. Finally the pH was adjusted to 4_5 by adding
NaHCO3. Haloperidol (0.25_2 mg/kg, Janssen, Beerse, Belgium) was dissolved in lactic acid and diluted with saline to the appropriate concen-trations.
Apomorphine (0.5 mg/kg, Brocades, ACF, the Netherlands) and MK801 (0.5 mg/kg, Sigma, Zwijndrecht, the Netherlands) were
dissolved in saline. In the paw test, all drugs were injected intraperitoneally 30 min before the experiment, in analogy with
previous papers, to obtain a signi-ficant reduction in motor
behaviour[18]. In the prepulse inhibi-tion experiments, solvent,
haloperidol, clozapine or SPD was injected intraperitoneally, 15 min before the test, in analogy with previous papers, in order
to not influence the basal motor activity too
much[34]. Immediately before the test, rats received a subcutaneous injection
with solvent, apomorphine or MK801. The time points were chosen on the basis of our previous experiments.
Statistics As FRT and HRT give non-parametric scores, data are represented as mean±SD and drug differences were
analysed with the Mann-Whitney U test. Differences in basal startle amplitude and prepulse inhibition were analysed with
a one way analysis of variance (ANOVA). In addition, Swerd-low et al suggested that analysis of the raw startle data would
give a better indication of a change in
gating[35]. Therefore, we also analysed the raw startle data for the startle alone and the
three prepulse intensities using a mixed ANOVA with prepulse intensities as within subject variable and drug treatment as
between subject variable.
Results
Effect of SPD, haloperidol and clozapine in the paw test All three drugs dose-dependently increased the HRT.
Haloperidol also potently increased the FRT, whereas clozapine in the dose range tested did not affect FRT. SPD slightly increased
FRT but only at the highest dose. Statistical analyses confirmed that SPD significantly increased HRT from a dose of 2
mg/kg. Only at 16 mg/kg did SPD significantly increase FRT. Haloperidol significantly increased both FRT and HRT at doses of
0.5 mg/kg and higher. Clozapine significantly increased HRT at all doses tested, but did not affect FRT at any of the given
doses (Figure 2).
Prepulse inhibition Apomorphine significantly increased basal startle amplitude
(F(1,22)<9.2; P<0.01), and significantly
reduced prepulse inhibition
(F(1,22)=27.8; P<0.01). Analysis of the raw startle data showed that there was a significant
drug×trial interaction
(F(3,66)=5.7; P<0.005). SPD did not significantly affect the basal startle amplitude of apomorphine
(F(3,32)<1). However, SPD did significantly reverse the effect of apomorphine on prepulse inhibition (Figure 3B, F(3,32)=
8.2; P<0.01). Post hoc LSD analysis showed that both 8 and 16 mg/kg were significantly different from apomorphine alone.
Analysis of the raw data showed a small but not significant drug × trial interaction
(F(9,96)=1.85; P=0.06) (Figure 3).
Again, apomorphine increased the basal startle response
(F(1,22)=8.9; P<0.01) but decreased prepulse inhibition
(F(1,22)=26.4; P<0.01). The analysis of the raw data again showed a significant drug × trial interaction
(F(3,66)=6.1; P<0.01). When
combined with apomorphine. clozapine significantly reversed the apomorphine-induced disruption of prepulse inhibition
(F(2,25)=3.5; P<0.04), and the basal startle amplitude
(F(2,25)= 6.6; P<0.01). Post hoc analysis showed that both doses of clozapine
significantly reversed the effects of apomorphine on prepulse inhibition. Analysis of the raw data showed again, as in the
case of SPD, that there was a nonsignificant drug×trial interaction
(F(6,75)=1.8; P=0.1) (Figure 4).
Apomorphine reduced prepulse inhibition
(F(1,22)=15.2; P<0.01) without affecting basal startle amplitude
(F(1,22)=1.1; P>0.3). Analysis of the raw data showed a small, but significant drug×trial interaction
(F(3,66)= 2.8; P<0.05). Like SPD
and clozapine, haloperidol reversed the
apomorphine-induced disruption of prepulse inhibition
(F(2,25)=14.9; P<0.001). Post-hoc
analysis showed that both doses of haloperidol significantly reversed effects of apomorphine on prepulse inhibition.
AnalyP>
0.1; Figure 8: F(1,22)=1.1; P>0.3), but significantly reduced prepulse inhibition (Figure 6: F(1,22)=37.5; P<0.001; Figure 7: F(1,22)=34.3; P<0.01; Figure 8: F(1,22)=30.9; P<0.01). Analysis of the raw startle data showed a significant drug×trial interaction
(Figure 6: F(3,66)=12.4; P<0.01; Figure 7: F(3,66)=11.6;
P<0.001; Figure 8: F(3,66)=9.9; P<0.01).
In contrast to the effects on apomorphine, neither cloza-pine
(F(3,32)>1) nor haloperidol
(F(2,25)=1.6; P>0.2)
significantly altered this MK801-induced reduction in prepulse inhibition. Although SPD altered the effects of MK801 significantly
(F(3,32)=4.1; P<0.02), inspection of Figure 6 shows that it actually potentiated the effects of MK801. Post hoc analysis showed that this effect of SPD was significant for all doses tested. Analysis of the raw startle data showed
that there was a significant drug×trial interaction
(F(9,96)=2.9; P<0.008).
Figure 9 shows the effects of SPD when administered alone. Statistical analysis and inspection of the figure shows that
SPD did not affect basal startle amplitude
(F(3,31)=1.2, P> 0.35), nor prepulse inhibition
(F(3,28)<1). Likewise clozapine and
haloperidol did not significantly affect basal startle amplitude or prepulse inhibition (Data not shown).
Discussion
SPD represents a novel compound with
D1 agonistic and D2 antagonistic dual
action[17]. Because it was found to reverse
dopamine agonist-induced behaviours in several paradigms, we decided to compare SPD with the standard classical
antipsychotic haloperidol and the standard atypical antipsychotic clozapine in two paradigms with known validity for detecting
antipsychotic drugs. The data show that SPD indeed behaved like an antipsychotic with more similarity to clozapine than to
haloperidol.
In the paw test, SPD, clozapine and haloperidol dose-dependently increased the HRT. It has been shown that all
antipsychotic drugs affect the
HRT[19,21,36]. However, when investigating the FRT there were clear differences; where
haloperidol potently increased the FRT, SPD only increased this parameter at the highest dose tested, and clozapine did not affect
FRT at all. The effects of clozapine and haloperidol correspond with previous
results[34,36]. The profile of SPD is similar to that
of other atypical antipsychotics, including clozapine, thioridazine, olanzapine, quetiapine and
risperidone[18,19,37]. At present it is difficult to explain the atypical profile of SPD in the paw test. Previous research has shown that anticholinergics and
serotonin antagonists can reverse the effects on haloperidol on the forelimb retraction time, thus leading to an atypical profile
like clozapine and SPD[20,38]. However, SPD has only a weak affinity for
5-HT1 or 5-HT2 receptor, and shows no affinity for
muscarinic Ach receptors[39]. In contrast, SPD has
D1 agonistic properties and this receptor has also been shown to influence
the FRT. Although the partial agonist SKF38393 was unable to significantly reduce the effects of haloperidol on the
FRT[40], a subthreshold dose of the
D1 antagonist SCH39166 significantly enhanced the haloperidol induced increase in
FRT[41]. These data indicate that there is a cooperative action
between D1 and D2 receptors in regulating the FRT. This might explain why SPD
does not influence the FRT (except at high concentrations). Its
D1 agonistic properties might counteract its
D2 antagonistic properties. Reasoning along these lines, at high doses the
D2 antagonistic properties could be strong enough to induce a
small increase in FRT. Further experiments, using a more selective full
D1 agonist might shed more light on the exact nature
of the D1-D2 interaction in regulating the FRT.
Apomorphine is known to strongly disrupt prepulse inhibition and it has been shown that all known antipsychotics
reverse this apomorphine-induced disruption of prepulse
inhibition[22,23,36]. The present study confirms that haloperidol and
clozapine can dose-dependently reverse the effects of
apomorphine[34]. Like these two antipsychotics, SPD also reversed the
apomorphine induced disruption in prepulse inhibition (Figure 3), suggesting that SPD also has antipsychotic effects. SPD
did not significantly alter the prepulse inhibition by itself, although it did tend to reduce the basal startle amplitude. This is
not an uncommon finding with other D2 antagonists, although sometimes a small increase in prepulse inhibition is
observed[34].
Like dopamine agonists such as apomorphine and amphetamine, glutamate antagonists, especially non-competitive
antagonists such as ketamine, MK801 and phencyclidine, can reduce prepulse
inhibition[27,36,42,43]. In the present study we
used MK801, which also significantly reduced the prepulse inhibition. However, in contrast to the disruptive effects of
apomorphine, those induced by MK801 appeared to be resistant to pretreatment with haloperidol, clozapine and SPD. The
failure to reverse the MK801-induced disruption of prepulse inhibition by haloperidol is in general agreement with the
published literature[22,27,36]. The situation is less clear with respect to the effects of clozapine on the glutamate
antagonist-induced disruption of prepulse inhibition. As discussed in the Introduction, both reversal and
non-reversal[24,26,32,33] have been described in previous studies. Our data show that in our set-up clozapine also failed to reverse the MK801-induced
disruption of prepulse inhibition. Likewise, SPD did not reverse the effects of MK801. In fact, it enhanced the effects of
MK801. Although the effect was only small, this might be because of a ceiling effect, as the effects of MK801 by itself were
already rather strong. So far, to our knowledge, this is the first time that a (potential) antipsychotic increased the effects of
MK801. It would be interesting to see whether this also applies to other behavioural effects of MK801, such as motor
stimulant effects.
In summary, SPD showed the preclinical profile of an atypical
antipsychotic[44]; it increased HRT, but had little influence
on the FRT in the paw test, and dose-dependently reversed the apomorphine-induced disruption of prepulse inhibition. Even
though it has a profile more similar to clozapine than to haloperidol there were some differences, most notably the
enhancement of MK801 induced a decrease in prepulse inhibition. These data therefore suggest that SPD might be a unique novel
antipsychotic. Indeed, SPD seems to be the only drug so far known in which both
D1 agonist and D2 antagonist properties
are combined. It has been suggested that
D1 receptors, especially in the prefrontal cortex might be involved in a number of the
cognitive deficits of schizophrenia, such as impaired working
memory[45] and in
attention[46]. Moreover, some deficits in
prefrontal D1 functioning have been observed in
schizophrenia[47_49] and they appear to be related to working memory
deficit[50]. Unfortunately, so far, the effects of SPD in an animal model for negative symptoms or cognitive deficits have not been
investigated. In addition, large-scale clinical trials will have to be performed to substantiate this claim.
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