Effects of phencyclidne (PCP) and (+)MK-801 on sensorimotor gating in CD-1 mice

Prq.

Neurc-Psychophczm~ocd.

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Vol. 22,

pp. 129-146

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EFFECTS OF PHENCYCLIDINE (PCP) AND (+)MK-801 SENSORMOTOR GATING IN CD-l MICE

ON

PETER CURZON AND MICHAEL W. DECKER

Neuroscience Department, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL USA.

(Final form, October 1997)

Curzon, Peter and Michael W. Decker: Effects of phencyclidine (PCP) and (+)MK-801 on sensorimotor gating in CD-l mice. Prog. Neuropsychopharmacol. & Biol. Psychiat. 1998, 22. PP. 129-146. @1998Elsevier Science Inc. 1.

Male CD-1 mice were tested for prepulse inhibition (PPI) following admistration of PCP and the PCP site ligand, (+)MK-801, as well as the dopamine (DA) agonist (-)-apomorhine and DA releaser d-amphetamine. Similar to reports in rats, PCP (0.36 -36.0 pmol/kg), (+)MK-801 (0.03-3.0 pmol/kg), (-)-apomorphine (3.3 and 10.0 PmoVkg) and d-amphetamine (3.0 and 8.0 pmol/kg) significantly reduced PPI when administered prior to testing.

2.

Because PCP also binds to sigma receptors, the authors tested the sigma ligand (+)-3-PPP at (118 pmol/kg) which marginally increased the PPI.

3.

Haloperidol (1 .l pmol/kg) pretreatment attenuated the reduction in PPI following (-)-apomorphine (10.0 pmol/kg), however no effects of haloperidol or clozapine pretreatment on (+)MK-801 disruption of PPI were observed.

4.

Because of the pharmacological similarities between mouse data and previously published rat data, it is concluded that the mouse is a viable alternative to the rat for testing PPI.

m: acoustic startle, amphetamine, apomorhine, (+)-MK-801, mice, phencyclidine, prepulse inhibition, schizophrenia. . . m: dopamine (DA) n-methy-d-aspartate (NMDA) phencyclidine (PCP) prepulse inhibition (PPI)

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P. Curzon and M.W. Decker

Abuse of phencyclidine (PCP), which binds in the NMDA receptor channel, or d-amphetamine, an indirect dopamine (DA) agonist, produces a psychomimetic state similar to schizophrenia (Javitt, 1987). The use of PCP has been put forward as a model for schizophrenia (Javitt and Zukin, 1991; Snyder, 1988) and it has been shown that schizophrenics have a deficit in sensorimotor gating (Bolino et al., 1994; Braff et al., 1992; Cadenhead et al., 1993), as measured by prepulse inhibition (PPI). In rats, compounds binding to the PCP site (Mansbach, 1991; Mansbach and Geyer, 1989) and DA agonists such as d-amphetamine and (-)-apomorphine (Swerdlow et al., 1986; Swerdlow et al., 1990b) disrupt PPI of acoustic startle.

However, in contrast to the large number of studies on the

pharmacology of PPI conducted in rats, relatively little work has been done with mice. Our aim was to assess the effects in mice using some of the compounds which have been shown to be disruptive in the rat.

The PPI procedure in the rat requires several days of habituation to achieve stable results. In order to find a rapid, less expensive model that does not require large quantities of novel compound the authors examined whether mice would produce similar results to rats in PPI. Mice have been used in acoustic startle (Collins et al., 1986; Willott and Carlson, 1995) but have not been used to any great extent in PPI. In order to validate the mouse model the authors repeated some of the published drug studies involving rats.

Previous work in rats has shown disruptions of the PPI can be produced by PCP, (+)MK801 (Johansson et al., 1994; Johansson et al., 1995, Mansbach, 1991, Mansbach and Geyer, 1989; Reijmers et al., 1995) and d-amphetamine (Mansbach et al., 1988; Ott and Mandel, 1995, Swerdlow et al., 1991). PCP is known to bind within the ion channel linked to the Nmethyl-D-aspartate (NMDA) selective glutamate receptor as well as to the sigma receptor (Largent et al., 1986; Quirion et al., 1987, Sonders et al., 1988) a site that has high affinity for haloperidol. However, PCP is known to bind to yet another PCP sensitive site that is not coupled to the NMDA receptor (Rao et al., 1990a, Rao et al., 1990~) that has been associated with the dopamine reuptake carrier (Rothman et al., 1989). In rats, the effects of dopaminergic agonists (Swerdlow and Geyer, 1993) can be reversed by the dopamine antagonist haloperidol and the atypical antipsychotic clozapine (Swerdlow and Geyer, 1993; Swerdlow et al., 1990a) but haloperidol does not alter PCP and (+)MK-801 induced disruption

PCP and (+)MK-80 1 on sensorimotor gating in CD- 1 mice

131

of PPI (Keith et al., 1991). This leads to the suggestion that the PPI disruption by PCP is NMDA receptor mediated.

Therefore to compare the mouse with results observed in the rat, the authors tested PCP and (+)MK-801 for disruption of PPI as well as d-amphetamine and the DA agonist (-)-apomorphine. Because PCP also binds to the sigma receptor the authors also tested the sigma ligand (+)3-PPP. Antagonism of PPI disruption of (-)-apomorphine with haloperidol and antagonism of (+)MK-801 disruption of PPI with haloperidol and clozapine was also examined.

Animals;

Male CD-1 mice, were obtained from Charles River, Portage Ml. The mice weighed between 28-40 g at the time of testing and were housed 14/cage with water and food available ad. libitum. ADDW&&

and Methods:

Eight San Diego Instruments (San Diego, CA) standard W-LAB startle response chambers with a small animal enclosure were used. Each mouse was placed in a Plexiglas cylinder (5.0 cm in diameter x 12.8 cm long) attached to a rigid frame, contained in a sound deadening, lighted, ventilated enclosure. Background noise and acoustic stimuli were delivered from a loudspeaker directly above the mouse. Startle responses, reflected by each movement immediately following the auditory stimulus, were measured for a period of 100 ms by a piezoelectric cartridge attached to the underside of the cylinder. The output was converted into a digital record by the interface. A HP Vectra computer controlled the timing of the stimuli and recorded the data output.

Sound levels were calibrated by a Radio Shack (Allied

Electronics) Sound Level Meter #33-2050 on slow response, “A” weighting. The background noise level was set at 65 dB. Animals were given a 5 min adaptation period after which the session started with three 120 dB, 40 ms sound bursts (not included in the analysis). Then, acoustic startle trials consisting of either the 120 dB acoustic startle stimulus alone, or the 120

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P. Curzon and M.W. Decker

dB preceded (100 ms) by acoustic prep&e

stimuli (30 ms) at levels between 5 and 15 dB

above background were presented in a quasi random order. A variable 25 s (min 10 max. 30 s) interval was interposed between trials.

PCP (phencyclidine hydrochloride), d-amphetamine sulfate and (-)-apomorphine hydrochloride were obtained from Sigma Chemical Co., St. Louis, MO. Haloperidol, clozapine, (+)-9PPP hydrochloride and (+)MK-801 hydrogen maleate were obtained from Research Biochemicals International (Natick, MA). (-)-apomorphine was dissolved in distilled water. Haloperidol and clozapine were dissolved in approximately 30 ul of glacial acetic acid, diluted with saline and the pH adjusted to 6.0 with 1N NaOH. All other drugs were dissolved in saline 0.9%.

Experiments were conducted with with PCP (0.36, 1.l,3.6, 11.O and 36.0 f.tmoWkg),(+)MK801(0.03, 0.09, 0.3, 0.9 and 3.0 umol/kg) and (+)-3-PPP (39.0 and 118.0 umol/kg) injected 15 min prior to testing. In the case of d-amphetamine (0.3, 0.8, 3.0, and 8.0 umol/kg i.p.) a 30 min pretreatment time was utilized and (-)-Apomorphine was injected S.C. 10 min prior to testing. Time course experiments were conducted with PCP (11 .O umol/kg ) and (+)-MK-801 (0.9 umol/kg) in which separate groups of mice were tested 15, 30, 60, and 120 min post treatment. For blockade experiments, mice were treated i.p. with haloperidol (0.1 or 1.l umot/kg) 15 min prior to (-)-apomorphine (0.10 umol/kg s.c.) and tested 10 min later. Mice were also treated i.p. with haloperidol (0.1 or 1.1 umol/kg), and in a separate study with clozapine (0.3 or 0.9 prnol/kg), 15 min prior to(+)-MK801 (O.Sumol/kg i.p.) and tested 30 min later. Statistical Analvsis

The data on prepulse trials are expressed as a mean percent of baseline startle, calculated as [( startle response with PPVthe startle response without PPI) x 1001. Although different dB levels of prepulse were used for testing, for clarity, the data are presented as an overall effect of PPI. Thus, a higher percent represents a disruption of prepulse inhibition and a lower PPI.

PCP and (+)MK-801 on sensorimotor gating in CD-l mice

133

Data were analyzed with repeated-measures one-way ANOVA. Comparisons were assessed using Fisher’s protected least significance difference test (PLSD).

Results Following the first experiments it became clear that within each group of mice there was a small percentage of animals that showed no, or very little response to the startle stimulus. To prevent these mice from skewing the data, in each experiment, the two lowest responders to the 120 dB startle stimuli in each group were removed from the analysis. of Ii&lK-801

and PCP

At the doses tested neither (+)MK-801, [F(5,54)=1.476,p=.212] nor PCP [F(5,45)=1.815, p=.13] (data not shown) produced an overall increase in the mean response to the 120 dB startle stimulus alone. On observation a small percentage of the animals treated with (+)-MK801 3.0 umol/kg and PCP 36 umolikg showed increased activity with some animals exhibiting “wild running behavior” prior to testing.

Analysis of PPI as shown in Fig. 1, revealed that (+)MK-801 [main effect, F(5,54)=5.825, p=.OOO2]decreased significantly the overall level of inhibition. There was no interaction between dose and prepulse level [F(5,54)=.195,p = .9633]. Subsequent post hoc analysis revealed significant differences (p-z.02) at both 0.9 and 3.0 umol/kg.

Analysis of the PPI ( Fig. 1) for PCP revealed a main effect [F(5,42)=2.513. pz.0451. Only the 11.O umol/kg dose was significantly different different by post hoc analysis. prepulse level interaction for PCP administration

The dose x

approached significance [F(2,10)=1.864,

p=.O62] and subsequent one-way ANOVA revealed PCP effects at 5 and 10 dB of prepulse but not at 15 dB above background.

Time course studies with the effective doses of both (+)MK-801 (0.9 umol/kg) and PCP (11 .O pmol/kg), as shown in Table 1, indicate a peak disruption of PPI when injected 30 min prior to the start of the test. Pre treatment with (+)MK-801 produced a disruption of PPI, main

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P. Curzon and M.W. Decker

effect [F(5,62)=5.752, p=.OOO2], with significant differences on post hoc analysis (pc.02) at

15, 30 and 60 min pretreatment.

A. effect of (t)MK-801

Ill1001

B. effect of PCP (Phencyclidine HCI)

4c

u)

I’ Y

H80 b 60 R

i 40 5 yj 20

c

SALINE 0.03 0.09 0.3 0.9 3.0 Doss(+)MK_801(ynoUkg)ip

e 00

3.6 11.0 36.0 DosePCP(pmolkgip)

SALINE0.36 1.1

Fig. 1. (A) (+)-MK-801 injected 15 min prior to testing. N=9-1 l/group. ANOVA p=.OO2 (B) PCP injected 15 min prior to testing, n=lO/group. ANOVA p=.O2, * sig p-z.05 PLSD.

Following treatment with PCP there is an initial tendency to disrupt PPI at 30 min followed by an enhancement in PPI at the 240 min pretreatment time. A significant main effect on PPI was observed [F(1,64)=4.838, p=.O3] and a significant time effect [F(1,64)=4.996, p=.O29], and subsequent post hoc comparison revealed a significant difference (pc.05) from control only at the 240 min.

In both the PCP and the (+)MK-801 time course experiments there was a significant effect of the drug on the response to startle alone. One-way analysis of the PCP effect was significant [F(5,67)=3.139, p=.O13] and post hoc analysis showed a significant (p=O.O18)

PCP and (+)MK-801 on sensorlmotor gating in CD- 1 mice

increase in startle at 60 min and a decrease to below the control level at 240 min. In the case of (+)MK-801 the increase in the startle response was significant ANOVA [F(5,62)=4.543, p=.OOl) at the same time points where the effect of (+)MK-801 treatment on PPI was significant (15, 30 and 60 min). The initial studies were carried out not at the peak pretreatment time, therefore changes in timing were made in subsequent testing.

Table 1 Time Course: Effect of PCP and (+)MK-801 on PPI Percent of 120 dB Response(S.E.M.) Drug dose

control

15 min

30 min

60 min

120 min

240 min

(+)MK-801 0.9 f.rmoVkg

40.9 (6.9)

62.3’ (3.3)

76.2’ (6.6)

61.6’ (4.0)

38.1 (4.1)

41.3 (3.7)

PCP 11.O umol/kg

45.1 (5.0)

47.7 (6.1)

62.5 (6.2)

54.2 (4.7)

31.6 (4.5)

25.0’ (6.0)

Time Course: Effect of PCP and (+)MK-801 on Acoustic startle Arbitrary Unlts(S.E.M.)

Drug dose

control

15 min

30 min

60 min

120 min

240 min

(+)MK-801 0.9 umot/kg

278 (52)

922. (181)

720’ (147)

627* (104)

307 (116)

412 (95)

PCP 11.O umotikg

429 (85)

514 (76)

501 (99)

730’ (116)

497 (63)

239 (65)

(+)MK-801, n=l l/group,

For PCP n=12/group,

l

indicates significant pc.05 Fisher’s PLSD.

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P. Curzon and M.W. Decker

__

orohtne and d-Amohetamine

(-)-apomorphine and d-amphetamine results are shown in Fig. 2. These compounds did not increase startle responses to the 120 dB stimulus (data not shown, the main effect of d-amphetamine ANOVA [F(4,45)=2.138,p=.OS], and (-)-apomorphine [F(4,55)-.915,p=.46]). Behavioral observations showed some increase in activity with d-amphetamine which was not evident in the (-)-apomorphine treated mice. There was, however, an overall significant effect of apomophine to disrupt PPI [F(4,55)=6.914, p=.OOOl] and subsequent post hoc analysis revealed that the 2 highest doses were significantly different (~~0.05) from control levels, at 1.0 umol there was a marginal effect (p=O.O5). The effect of d-amphetamine was similar to (-)-apomorphine, a significant main effect [F(4,45)=2.54, p=.O5], with the 3.3 and 10.0 umolkg doses significantly different ( ~~0.05) from control on post hoc analysis.

B. Effect of apomorphine

A. Effect of d-amphetamine

Ill

P 2 P

3 100 z PO g 80

100 60

*

K $

b ::

60

8 : 0 s w g

z 0

40

60

40

‘; #

20

20

E

h

0

’

SALINE

0.3

0.8

3.0

Dose (pmolkg ip)

8.0

SALINE 0.3

1.0

3.3

10.0

Dose (PmoUkg SC)

Fig. 2. (A) d-amphetamine sulfate administered 30 min prior to testing, n=lO/group, ANOVA p=.O5. (B) (-)-apomorphine hydrochloride injected 10 min prior to testing, n=Wgroup. * pc.05 PLSD.

PCP and (+)MK-801 on sensorhnotorgating in CD- 1 mice

There was no effect of (+)-3-PPP on the startle response alone (data not shown) [F(2,27)=.035, ~~971. As can be seen in Fig. 3, there was an marginal increase in PPI, [F(2,27)=3.02, ~~06551, this is reflective of an increase at the 116 umol/kg dose. (-I-Aoomorohine/Halooeridol

The effect of haloperidol (0.1 and 1.l umol/kg) on (-)-apomorphine (10.0 umol/kg) is shown in Fig. 4. Two-way repeated measures analysis revealed a highly significant reduction of PPI

Effect of (+)-3-PPP WlOO (2 i? m 8o W K

I

SALINE 39 118 Dose (+)&PPP (ClmoUkgip)

Fig. 3. (+)3-PPP treatment i.p. 15 min prior to testing, n=lO/group, ANOVA p=.O65.

with (-)-apomorphine treatment [F(l $X9=25.116, p=.OOl]. There was also significant effect of haloperidol (F(2,66)=7.235, P=.OOl] with no interaction (-)-apomorphine/haloperidol (F(2,66)=.388, p=.68]. Post hoc evaluation of these effects showed a significant (p=c.OOl)

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P. Cunon and M.W. Decker

reduction in PPI in both the saline/(-)-apomorphine (-)-apomorphine

and the haloperidolO.1

pmol /

groups compared to saline/saline control but no significant difference

between the saline/saline and haloperidol 1.1 umol/kg /(-)-apomorphine group.

Although

there was no effect of the low dose of haloperidol (0.1 pmol/kg), there was a significant (p=.Ol) attenuation of the PPI disruption by (-)-apomorphine following haloperidol 1.1 pmol/kg pretreatment. (+IMK-801 / Halooeridol

The effect of haloperidol on (+)MK-801 treated mice is shown in Fig. 5. Two-way repeated measures analysis revealed a highly significant effect with (+)MK-801 0.9 umol/kg, [F(1,66)=56.524, p=.OOOl]. There was no reversal of the (+)MK-801 disruption of PPI with any dose of haloperidol treatment [haloperidol main effect, F(2,66)=2.345, p=.104; interaction

Effect of haloperidol on apomorphine disruption of PPI

I

0.1

0 Dose

SALINE

1.1

Haloperidol pmot/kg i.p.

Fig. 4. Haloperidol injected i.p. 15 min prior to apomorphine 10.0 umol/kg i.p., then tested 10 min later, n=Wgroup. (‘) indicates significant difference from saline control; (+) indicates significant difference from saline/apomorphine group.

PCP and (+)MK-801 on sensorimotor gating in CD-1 mice

between haloperidol and (+)MK-801 [F(2,66)=0.541, p=.565]. There was a significant increase [F(1,66)=45.074, p=.OOOl] in startle response following (+)MK-801 treatment (data not shown), and post hoc analysis revealed that all (+)MK-801 treated mice had elevated startle thresholds. There was no significant effect of haloperidol on acoustic startle [F(2,66)=2.653, p=.O6) even though the haloperidol 1.l umol/kg treated mice were observed to be quite sedated.

The effects of clozapine pretreatment on (+)MK-801 effects on PPI are shown in Fig. 6. Two-way repeated measures analysis showed a highly significant effect with (+)MK-801 0.9 umol/kg, [F(1,66)=46.332, p=.OOOl]. There was no effect of clozapine treatment [F(2,66)=.017, p=.98] and no (+)MK-801 x clozapine interaction [F(2,66)=2.077, ~~131. There

Effect of haloperidol on (+)MK-801 disruption of PPI 100

eo

*

1 *

0

0.1

n *

SALINE hJ (+) MK-SOI

1.1

Dose Haloperidol pmol/kg i.p.

Fig. 5. Haloperidol injected i.p. 15 min prior to (+)MK-801 0.9 umol/kg i.p., then tested 30 min later, n=l2/group. (‘) indicates significant (pc.05) difference from saline control.

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P. Curzon and M.W. Decker

was a significant increase in the startle response (data not shown) with (+)MK-801 treatment [F(1,88)=25.319, p=.OOl] but no clozapine treatment effect [F(2,86)=0.503, p=.61] at any dose even though the clozapine treated mice did appear to be sedated.

Discussion

In the dose response experiments, acute injections of PCP and (+)MK-801 resulted in no significant increase in the acoustic startle response, although there was a tendency to increase with (+)MK-801 at 0.9 umolkg and PCP at 11.O urnolkg. There was, however, a significant disruption of PPI at these doses. This is consistent with rat studies in which PCP and (+)MK-801 have been shown to reduce PPI (Johansson et al., 1995; Mansbach, 1991; Miller et al., 1992; Varty and Higgins, 1995) and sometimes to increase the acoustic startle

Effect of clozapine on (+)MK-801 disruption of PPI

n

0

SALINE

0.9 0.3 Dose Clozapine FmoUkg i.p.

Fig. 6. Clozapine injected i.p. 15 min prior to (+)MK-801 0.9 umol/kg i.p., then tested 30 min later, n=l2/group. (‘) indicates significant (p<.O5) difference from saline control.

PCP and (+)MK-801 on sensorimotor gating in CD- 1 mice

response.

The time course effects of PCP and (+)MK-801 are very similar in that both drugs

peak at a pretreatment time of 30 min, this is the time of peak increase in locomotor activity in the rat (Cgren and Goldstein, 1994).

It is well known PCP and (+)MK-801 interact with multiple receptor sites including the NMDA receptor associated ion channel, and they differ from one another in affinities at different sites. PCP is more potent than (+)MK-801 as a dopamine uptake inhibitor but (+)MK-801 is more potent than PCP as an inhibitor of NMDA induced [3H]norepinephrine release and [3H]TCP binding in the hippocampus (Snell et al., 1987). Numerous studies have reported differences between PCP and (+)MK-801 on regional DA release in different brain areas (Rao et al., 1990b; Rao et al., 199Oc; Reid et al., 1990; Rothman et al., 1989; Sun and Larson, 1993). The relative potency of PCP over (+)MK-801 and the sigma ligands to release DA and the lack of effect of haloperidol pretreatment of PCP and (+)-MK-801 disruption of PPI in rats (Keith et al., 1991) have been discussed by Mansbach and Geyer, 1989. PCP is less potent than (+)-MK-801and the disruptions of PPI following PCP and (+)-MK-801 treatment are not altered by haloperidol pretreatment, thus appears unlikely that dopamine changes are responsible, but more probably it is (Swerdlow et al., 1986) an NMDA mediated effect.

The direct dopamine agonist (-)-apomorphine disrupted PPI in the mice in a dose dependent manner. This disruption is agreement with published rat data (Swerdlow and Geyer, 1993) . A similar disruption of PPI was also observed with the indirect DA agonist, d-amphetamine, these results also reflect those obtained with rats (Ott and Mandel, 1995; Swerdlow et al., 1990b). From experiments with d-amphetamine in rats there is a dissociation between the effects of drugs on increasing startle responses and the effects on PPI (Ott and Mandel, 1995). This finding is also consistent with the results we obtained in mice. At the doses tested in the mice there was no increase in acoustic startle response while in other reports these doses produce a significant increase in locomotor activity (Clineschmidt et al., 1982). The effects of (-)-apomorphine on PPI in rats has been shown to be reversible by haloperidol pretreatment (Swerdlow and Geyer, 1993). In the current experiments in mice, this was also found to be so, in that the disruption of PPI was attenuated with haloperidol 1.l umol/kg pretreatment but a lower dose was ineffective. This would suggest that the disruption by (-)apomorphine may be a direct dopamine agonist effect on PPI.

Pretreatment with the sigma receptor ligand (+)3-PPP 118 umoWkgresulted in a marginally significant increase in PPI. This effect was not accompanied with any change in the acoustic

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P. Curzon and M.W. Decker

startle response. This increase in PPI is in direct contrast with the results in the rat which with similar doses resulted in a decrease in PPI (Johansson et al., 1995).

The PPI deficit produced by (+)MK-801 was more robust than the disruption by PCP and was thus used for reversal studies. Haloperidol pretreatment did not prevent (+)MK-801 disruption of PPI in this study. This is consistent with previous findings with rats. Although, in mouse locomotor activity studies, at similar doses, haloperidol completely reversed increases by (+)MK-801 (Clineschmidt et al., 1982). This suggests that there is a dissociation of the effects of (+)MK-801 on the acoustic startle response and PPI with other actions of (+)MK-801. In this study clozapine did not reverse the (+)MK-801 PPI deficit. The dose of clozapine was the highest dose that could be used before the acoustic startle response was significantly reduced (data not shown). However, a preliminary report in the rat has shown a reversal of the PCP induced PPI deficit with higher dose of clozapine (Bakshi and Geyer, 1993) this effect may be because both PCP and clozapine bind to multiple receptors.

The failure to reverse the disruption by (+)-MK-801 and (-)-apomorphine by haloperidol and clozapine in these experiments was limited by the sedative effects that occur with higher doses of both clozapine and haloperidol. There are several other new antipsycotic compounds that cause less sedation that would be interest in this paradigm. It should be kept in mind that although this PPI model is thought to reflect the sensory motor gating deficit observed in schizophrenia, this gating deficit is only one of many deficits associated with this disease state.

ConclusiQa

From these limited studies it can be seen that the mouse and rat respond pharmacologically with a great deal of similarity in prepulse inhibition of the acoustic startle response. The disruption of PPI is observed with both PCP and (+)MK-801 occurs at the same doses where effects are seen in the rat. Also, in mice and rats haloperidol and clozapine fail to reverse (+)MK-801 disruption of PPI. As in the rat, the dopamine agonists d-amphetamine and (-)apomorphine disrupt PPI in the mouse and the (-)-apomorphine disruption can be attenuated by haloperidol pretreatment. The only drug which does not produce similar effects on PPI in

PCP and (+)MK-801 on sensorimotor

gathg

in CD- 1 mice

the rat and mouse is (+)-3-PPP. While obviously more pharmacological studies are necessary, the authors believe that the mouse is a viable alternative to the rat for use in PPI.

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