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BEHAVIORAL PHARMACOLOGY
Program of Medical Neurobiology, Indiana University School of Medicine, Indianapolis, Indiana (C.K.J., D.L.M., H.E.S.); and The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.K.J., E.L.E., D.B.S., D.L.M., H.E.S.)
Received August 9, 2004; accepted November 24, 2004.
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Abstract |
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). PPI theoretically represents a mechanism for the gating or filtering out of irrelevant or distracting stimuli and is operationally defined as the reduction in startle response produced by a low-intensity stimulus presented before a high-intensity, startle-inducing stimulus (Graham, 1975). The role of various neurotransmitter systems in modulating PPI (Geyer et al., 2001) has been reviewed, and multiple lines of evidence have indicated that D2 dopamine receptors are critical for modulating PPI in rats (Peng et al., 1990; Swerdlow et al., 1994). In addition, a synergistic interaction between D1 and D2 dopamine receptors in mediating PPI also exists (Wan et al., 1996). For example, administration of the mixed D1/D2 dopamine receptor agonist apomorphine, the selective D2 dopamine receptor agonist quinpirole, and the selective D1 dopamine receptor agonist SKF 38393 in combination with a D2 dopamine receptor agonist, but not the administration of SKF 38393 alone, produced dose-dependent disruptions in PPI (Wan et al., 1996). Moreover, the disruptions of PPI by quinpirole or apomorphine are revered by either selective D1 or D2 dopamine receptor antagonists (Hoffman and Donovan, 1994).
Recent evidence has also indicated a role for the muscarinic cholinergic system in modulating PPI. Jones and Shannon (2000a,b) demonstrated that the nonselective muscarinic receptor antagonists scopolamine, trihexyphenidyl, and benztropine disrupt PPI, indicating that a loss of overall cholinergic tone leads to deficits in PPI. In contrast, direct- and indirect-acting muscarinic receptor agonists, such as oxotremorine, pilocarpine, and physostigmine, have no effect on PPI, indicating that increases in muscarinic receptor activation above a certain level in normal animals will not enhance PPI. Furthermore, the disruption of PPI by scopolamine was dose-dependently reversed by the nonselective, high-efficacy muscarinic agonist oxotremorine, indicating that the functional integrity of muscarinic cholinergic neurotransmission is also important for normal PPI (Jones and Shannon, 2000b).
Interactions between the muscarinic cholinergic and dopaminergic systems are well documented, most notably in the regulation of limbic motor circuitry. Preclinically, pharmacologic studies have shown that muscarinic agonists reverse apomorphine-induced climbing and turning behaviors (Bymaster et al., 1998b; Fink-Jensen et al., 1998). Clinically, muscarinic receptor antagonists have been used in the treatment of parkinsonian movement disorders and dopamine receptor antagonist-induced extrapyramidal motor side effects (Brown and Taylor, 1996). In addition, imbalances between the muscarinic cholinergic and dopaminergic systems have been postulated to play an important role in the underlying pathophysiology of schizophrenia (Davis et al., 1975). For example, Janowsky et al. (1973) reported that the exacerbation in psychotic symptoms in individuals with schizophrenia produced by methylphenidate, which enhances dopamine neurotransmission, was reversed by the acetylcholinesterase inhibitor physostigmine. To date, there has been no investigation of the possible interactions between the muscarinic cholinergic and dopaminergic systems in the cognitive impairments, including the deficits in PPI, observed in individuals with schizophrenia. However, apomorphine-induced disruption of PPI in rats was reversed by the M1/M4-preferring agonist xanomeline (Stanhope et al., 2001), suggesting that interactions between the muscarinic cholinergic and dopaminergic systems might also be important for cognitive functions and might contribute at least in part to the PPI deficits observed in individuals with schizophrenia.
Therefore, the purpose of the present studies was to further investigate the pharmacologic interactions between the muscarinic cholinergic and dopaminergic systems in modulating PPI. In particular, the effectiveness of the M1/M4-preferring agonist xanomeline (Bymaster et al., 1994; Shannon et al., 1994), the M2/M4-preferring agonist BuTAC (Shannon et al., 1997), the high-efficacy muscarinic receptor agonist oxotremorine, the low-efficacy muscarinic agonists pilocarpine and RS86, and the newer muscarinic agonists milameline and sabcomeline in reversing the apomorphine-induced disruption of PPI was examined. For comparison purposes, the clinically efficacious agents haloperidol and olanzapine were also examined. Finally, reversal of scopolamine-induced disruption of PPI was assessed using xanomeline, the D1-like receptor antagonist SCH23390 and the D2-like receptor antagonist haloperidol.
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Materials and Methods |
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Apparatus. For apomorphine-reversal studies, test sessions were conducted using San Diego Instruments startle chambers (SR-LAB; San Diego Instruments, San Diego, CA) consisting of a Plexiglas (Degussa AG, Darmstadt, Germany) cylinder 8.2 cm in diameter resting on a 12.5-x 22.5-cm Plexiglas frame within a ventilated enclosure. A super tweeter, mounted 24 cm above the cylinder, produced acoustic stimuli. A piezoelectric accelerometer mounted below the Plexiglas base detected and transduced motion within the cylinder. A Compaq Deskpro 386 computer (Hewlett Packard, Palo Alto, CA) with SR-LAB software controlled the delivery of acoustic stimuli and also digitized (range, 0–4095) and recorded accelerometer readings, with 200, 1-ms readings collected beginning at startle pulse onset.
For the scopolamine-reversal studies, all test sessions were conducted using Coulbourn Instruments startle chambers (Coulbourn Instruments, Allentown, PA), consisting of two ventilated, sound-attenuating chambers with four force transducer platforms per chamber. Each rat was placed in a testing holder (16.5 x 8.5 x 7.6 cm) with a top made of aluminum rods 0.5 cm in diameter spaced 1.25 cm center to center that allowed full exposure to acoustic stimuli. Each holder was positioned on an individual force transducer platform. A Compaq Deskpro 386 computer with Coulbourn startle system software controlled the delivery of acoustic stimuli and also digitized (range, 0–4095) and recorded force transducer readings, with 200, 1-ms readings collected beginning at stimulus onset. The Coulbourn Instruments chambers were used for the scopolamine-reversal studies because the effects of scopolamine have been demonstrated to depend on the background noise level (Davis, 1980; Shannon and Jones, 2000a). In pilot experiments, we were unable to consistently disrupt PPI when the background noise level was above approximately 50 db, such as with the 65 db obtainable with the San Diego Instruments chambers. Therefore, we used the Coulbourn Instruments chambers, which have more soundproofing and in which ambient background noise can be reduced to 50 db, for the scopolamine-reversal experiments.
Sound levels in all chambers were determined using a Radio Shack digital sound level meter (catalog no. 33-2055) set on the A scale. Sound levels were calibrated in all chambers using at least a five-point calibration curve. There were no significant differences among the chambers on sound delivery or response amplitude.
Procedure. For the initial interaction studies with apomorphine using multiple intensities of the prepulse stimulus, animals were injected s.c. with vehicle or a dose of drug and 25 min later with vehicle or apomorphine (1.0 mg/kg s.c.) and then placed into an individual chamber. After a 5-min acclimation period, the rats were presented with four presentations of the startle stimulus alone, followed by seven randomized presentations of the following seven trial types (total of 46 trials/session): no stimulus, startle pulse alone (120 db, 40-ms broadband noise burst), prepulse noise alone (81db, 40-ms broadband noise burst), and four prepulse (69, 73, 77, or 81 db; 20 ms) plus startle pulse combinations. The intertrial interval averaged 30 s and was varied pseudorandomly between 15 and 45 s. The interstimulus interval was 100 ms. Background noise of 65 db was present throughout the test session.
For evaluating multiple muscarinic agonists, a single prepulse intensity was used. For these studies, rats were injected s.c. with vehicle or a dose of drug and 20 min later with vehicle or apomorphine (1.0 mg/kg), and each rat was placed into an individual chamber. After a 5-min acclimation period, rats were presented with 12 randomized presentations of the following four trial types (total of 48 trials/session): no stimulus, startle pulse alone (120 db, 40-ms broadband noise burst), prepulse noise alone (85 db, 40-ms broadband noise burst; 17 db above background), and prepulse plus startle pulse trials. The intertrial interval averaged 20 s and was varied pseudo-randomly between 15 and 25 s. The interstimulus interval was 100 ms. Background noise of 68 db was present throughout the test session.
For the interaction studies with scopolamine, the procedure was identical to the interaction studies with apomorphine with multiple prepulse intensities, except that the ambient background noise was 50 db, the prepulse stimulus was a 10-kHz tone rather than white noise, and the absolute values of the prepulse stimuli were 54, 58, 62, and 66 db (4, 8, 12, and 16 db above background).
Drugs. Pilocarpine hydrochloride, oxotremorine sesquifumarate, R-(–)-apomorphine hydrochloride, haloperidol, (–)-scopolamine hydrobromide (Sigma-Aldrich, St. Louis, MO), R-(+)-SCH23390 hydrochloride (Sigma/RBI, Natick, MA), RS86 hydrochloride, xanomeline tartrate, BuTAC oxalate, olanzapine, milameline oxalate, and sabcomeline oxalate (SB202026) (Lilly Research Laboratories, Indianapolis, IN) were used. All doses refer to the form listed and were injected s.c. in a 1.0-ml/kg volume. Each compound was dissolved in double-deionized water, except haloperidol and olanzapine were dissolved in deionized water to which a small amount of lactic acid was added, and R-(–)-apomorphine hydrochloride was dissolved in deionized water to which a small amount of ascorbic acid was added.
Data Analysis. Startle amplitude was defined as the average of the 200, 1-ms readings. The percentage of PPI was calculated using the equation 100 x [(mean startle amplitude in startle pulse alone trials–mean startle amplitude in prepulse + pulse trials)/(mean startle amplitude in startle pulse alone trials)]. The percentage of PPI and startle amplitude data for the dose-response studies were analyzed by a between-groups analysis of variance with a Dunnett's test that compared each of the dose groups with the appropriate vehicle control group. For the interaction studies, data were analyzed by a between-groups analysis of variance using a Dunnett's test for the comparison of the apomorphine or scopolamine alone dose group with the vehicle/vehicle (V/V) control group; if there was a main effect of dose, then each dose group was compared with either the apomorphine or scopolamine alone dose group using a Dunnett's test. Calculations were performed using JMP (SAS Institute, Cary, NC) statistical software.
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Haloperidol, when administered alone, had no significant effect on PPI (Fig. 1, top left) or on startle amplitude (Table 1) for the dose range of 0.03 to 0.3 mg/kg and across all of the prepulse intensities. However, haloperidol produced a dose-dependent reversal of the apomorphine-induced disruption of PPI (Fig. 1, bottom left), as evidenced by a main effect of dose [F(4,210) = 9.28; P < 0.0001]. Apomorphine alone and after a dose of 0.03 mg/kg haloperidol significantly decreased PPI at the 8-, 12-, and 16-db prepulse intensities based on a Dunnett's comparison with the vehicle/vehicle group. There was also a significant dose/prepulse intensity interaction [F(12,105) = 2.48; P = 0.0068], primarily because of a lack of significant effect of apomorphine alone at the 4-db prepulse intensity (Fig. 1, solid squares above V/A). Furthermore, the effects of apomorphine in the presence of 0.1 and 0.3 mg/kg haloperidol were significantly different from apomorphine alone (Fig. 1). Olanzapine, when administered alone, also had no effect on PPI (Fig. 1, top right) or startle amplitude (Table 1) for the dose range of 0.3 to 3.0 mg/kg and across all of the prepulse intensities. However, olanzapine produced a dose-related reversal of the apomorphine-induced disruption in PPI (Fig. 1, bottom right), as evidenced by a main effect for dose [F(4,102) = 11.4; P < 0.0001). Apomorphine alone and after a dose of 0.3 mg/kg olanzapine significantly decreased PPI across all of the prepulse intensities. The dose/prepulse intensity interaction was not significant, indicating that the effects of olanzapine were similar at all prepulse intensities. The effects of apomorphine in the presence of olanzapine were significantly different from apomorphine alone at the 12- and 16-db prepulse intensities after a dose of 1.0 mg/kg olanzapine and at all prepulse intensities after 3.0 mg/kg of olanzapine.
The M1/M4-preferring muscarinic receptor agonist xanomeline had no effect on PPI for the dose range of 3.0 to 30 mg/kg when administered alone (Fig. 2, top). However, xanomeline decreased startle amplitude, as evidenced by a main effect for dose [F(3,96) = 24.1; P < 0.0001]; the decrease was significant at the 30-mg/kg dose by a Dunnett's comparison with the vehicle group (Table 1). Xanomeline produced a dose-related reversal of the apomorphine-induced disruption of PPI (Fig. 2, bottom). Apomorphine significantly decreased PPI at the 8-, 12-, and 16-db prepulse intensities in the presence of vehicle and at the 4-, 8-, and 16-db prepulse intensities in the presence of 3.0 mg/kg xanomeline. The effects of apomorphine in presence of 10 and 30 mg/kg xanomeline were significantly attenuated compared with apomorphine alone. The dose/prepulse intensity interaction was not significant, indicating that the effects of xanomeline were similar at all prepulse intensities.
To evaluate the potential interactions between apomorphine and multiple additional muscarinic agonists on PPI, the procedure was simplified by reducing the number of prepulse intensities to just one. In these conditions, xanomeline still produced a dose-related reversal of the apomorphine-induced disruption of PPI for the dose range of 3 to 30 mg/kg, as evidenced by a main effect of dose [F(4,35) = 4.27; P < 0.0064; Fig. 3, left]. Consistent with the previous experiment, the effects of apomorphine were significantly decreased in the presence of 30 mg/kg xanomeline. In addition, the M2/M4-preferring agonist BuTAC, tested across a dose range of 0.01 to 0.1 mg/kg, also produced a dose-related reversal of the apomorphine-induced disruption of PPI [F(4,34) = 9.24; P < 0.0001; Fig. 3, right]; the 0.1-mg/kg dose was significantly different from the vehicle/apomorphine group by a Dunnett's comparison. As observed in the previous experiment using multiple prepulse intensities, xanomeline significantly attenuated startle amplitude at 30 mg/kg (Table 2). BuTAC reduced startle amplitude at 0.1 mg/kg when administered alone (Table 2). For reference purposes, startle amplitude during prepulse + startle pulse trials is also presented in Table 2; it may be noted that the percentage of PPI during prepulse + startle pulse trials was largely independent of startle amplitude during startle pulse alone trials.
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The high-efficacy, nonselective muscarinic agonist oxotremorine also reversed the effects of apomorphine (Fig. 4, left). The effects of apomorphine were significantly attenuated by 0.3 mg/kg oxotremorine. The low-efficacy muscarinic agonists RS86 and pilocarpine similarly reversed the disruptive effects of apomorphine, although the reversals were not clearly related to dose (Fig. 4, middle and right). Apomorphine was significantly attenuated by 1.0 mg/kg RS86 but not by 0.3 or 3.0 mg/kg RS86. Similarly, apomorphine was significantly attenuated by 10 mg/kg pilocarpine but not by 3.0 and 30 mg/kg pilocarpine. The 30-mg/kg dose of pilocarpine significantly decreased startle amplitude (Table 2); this decrease seems to have limited the magnitude of the reversal of apomorphine by pilocarpine (Table 2).
In addition, the newer muscarinic receptor agonists milameline and sabcomeline produced reversals of the disruptive effects of apomorphine on PPI (Fig. 5). Apomorphine was significantly reversed by 3.0 mg/kg milameline. Furthermore, apomorphine was significantly reversed by 3.0 mg/kg sabcomeline.
To further characterize the interactions between the dopaminergic and cholinergic systems, we determined the effects of the D2-like receptor antagonist haloperidol and the D1-like receptor antagonist SCH23390on the disruption of PPI by the muscarinic receptor antagonist scopolamine. When administered alone, the nonselective muscarinic receptor antagonist scopolamine (0.5 mg/kg) produced a significant disruption in PPI when comparing the vehicle/vehicle control group with the vehicle/scopolamine (V/S) group across all of the prepulse intensities (Fig. 6, points above V/V and V/S). In addition, scopolamine significantly decreased startle amplitude (Table 3).
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The selective D2-like dopamine receptor antagonist haloperidol produced a graded reversal of the scopolamine-induced disruption of PPI. Scopolamine significantly decreased PPI at 4, 8, 12, and 16 db in the presence of vehicle and 0.1 mg/kg haloperidol. Scopolamine was significantly reversed at 4, 8, and 12 db in the presence of 0.3 mg/kg haloperidol and at all of the prepulse intensities by 1.0 mg/kg of haloperidol (Fig. 6, left). There was also a significant dose/prepulse intensity interaction [F(12,102) = 2.58; P = 0.0068] because of a possible floor effect at the 4-db prepulse intensity. Haloperidol (1.0 mg/kg) had no effect on startle amplitude (Table 3). Scopolamine (0.5 mg/kg) in combination with haloperidol significantly decreased startle amplitude in the presence of 0.3 and 1.0 mg/kg haloperidol (Table 3).
The selective D1-like receptor antagonist SCH23390did not reverse the scopolamine-induced disruption of PPI for the dose range of 0.03 to 0.3 mg/kg (Fig. 6, right). SCH23390(0.3 mg/kg) had no effect on PPI (data not shown) or startle amplitude (Table 3) when administered alone. SCH23390in combination with scopolamine produced a significant decrease in startle amplitude at the 0.1- and 0.3-mg/kg doses of SCH23390(Table 3).
To determine whether the M1/M4-preferring muscarinic cholinergic receptor agonist xanomeline would reverse the effects of scopolamine on PPI, scopolamine was administered alone and in the presence of 30 mg/kg xanomeline, a dose that completely reversed the apomorphine-induced disruption of PPI. Scopolamine produced a dose-related decrease in PPI as evidenced by a main effect of dose [F(4,105) = 2.8; P = 0.05]; the decreases were significant at doses of 0.1, 0.3, and 1.0 mg/kg (Fig. 7). In the presence of xanomeline (30 mg/kg), the scopolamine dose-response curve for changes in PPI was shifted to the right by approximately 3-fold (Fig. 7). Moreover, the disruption of PPI by scopolamine was significantly smaller in magnitude in the presence of xanomeline (Fig. 7).
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). Moreover, in general, the reversal of the apomorphine-induced disruption of PPI by the muscarinic agonists was similar to the reversal produced by the D2-like receptor antagonists haloperidol and olanzapine. In addition, the disruption of PPI by the muscarinic cholinergic receptor antagonist scopolamine was reversed by haloperidol but not by the D1-like receptor antagonist SCH23390 Moreover, the M1/M4-preferring muscarinic agonist xanomeline also ameliorated the disruption of PPI by scopolamine. Together with previous studies, the present findings indicate that functional interactions occur between the muscarinic cholinergic and dopaminergic systems in the modulation of PPI.
Five muscarinic receptor subtypes, belonging to a super-family of G protein-coupled receptors, have been identified by molecular cloning techniques and are referred to as the M1 to M5 receptor subtypes (Buckley et al., 1989). The M1, M3, and M5 receptors are positively coupled to phosphoinositide turnover, whereas the M2 and M4 receptors are negatively coupled to adenylate cyclase (Richards and van Giersbergen, 1995). In the present study, several nonselective, high-efficacy, and partial muscarinic receptor agonists, including oxotremorine, pilocarpine, and RS86, attenuated the apomorphine-induced disruptions of PPI, whereas the M1/M4-preferring muscarinic agonists xanomeline and BuTac produced complete reversals of the apomorphine-induced disruptions of PPI, suggesting that one or a subset of the muscarinic receptor subtypes are involved, or predominate, in the interaction with the dopaminergic system in modulating PPI. With regard to M1 receptors, xanomeline, oxotremorine, RS86, and pilocarpine functioned as M1 receptor agonists in vivo to increase phosphoinositide levels, whereas sabcomeline and milameline were antagonists of M1 receptor-mediated increases in phosphoinositide levels produced by pilocarpine (Bymaster et al., 1998a), and BuTAC is an antagonist at M1 receptors (Bymaster et al., 1997, 1998a; unpublished observations). Because all of these compounds reversed apomorphine but did not all function as agonists or antagonists at M1 receptors, the data do not support a primary role for M1 receptors in reversing apomorphine-induced disruption. A role for M2 receptors seems similarly unlikely because oxotremorine, pilocarpine, RS86, milameline, and BuTAC are agonists at human M2 receptors (Richards and van Giersbergen, 1995; Sedman et al., 1995), but xanomeline is relatively inactive at M2 receptors (Bymaster et al., 1997, 1998a). A primary role for M3 receptors can similarly be ruled out because BuTAC is an antagonist at M3 receptors, whereas oxotremorine and milameline are agonists at M3 receptors in Chinese hamster ovary cells (Richards and van Giersbergen, 1995; Bymaster et al., 1997, 1998a). Moreover, pilocarpine and RS86 exhibit antagonist activity at M3 receptors in rat aorta, whereas xanomeline lacks activity in this preparation (Sawyer et al., 1999). However, a prominent role for M4 receptors is suggested because xanomeline is an M1/M4-preferring agonist and BuTAC is a partial agonist at M2/M4 receptors (Bymaster et al., 1997, 1998a; unpublished observations). Moreover, milameline has been demonstrated to be an agonist at human M4 receptors expressed in Chinese hamster ovary cells (Richards and van Giersbergen, 1995; Sedman et al., 1995). The efficacy of sabcomeline at M4 receptors has not been reported (Loudon et al., 1997). In addition, studies in muscarinic receptor knockout mice also support the concept that interactions occur between M4 muscarinic receptors and the dopaminergic system (Gomeza et al., 1999; Karasawa et al., 2003). Thus, the data presently available indicate that M4 muscarinic receptors may have a more direct involvement in mediating the reversal of apomorphine-induced disruption of PPI by muscarinic agonists. However, a possible role for a combination of agonist and/or antagonist activity at multiple muscarinic receptors cannot entirely be ruled out.
The present findings agree with previous findings demonstrating a role for the dopamine system in modulating PPI. Previous studies have reported that dopamine receptor agonists disrupt PPI and that dopamine receptor antagonists reverse this disruption (Peng et al., 1990; Hoffman and Donovan, 1994). We observed herein that apomorphine (1.0 mg/kg) produced a substantial disruption of PPI at each of the four prepulse intensities tested. In addition, haloperidol and olanzapine produced dose-related reversals of the apomorphine-induced disruptions in PPI across all of the prepulse intensities, consistent with previous findings (Swerdlow et al., 1994; Rasmussen et al., 1997). The changes in the mesocorticolimbic dopamine system produced by apomorphine leading to deficits in PPI in rats has been proposed as a model with predictive, face, and construct validity for the PPI deficits observed in individuals with schizophrenia (Swerdlow et al., 1994). In clinical studies using between-subjects (i.e., cross-sectional) designs, some studies have indicated that patients with schizophrenia receiving typical, but not atypical, antipsychotics exhibited less PPI compared with healthy control subjects (Kumari et al., 1999; Kumari and Sharma, 2002). However, in longitudinal, or crossover, studies, neither typical nor atypical antipsychotics significantly changed PPI in patients before and after receiving medication (Hamm et al., 2001; Mackeprang et al., 2002; Duncan et al., 2003). Thus, it may be suggested that antipsychotic therapies targeting neurotransmitter systems other than or in addition to the dopamine system may be important for normal PPI function. The present findings indicate that the muscarinic cholinergic system may be one such system.
The present findings that the muscarinic antagonist scopolamine disrupted PPI in a manner qualitatively and quantitatively similar to the dopamine agonist apomorphine replicate and confirm previous findings by us (Jones and Shannon, 2000a) and others (Stanhope et al., 2001). However, in our laboratories, we are unable to get reliable disruption by PPI when the background noise level is above approximately 50 db (unpublished observations). That the background noise level can influence the effects of scopolamine is consistent with the findings of Davis (1980). Our experience contrasts with the report by Stanhope et al. (2001) that scopolamine disrupted PPI even when the background intensity was 70 db. Although the reason(s) for the effects of background noise intensity on the effects of scopolamine are presently unclear, we have reliably obtained disruption of PPI with scopolamine using lower, but not higher, background noise levels, suggesting that environmental conditions (e.g., low versus high background noise intensity) can be important determinants of the role of the cholinergic system on PPI. In light of the effects of background noise levels on the scopolamine-induced disruption of PPI, the possibility that different neurobiological substrates underlie the reversal of the scopolamine-induced disruption of PPI by D2-like dopamine receptor antagonists compared with the reversal of apomorphine-induced disruption of PPI by muscarinic agonists cannot be ruled out at the present time.
Several lines of evidence suggest that interactions between the muscarinic cholinergic and dopaminergic systems may play an important role in the pathophysiology of schizophrenia and specifically in the cognitive impairments observed in individuals with schizophrenia. The dopamine hypothesis of schizophrenia postulates that the pathophysiology of schizophrenia is caused in large part by functional imbalances between the mesocortical and mesolimbic dopaminergic pathways of individuals with schizophrenia (Deutch, 1992). Several investigators have demonstrated that the brain stem muscarinic cholinergic nuclei (Ch5 and Ch6) synapse onto, and are involved in the modulation of, the mesocorticolimbic dopaminergic system, suggesting a role for the brain stem cholinergic system in the pathophysiology of schizophrenia (Yeomans, 1995). Based on the present findings, treatment with muscarinic cholinergic receptor agonists may restore, at least in part, a normal functional balance to the mesocortical and mesolimbic dopaminergic pathways and thereby may have therapeutic utility in patients with schizophrenia. Early clinical trials with various muscarinic agonists, such as arecoline (Pfeiffer and Jenny, 1957) or the acetylcholinesterase inhibitor physostigmine (Edelstein et al., 1981), reported transient improvements in the symptoms of schizophrenia. In particular, observations (albeit largely anecdotal by today's standards) by Pfeiffer and Jenny (1957) described "lucid intervals" in usually catatonic schizophrenic patients when administered arecoline. As previously mentioned, Janowsky et al. (1973) reported that the exacerbation in psychotic symptoms in individuals with schizophrenia produced by methylphenidate, which enhances dopamine neurotransmission, was reversed by physostigmine. More recently, Shannon et al. (1999) reported that muscarinic cholinergic receptor agonists, including xanomeline, pilocarpine, and RS86, inhibited conditioned avoidance responding in a manner similar to dopamine receptor antagonists, such as the clinically efficacious antipsychotic drugs haloperidol and clozapine, suggesting that muscarinic agonists might be as effective as haloperidol and olanzapine in treating the symptoms of schizophrenia. In addition, recent clinical trials using the M1/M4-preferring muscarinic receptor agonist xanomeline significantly reduced psychotic behaviors, particularly the hallucinations and delusional behaviors, in patients with Alzheimer's disease (Bodick et al., 1997). Based on these clinical data and in light of the important interactions between the muscarinic cholinergic and dopaminergic systems in the modulation of PPI, a form of cognition disrupted in individuals with schizophrenia, it may be suggested that muscarinic cholinergic agonists such as xanomeline may be effective in the treatment of the cognitive impairments observed in schizophrenia.
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ABBREVIATIONS: PPI, prepulse inhibition; SKF 38393, 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; BuTAC, ([5R-[exo]-6-[butylthio]-1,2,5-thiadiazol-3-yl-]-1-azabyciclo-[3.2.1])octane oxalate; RS86, [2-ethyl-8-methyl-2,8-diazaspiro(4.5)decane-1,3-dione] hydrochloride; SCH23390 R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; V/V, vehicle/vehicle; V/A, vehicle/apomorphine; V/S, vehicle/scopolamine.
Address correspondence to: Dr. Harlan E. Shannon, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285. E-mail: h.shannon{at}lilly.com
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