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NEUROPHARMACOLOGY
ozPsychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, Croissy-sur-Seine, Paris, France (M.J.M., A.D., M.B., B.D.C., F.L., L.C., S.G., L.I., S.V., A.G.); Karolinska Institutet, Section of Translational Neuropharmacology, Department of Physiology and Pharmacology, Stockholm, Sweden (P.S., M.E.); Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York (C.R.A.); Motac Neuroscience Ltd, Williams House, Manchester Science Park, Manchester, United Kingdom (M.H., A.C.); and Therapeutical Division, Institut de Recherches International Servier, Courbevoie Cdx, France (N.T., C.M., E.M.)
Received October 3, 2007; accepted November 14, 2007.
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Abstract |
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2C-adrenoceptors were revealed by an increased firing rate of adrenergic perikarya. Finally, antagonism of 5-hydroxytryptamine (5-HT2A and 5-HT7) receptors was shown by blockade of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane-induced head twitches (0.63–10.0 s.c.) and 5-carboxytryptamine-induced hypothermia (2.5–20.0 i.p.), respectively. In conclusion, S33138 displays modest antagonist properties at central 2C-adrenoceptors, 5-HT2A and 5-HT7 receptors. Furthermore, in line with its in vitro actions, it more potently blocks cerebral populations of D3 versus D2 receptors.
), the benzopyranopyrrolidine derivative, S33138, was shown to behave as a potent antagonist at human (h) dopamine D3 receptors and, at higher concentrations, as an antagonist at hD2L (long isoform) and hD2S (short isoform) receptors. In addition, S33138 expressed modest antagonist properties at h2C-adrenoceptors (ARs), serotonin (5-HT)2A receptors, and h5-HT7 receptors and weak antagonist actions at hD1 receptors. Thus, S33138 possesses a cellular profile, distinguishing it from previously documented antipsychotics. The purpose of the present studies was 3-fold: first, employing a range of electrophysiological, neurochemical, and behavioral procedures to determine whether S33138 behaves as an antagonist at presynaptic and postsynaptic populations of cerebral D3 and D2 receptors; second, employing procedures in which the actions of selective D3 versus D2 antagonists have previously been documented (see citations below) to evaluate whether S33138 preferentially antagonizes D3 versus D2 receptors in vivo; and third, to establish whether S33138 antagonizes central nervous system populations of 2C-ARs, 5-HT2A receptors, 5-HT7 receptors, and D1 receptors.
Activity of the cellular marker of neuronal activity, c-fos, is controlled by both D3 and D2 receptors. Selective D3 versus D2 receptor antagonists preferentially induce its gene expression in the Isles of Calleja (IOC) and nucleus accumbens (Kovacs et al., 2001; Southam et al., 2007), structures enriched in D3 receptors compared to the striatum wherein D2 receptors predominate (Landwehrmeyer et al., 1993; Joyce, 2001). Interest in the influence of S33138 upon c-fos is reinforced by studies indicating that the atypical antipsychotic, clozapine, but not haloperidol, also preferentially enhances c-fos expression in the IOC and nucleus accumbens (Vahid-Ansari and Robertson, 1996; Merchant et al., 1996; Guo et al., 1998; Carta and Gerfen, 1999; Kovacs et al., 2001). A further parallel between selective D3 receptor antagonists and clozapine is that, upon chronic administration, both preferentially decrease the number of spontaneously active dopaminergic neurones in the ventral tegmental area (VTA) versus the substantia nigra, pars compacta (SNPC) (Ashby and Wang, 1996; Ashby et al., 2000). Likewise, this approach suggests that blockade of D3 receptors principally modulates the activity of D3 receptor-rich limbic versus striatal structures.
D3 autoreceptors are colocalized with D2S receptors on dopaminergic perikarya and terminals (Stanwood et al., 2000; Usiello et al., 2000; Joyce, 2001; Joyce and Millan, 2005) where they play complementary roles in controlling the synthesis, release, and clearance of dopamine (DA), as well as the electrical activity of dopaminergic neurones (Millan et al., 2000d; Usiello et al., 2000; Roberts et al., 2006; Sokoloff et al., 2006). Blockade of tonically active, mesolimbic D2S autoreceptors by haloperidol enhances DA release in the nucleus accumbens (Millan et al., 2000d), whereas their activation by the partial agonist aripiprazole may, in moderating limbic DA release, contribute to its antipsychotic properties (Davies et al., 2004). Inasmuch as acute administration of selective D3 receptor antagonists abrogates the phasic suppression of DA release and VTA firing by the preferential D3 versus D2 receptor agonist, PD128,907, we examined the influence of S33138 upon its actions.
Discriminative stimulus (DS) properties of dopaminergic agonists reflect recruitment of D3 and/or D2 autoreceptors (Cory-Slechta et al., 1996; Bristow et al., 1998; Millan et al., 2000b). By contrast, yawning involves postsynaptic D2 and/or D3 receptors on oxytocinergic neurones in the paraventricular nucleus of the hypothalamus (Argiolas and Melis, 1998; Chen et al., 1999; Millan et al., 2000a; Collins et al., 2005). With regard to the hypothermic actions of dopaminergic agonists integrated in the IOC, perifornical hypothalamus, and other structures, the contribution of postsynaptic D3 versus D2 receptors remains controversial (Barik and Beaurepaire, 1998; Boulay et al., 1999; Millan et al., 2000a; Perachon et al., 2000; Chaperon et al., 2003). It is interesting that there is compelling evidence for a contrasting influence of postsynaptic D3 versus D2 sites upon motor function. Thus, blockade of mesolimbic and striatal D2 sites disrupts motor behavior, whereas the selective inactivation of D3 receptors enhances motor behavior (Boulay et al., 1999; Millan et al., 2000a; Joyce, 2001; Sokoloff et al., 2006). This opposing influence of D3 versus D2 receptors can be revealed in primates rendered parkinsonian by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In such akinetic subjects, improvement of motor performance by antiparkinson agents is potentiated and abrogated by selective antagonists at D3 and D2 receptors, respectively (Silverdale et al., 2004; Hill et al., 2006). In light of the differential implication of D3 and D2 sites in these behavioral procedures, they were also used to examine the actions of S33138.
Dopamine D1 receptors in limbic and striatal regions control motor drive and coordination, as reflected in the induction of rotation by agonists in rats sustaining a unilateral lesion of the SNPC (Gulwadi et al., 2001; Gerfen et al., 2002). Thus, we examined the influence of S33138 upon rotation elicited by SKF81297. Despite the significance of 2C-ARs to cognition and mood (Svensson, 2003), in vivo models of drug actions at 2C-AR sites remain to be established. Nonetheless, 2C-AR autoreceptors regulate the activity of adrenergic perikarya in the locus coeruleus (LC) (Arima, 1998; Millan et al., 2000d; Owesson et al., 2003), so the influence of S33138 upon its firing rate was determined in anesthetized rats. Finally, activation of 5-HT2A receptors by the agonist 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) elicits head twitches (HTW) in rats (Schreiber et al., 1995; Willins and Meltzer, 1997), whereas stimulation of 5-HT7 receptors in guinea pigs evokes hypothermia (Hagan et al., 2000; Hedlund and Sutcliffe, 2004). In relation, potential antagonist actions of S33138 at these sites were evaluated using these procedures.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Drug Testing. Unless otherwise specified, S33138 was examined by the subcutaneous route, and full dose-response curves were generated. In the protocols of D3 and D2 receptor-mediated activity, we have characterized the actions of selective D3 (and D2) receptor antagonists in previous studies (see Discussion). The equilibrated D2/D3 receptor antagonist, haloperidol, was employed herein as an internal reference ligand to "validate" this series of experiments; data are summarized under Results. For protocols of activity at D1 receptors, 2C-ARs, 5-HT2A receptors, and 5-HT7 receptors, the selective antagonists SCH23390, idazoxan, MDL100,907, and SB269,970, respectively, were similarly used as "internal" validators in parallel with S33138 (see Results).
Influence of S33138 upon Cerebral Levels of mRNA Encoding c-fos. In mice, the influence of a single i.p. injection of S33138 upon levels of mRNA encoding c-fos was evaluated in cerebral structures differentially expressing D3 versus D2 receptors (IOC, nucleus accumbens, and striatum) employing in situ hybridization as described in detail previously (Svenningsson et al., 1997). In brief, mRNA levels encoding c-fos were quantified in coronal, cryostat brain sections using a 35S-labeled cRNA probe and standard hybridization and washing conditions. After washing, sections were dried and apposed to betaMAX hyperfilm for 4 weeks. Autoradiograms were quantified with a Microcomputer Imaging Device system using NIH Image 1.62 software. Slides were subsequently dipped in liquid photographic emulsion and counterstained in cresyl violet for cellular analyses of neurons labeled for c-fos.
Influence of Chronic S33138 upon Spontaneously Active Dopaminergic Neurones in the VTA versus SNPC of Anesthetized Rats. The procedure used was essentially as described previously (Ashby et al., 2000). Male Sprague-Dawley rats (Taconic Farms, NY) (150–175 g at the beginning of the treatment) received one p.o. administration of vehicle or S33138 (0.16 to 10.0 mg/kg) or the "positive control" haloperidol (0.5 and 2.0 mg/kg) once a day for 21 consecutive days. All experiments were conducted 2 h after the last administration on day 21. Animals were anesthetized with chloral hydrate (400 mg/kg i.p.) and mounted in a stereotaxic instrument. Single barrel microelectrodes (glass borosilicate; World Precision Instruments, Sarasota, FL) were used for recording the electrical activity of single dopaminergic neurones in the A10, VTA (AP: 3.0–3.5 mm; L: 0.5–1.0 mm, and DV: 6.0–8.5 mm to the cortical surface), and the A9, SNPC (AP: 3.0–3.5 mm to lambda, L: 1.8–2.5 mm, and DV: 6.0–8.5 mm). The number of spontaneously active dopaminergic neurons in each region was determined across 10 stereotaxic descents.
Influence of S33138 upon the Actions of the D3/D2 Receptor Agonist, Ropinirole, in Parkinsonian Primates. The procedure employed was essentially that described previously (Silverdale et al., 2004; Hill et al., 2006). In brief, six adult marmosets were rendered parkinsonian by subcutaneous injection of 2 mg/kg MPTP for 5 consecutive days. This produced a parkinsonian state that was stable after 18 weeks. Marmosets were then treated orally with 12.5 mg/kg L-(3,4-dihydroxyphenyl)-alanine and 3.1 mg/kg benserazide (as Madopar, 62.5 mg dispersible, dissolved in apple juice; Roche Diagnostics, Indianapolis, IN) twice daily for 4 weeks. Thereafter, the studies with S33138 were performed. On the day of experiment, ropinirole plus vehicle, or ropinirole plus S33138, was administered orally in volumes of 5 ml/kg. In a separate experiment, S33138 or vehicle was administered in the absence of ropinirole. Immediately after treatment, the animals were transferred to an observation cage (60 x 55 x 75 cm). Locomotor activity was monitored for 2 consecutive hours using computer-based infrared activity monitors, which provide a quantitative assessment of the total amount of movement in each 5-min time period throughout the experiment.
Influence of S33138 upon the Hypothermia Induced by the Preferential D3 versus D2 Receptor Agonist, 7-OH-DPAT. Core temperature (CT) was determined in lightly restrained rats by use of a rectal thermistoprobe as described previously (Millan et al., 2000a). Basal CT was measured; S33138, haloperidol, or vehicle was administered s.c.; and 30 min later, 7-OH-DPAT (0.16 mg/kg s.c.) or vehicle was injected. Thirty minutes later, CT was reevaluated, and the difference (
) to pretreatment values was calculated.
Influence of S33138 upon the Yawns Elicited by 7-OH-DPAT. As described previously (Millan et al., 2000a), rats (120–140 g) were individually placed in Plexiglas observation cages (11 x 26 x 30.5 cm), behind which mirrors were positioned to facilitate monitoring of behavior. Thirty minutes after injection of S33138, haloperidol, or vehicle, 7-OH-DPAT (0.04 mg/kg s.c.) was administered, and the number of yawns was measured over a 30-min observation period.
Influence of S33138 upon DS properties of the Preferential D3 versus D2 Receptor Agonist, PD128,907. Employing a procedure detailed in previous work (Millan et al., 2000b), rats were trained to discriminate PD128,907 (0.16 mg/kg i.p.) from saline using a two-lever, fixed-ratio 10, food-reinforced procedure. Each 15-min daily session started 15 min after injection. The discrimination criterion was 10 consecutive sessions of correct responses (defined as a maximum of 13 responses on both reinforced and nonreinforced levels before the first reinforcement). Thereafter, tests were performed on Wednesdays and Fridays, and training sessions were performed on the other days. Only rats responding appropriately on the two most recent training days were examined. In test sessions, responses on the selected lever (on which 10 responses were emitted first) were reinforced for the rest of the session. S33138 or haloperidol was injected s.c. 30 min before PD128,907. Data recorded during the test sessions were lever selection and response rate (the total number of presses on both levers).
Blockade by S33138 of the Inhibitory Influence of PD128,907 upon the Electrical Activity of Dopaminergic Cell Bodies. The procedure used has been detailed previously (Millan et al., 2000c, 2004a). After anesthesia with chloral hydrate (400 mg/kg i.p.) and femoral vein cannulation, rats were placed in a stereotaxic apparatus, and a tungsten microelectrode was lowered by an electronic microdrive (Unimechanique, Epinay sur Seine, France) into the VTA (AP: –5.5 from bregma, L: 0.7, H: –7/–8.5 from dura) for recording of extracellular unit activity. Dopaminergic neurones were characterized by their distinctive waveforms and discharge patterns (Millan et al., 2000c). One cell was recorded in each animal. Following baseline recording ((5 min), PD128,907 (0.01 mg/kg i.v.) or vehicle was injected; 1 min later, S33138 (0.001–0.25 mg/kg i.v., one dose per rat) or vehicle was injected, and firing rate was again recorded. In a separate experiment, the influence of cumulative (every 2–3 min) administration of S33138 (0.125–4.0 mg/kg i.v.) versus vehicle was examined. At the end of the treatment, the prototypical dopaminergic agonist, apomorphine (0.031 mg/kg i.v.), was injected, and firing rate was again recorded. Haloperidol was evaluated at a single dose of 0.031 mg/kg i.v. Drug effects were quantified over a 60-s bin at the time of peak action. Spike2 version 5.11 software (CED, Cambridge, England) was used for data acquisition and off-line analysis. Drug effects are expressed as percentage change from baseline (predrug) firing rate (defined as 0%).
Blockade by S33138 of the Inhibitory Influence of PD128,907 upon Dialysate Levels of Dopamine in Freely Moving Rats. Extracellular levels of DA in single dialysate samples of the frontal cortex (FCX), nucleus accumbens, and striatum were determined as described previously (Millan et al., 2000c, 2004a). In brief, guide cannulae were implanted under pentobarbital anesthesia (60 mg/kg i.p.) 1 week before experimentation, and on the test day, a cuprophane CMA/11 probe (4 mm in length for the FCX and striatum, 2 mm for the nucleus accumbens, and, in each case, 0.24 mm outer diameter) was lowered into position. Three basal samples of 20 min each were taken. Vehicle, S33138, or haloperidol was administered s.c. followed 20 min later by PD128,907 (0.16 mg/kg s.c.) or vehicle, and samples was taken for another 3 h. DA levels were quantified by high-performance liquid chromatography followed by amperometric detection. The assay limit of sensitivity was 0.1 to 0.2 pg/sample. Influence of S33138 upon Rotation Elicited by the D1 Receptor Agonist, SKF81297, in Rats with a Unilateral Lesion of the SNPC. As described previously (Millan et al., 2000a, 2004b), rotation was measured in rats (350–400 g at the time of the study) that had received a unilateral 6-hydroxydopamine (8 µg/4 µl) lesion of the SNPC. Rotation was measured by use of an Rotacount 8 (Columbus Instruments, Columbus, OH) apparatus. Sessions were performed weekly employing an "ABACADA" design where "A" corresponded to injection of the selective D1 agonist, SKF81297 (0.04 mg/kg s.c.) (control sessions) and "B, C, and D" corresponded to test sessions with s.c. administration of S33138 or the selective D1 receptor antagonist SCH23390 followed by SKF81297. In SKF81297-control sessions, vehicle was given 30 min before SKF81297, and rotation was measured for 1 h. In test sessions, S33138 or SCH23390 was given 30 min before SKF81297, and likewise, rotation was measured for 1 h. Thus, animals were their "own" controls.
Influence of S33138 upon the Electrical Activity of Adrenergic Compared to Serotonergic Cell Bodies. The basic procedure used was as described above for the VTA and documented previously (Millan et al., 2000c, 2004a). Thus, a tungsten microelectrode was lowered by an electronic microdrive into the LC (AP: –1.0 from 0; L: 1.0–1.2; H: –5.5/–6.0 from the sinus surface) of anesthetized rats. Adrenergic neurones were characterized by their distinctive waveforms and discharge patterns (Millan et al., 2000c, 2004a). One cell was recorded in each animal. Following baseline recording (
5 min) and vehicle injection (0.5 ml/kg i.v.), S33138 was administered in cumulative doses every 2 to 3 min. Subsequent to S33138 administration, a further injection was made of the 2-AR autoreceptor agonist clonidine (0.01 mg/kg i.v.), followed by the 2-AR antagonist idazoxan (0.063 mg/kg i.v.). In a separate group of subjects, the influence of idazoxan alone was also tested. In a further study, the influence of S33138 upon the activity of serotonergic neurones in the dorsal raphe nucleus (DRN) was examined. Coordinates were as follows: AP: –7.8 from bregma; L: 0; H: –5/–6.5 from the sinus surface. Cumulative administration of S33138 was followed by injection of the 5-HT1A receptor agonist 8-OH-DPAT (0.005 mg/kg i.v.), followed by the selective 5-HT1A antagonist WAY100,635 (0.1 mg/kg i.v.). In a separate experiment, WAY100,635 was injected followed by 8-OH-DPAT. Effects of S33138 were quantified over 60-s bins at the time of peak action. Drug effects were expressed versus baseline (predrug) firing rate (defined as 0%).
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), DOI (2.5 mg/kg i.p.) was injected into rats placed in Plexiglas observation cages (33.5 x 23.5 x 19 cm). Five minutes after DOI, the number of HTW made in 5 min was counted. Vehicle, S33138, or the selective 5-HT2A receptor antagonist MDL100,907 was given s.c. 30 min before DOI.
Influence of S33138 upon the Induction of Hypothermia by the 5-HT7 Receptor Agonist, 5-Carboxytryptamine (5-CT), in Guinea Pigs. Essentially as described elsewhere (Hagan et al., 2000), CT was determined in lightly restrained male guinea pigs with a digital thermistoprobe placed into the ear for 30 s. Basal CT was measured; S33138, the selective 5-HT7 receptor antagonist SB269,970, or vehicle was administered i.p.; and 30 min later, 5-CT (3 mg/kg i.p.) or vehicle was injected. Ninety minutes later, CT was reevaluated, and the difference () to pretreatment values were calculated.
Drug Salts and Sources. Haloperidol and S33138 were dissolved in sterile water plus a few drops of lactic acid, and the pH was adjusted close to neutrality (pH 5.5) using NaOH. All other drugs were dissolved in sterile water. Doses are in terms of the base. Drug structures, sources, and salts were as follows: MPTP HCl was purchased from Sigma (Dorset, UK). Clonidine HCl, DOI HCl, 7-OH-DPAT HCl, 8-OH-DPAT HBr, PD128,907 HCl, and SCH23390 HCl were obtained from Research Biochemicals International (Natick, MA). Apomorphine, idazoxan, haloperidol, SKF81297, and benserazide HCl were acquired from Sigma Chimie (St Quentin-Fallavier, France). S33138 HCl, 5-carboxytryptamine, maleate, and MDL100,907 were synthesized by G. Lavielle (Servier). Ropinirole, SB269,970, and WAY100,635 were synthesized by J.-L. Péglion (Servier).
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Influence of Chronic Administration of S33138 on Spontaneously Active Dopaminergic Neurones in Anesthetized Rats (Fig. 3). After chronic (3 week) daily p.o. administration of vehicle, 1.21 ± 0.13 active neurons were identified in the VTA. Chronic administration of S33138 (0.16–10.0 mg/kg p.o.) potently and dose-dependently reduced the number of active neurons. In contrast, S33138 decreased spontaneously active neurons in the SNPC only at the highest dose of 10.0 mg/kg. Moreover, the maximal reduction in number of spontaneously active neurons (–58%) was less than that for the VTA (–83%). Haloperidol (0.5 mg/kg p.o.) produced a significant (P < 0.01) reduction in the number of active neurons in the VTA (–66 + 6.6%) and in the SNPC (–62 ± 6.2%) compared to vehicle (0%).
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Influence of S33138 upon Actions of the D3/D2 Receptor Agonist, Ropinirole, in Parkinsonian Primates (Fig. 4). In marmosets exposed to MPTP, ropinirole (0.63 mg/kg p.o.) increased motor activity compared to vehicle: 3091 ± 556 versus 235 ± 132 counts, respectively (P < 0.01 in a two-tailed t test). Over a low-dose range, S33138 (0.0025–0.16 mg/kg p.o.) dose-dependently and significantly enhanced this facilitatory influence of ropinirole. In contrast, a higher dose of S33138 (2.5 mg/kg) reduced the action of ropinirole. S33138 (0.16 mg/kg) did not significantly modify motor behavior when given alone (Fig. 4; data not shown).
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Antagonism by S33138 of the Discriminative Stimulus Properties of the Preferential D3 versus D2 Receptor Agonist, PD128,907 (Fig. 5C). PD128,907 (0.16 mg/kg i.p.) elicited a stable DS in rats. S33138 (0.0025–0.63 mg/kg s.c.) blocked its DS properties with an ED50 (95% confidence limits) of 0.02 (0.01–0.04) mg/kg s.c. S33138 did not significantly decrease response rates: for the dose of 0.63 mg/kg, +23 ± 18% versus previous control session (0%). Haloperidol (0.0025–0.04 mg/kg s.c.) also attenuated the PD128,907 cue, exerting a maximal 50% inhibition at 0.04 mg/kg (n = 7). At this dose, there was a pronounced decrease (–75 ± 32%, P < 0.01, paired t test) in the response rate. At a higher dose of haloperidol (0.08 mg/kg), rats were unable to select a lever because of motor perturbation.
Antagonism by S33138 of the Inhibitory Influence of PD128,907 upon the Electrical Activity of Dopaminergic Cell Bodies (Fig. 6). The firing rate (baseline, 4.0 ± 0.3 Hz) of dopaminergic perikarya in the VTA was markedly reduced by PD128,907 (0.01 mg/kg i.v.). S33138 (one dose per subject, 0.001–0.25 mg/kg i.v.) blocked this action of PD128,907 with a minimally effective dose of 0.004 mg/kg i.v. and without itself affecting firing rate. Likewise, haloperidol (0.031 mg/kg i.v.) reversed the action of PD128,907 and yielded an "overshoot" in firing rate relative to baseline values (0%): vehicle/vehicle, + 0.1 ± 2.7%; PD128,907/vehicle, –99.9 ± 0.1%; vehicle/haloperidol, + 46.1 ± 25.6% and PD128,907/haloperidol + 58.7 ± 36.5%, F(3,18) = 10.3, P < 0.01. In a separate experiment, cumulatively administered over a higher range of doses (0.125–4.0 mg/kg i.v.), S33138 slightly increased firing rate with a maximal effect of +29% (1.0 mg/kg). Apomorphine (0.031 mg/kg i.v.) failed to inhibit dopaminergic neurons (+1.7 ± 5.5%) following administration of S33138 compared to vehicle (–98.2 ± 0.4%): P < 0.01 (two-tailed t test). After haloperidol, apomorphine was likewise ineffective (data not shown).
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Antagonism by S33138 of the Suppressive Influence of PD128,907 upon DA Levels in the FCX, Nucleus Accumbens and Striatum (Fig. 7). PD128,907 (0.16 mg/kg s.c.) decreased dialysis levels of DA in the FCX of freely moving rats, an action dose-dependently prevented by S33138 (0.16–2.5 mg/kg s.c.), which did not influence DA alone. Haloperidol (0.63 mg/kg s.c.) also blocked the action of PD128,907 and itself increased levels of DA. Relative to basal values (100%), "area under the curve" analysis was as follows: vehicle/vehicle, 98.1 ± 1.8%; vehicle/PD128,907 (0.16), 82.2 ± 3.1%; haloperidol/vehicle, 127.6 ± 2.9% and haloperidol/PD128,907, 132.2 ± 5.9%; n = 5–9 per group. Influence of PD128,907, F(1,16) = 10.0, P < 0.01; influence of haloperidol, F(1,15) = 25.6, P < 0.01 and interaction, F(1,12) = 19.0, P < 0.01. S33138 likewise abolished the influence of PD128,907 (0.16 mg/kg s.c.) on levels of DA in the nucleus accumbens and the striatum (Fig. 7, C and D). Haloperidol (0.63 mg/kg s.c.) also blocked the actions of PD128,907 in nucleus accumbens and striatum and alone increased levels of DA. Nucleus accumbens: vehicle/vehicle, 93.7 ± 1.9%; vehicle/PD128,907, 75.0 ± 3.2%; haloperidol/vehicle, 153.1 ± 3.2% and haloperidol/PD128,907, 154.8 ± 8.2%; n = 5–8 per group. Influence of PD128,907, F(1,13) = 6.9, P < 0.05, influence of haloperidol, F(1,12) = 55.3, P < 0.01 and interaction, F(1,11) = 18.7, P < 0.01. Striatum: vehicle/vehicle, 96.5 ± 1.7%; vehicle/PD128,907, 67.2 ± 2.7%; haloperidol/vehicle, 179.0 ± 5.6% and haloperidol/PD128,907, 205.7 ± 4.0%; n = 5–8 per group. Influence of PD128,907, F(1,14) = 20.1, P < 0.01; influence of haloperidol, F(1,13) = 25.6, P < 0.01 and interaction, F(1,11) = 305.0, P < 0.01.
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Influence of S33138 upon the Electrical Activity of Adrenergic and Serotonergic Cell Bodies in Anesthetized Rats (Fig. 8A). S33138 dose-dependently (0.125–4.0 mg/kg i.v.) increased the activity of LC-localized adrenergic neurons (baseline firing rate, 1.1 ± 0.2 Hz). Relative to basal values (0%), S33138 exerted a maximal effect of +177 ± 7% at 4.0 mg/kg. Following S33138, the 2-AR agonist, clonidine (0.01 mg/kg i.v.), still inhibited firing (–100.0 ± 0.0%). This effect was reversed by the 2-AR (rat 2-adrenoceptors, pKi, 8.5) antagonist, idazoxan (0.063 mg/kg i.v.), which yielded an "overshoot" of +81 ± 16.3%. Alone, idazoxan (0.063 mg/kg i.v.; n = 5) significantly (+142.0 ± 13.9%, P < 0.01) increased the firing rate relative to vehicle (n = 5), (–2.2 ± 1.3%). In contrast to the LC, S33138 (0.125–4.0 mg/kg i.v.) did not affect the electrical activity of DRN-localized serotonergic neurons (baseline firing rate, 1.2 ± 0.2 Hz). Following S33138, the 5-HT1A receptor agonist, 8-OH-DPAT (0.005 mg/kg i.v.), still abolished the activity of serotonergic perikarya (–97.6 ± 2.4%). This effect was reversed by the 5-HT1A receptor antagonist, WAY100,635 (0.1 mg/kg, i.v.: +29.0 ± 12.8% (P < 0.01).
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Antagonism by S33138 of the Induction of Head Twitches in Rats by the 5-HT2A Receptor Agonist, DOI (Fig. 8B). DOI elicited HTW in rats. S33138, which did not itself elicit HTW (data not shown), dose-dependently (0.63–10.0 mg/kg s.c.) abrogated their induction. The potent (rat 5-HT2A receptors, pKi, 9.1) 5-HT2A receptor antagonist, MDL100,907, also abolished induction of HTW: vehicle + DOI, 6.1 ± 0.7; MDL100,907 (0.0025 mg/kg s.c.) + DOI, 5.2 ± 0.5; MDL100,907 (0.005) + DOI, 3.0 ± 1.1; MDL100,907 (0.01) + DOI, 0.8 ± 0.5 and MDL100,907 (0.04) + DOI, 0.0 ± 0.0; n = 5–8 per value, F(4,31) = 11.0, P < 0.01. Doses of 0.01 and 0.04, significantly different (P < 0.05) from vehicle in Dunnett's test. MDL100,907 itself did not elicit HTW (data not shown).
Antagonism by S33138 of the Induction of Hypothermia by the "5-HT7" Receptor Agonist, 5-Carboxytryptamine, in Guinea Pigs (Fig. 8C). 5-Carboxytryptamine (3.0 mg/kg i.p.) elicited hypothermia in guinea pigs, an effect dose-dependently attenuated by S33138 (2.5–20.0 mg/kg i.p.). S33138 did not modify CT alone (data not shown). By analogy, the potent (rat 5-HT7 receptors, pKi, 8.8) 5-HT7 receptor antagonist, SB269,970, also inhibited induction of hypothermia: Vehicle + 5-CT, –1.81 ± 0.30°C; SB269,970 (0.63 mg/kg i.p.) + 5-CT, –1.56 ± 0.22°C, SB269,970 (2.5) + 5-CT, –0.50 ± 0.36°C and SB269,970 (10.0) + 5-CT, –0.22 ± 0.23°C; n = 5–8 per value, F(3,25) = 4.4, P < 0.01. Doses of 2.5 and 10.0, significantly different (P < 0.05) from vehicle in Dunnett's test. SB269,970 did not affect CT alone (data not shown).
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; Joyce, 2001; Sokoloff et al., 2006) correlates well with its higher affinity for D3 over D2 sites. Furthermore, this finding parallels similar actions of selective antagonists at D3 versus D2 receptors (Kovacs et al., 2001; Southam et al., 2007; P. Svenningsson and M. J. Millan, unpublished observations). Interestingly, functional "MRI" imaging studies also revealed greater activation of neurones in limbic versus striatal structures by selective blockade of D3 receptors (Schwarz et al., 2004). Preferential limbic versus striatal induction of c-fos has been related to a high margin between doses controlling positive symptoms versus those eliciting extrapyramidal symptoms, and a similar pattern of effects to S33138 is seen with atypical antipsychotics (Robertson et al., 2004; Guo et al., 1998). However, it is unclear whether D3 receptors are involved in their effects. Thus, preferential D3 versus D2 receptor agonists blunted limbic induction of c-fos by clozapine in rats (Vahid-Ansari and Robertson, 1996; Guo et al., 1998). However, mice genetically deprived of D3 receptors revealed no attenuation in the influence of clozapine, which may engage cells different from D3 antagonists (Merchant et al., 1996; Carta and Gerfen 1999; Kovacs et al., 2001).
Inhibition of Spontaneously Active VTA Neurones by Long-Term Administration of S33138. By analogy to clozapine and olanzapine (Stockton and Rasmussen, 1996; Grace et al., 1997; Ashby and Wang, 1996), and in contrast to haloperidol, chronic administration of S33138 selectively decreased the number of spontaneously active VTA versus SNPC dopaminergic neurones. Supporting a role of D3 receptor blockade, the action of S33138 was expressed at low doses similar to those inducing c-fos in limbic structures. Furthermore, a selective reduction in spontaneously active VTA versus SNPC neurones was likewise seen employing highly selective D3 antagonists (Ashby et al., 2000; MacDonald et al., 2003). Chronic administration of haloperidol may decrease the number of spontaneously active VTA and SNPC neurones by "depolarization" blockade because manipulations that hyperpolarize neurones, such as apomorphine administration, reverse its effects (Grace et al., 1997). However, the influence of chronic SB-277011, a selective D3 receptor antagonist, upon VTA neurones was not blocked by apomorphine (Ashby et al., 2000). Accordingly, depolarization blockade is probably not involved in long-term effects of S33138. Rather, the reduction in spontaneously active VTA neurones produced by S33138 and selective D3 receptor antagonists may reflect feedback actions initiated in structures like the nucleus accumbens (Grace et al., 1997; Ashby et al., 2000).
Dose-Dependent Facilitation and Attenuation by S33138 of the Antiparkinson Properties of Ropinirole. MPTP selectively lesions nigrostriatal dopaminergic projections, provoking a parkinsonian-like syndrome alleviated by D2/D3 receptor agonists (Pearce et al., 1998; Millan et al., 2004b; Silverdale et al., 2004). Blockade of D2 receptors by a high dose of S33138 probably underlies its abrogation of the motor-relief afforded by ropinirole. By contrast, mirroring the facilitatory influence of selective D3 receptor antagonists (Silverdale et al., 2004; Hill et al., 2006), low doses of S33138 potentiated the actions of ropinirole. These findings agree well with the notion that D2 receptors mediate the beneficial actions of antiparkinson agents, whereas D3 receptor blockade enhances their efficacy and reduces dyskinesias (Bezard et al., 2003; Millan et al., 2004b; Silverdale et al., 2004; Hill et al., 2006; Sokoloff et al., 2006).
Antagonist Properties of S33138 in Behavioral Models. Although D2 receptors mediate hypothermia in mice (Boulay et al., 1999; Perachon et al., 2000), a predominant role of D3 sites has been implicated in rats (Millan et al., 2000a; Chaperon et al., 2003). Furthermore, 7-OH-DPAT elicits hypothermia upon microinjection into the IOC, a postsynaptic action unaffected by elimination of dopaminergic neurones (Barik and Beaurepaire, 1998). Nonetheless, a role of both D3 and (at higher doses) D2 sites in the antagonism of 7-OH-DPAT-induced hypothermia by S33138 is possible. Collins et al. (2005) asserted that stimulation of D3 and D2 receptors, respectively, mediates and opposes induction of yawns by PD128,907 in rats. However, a high dose (56.0 mg/kg s.c.) of the D3 antagonist, SB-277011, was needed for full blockade, whereas the D2 antagonist, L741,626, which enhanced yawns, may have been "underdosed" at 1.0 mg/kg (Bristow et al., 1998; Millan et al., 2000a, 2004b; Pak et al., 2006). Moreover, dopaminergic agonists elicit yawns by postsynaptic actions in the paraventricular nucleus, a structure lacking D3 receptors (Argiolas and Melis 1998; Chen et al., 1999; Joyce 2001); yawns evoked by 7-OH-DPAT are unaffected by selective D3 antagonists yet abolished by L741,626 (Millan et al., 2000a, 2004b). Accordingly, blockade by S33138 probably reflects its antagonism of D2 receptors. DS properties of low doses of dopaminergic agonists principally reflect recruitment of presynaptic D3 and/or D2 receptors (Cory-Slechta et al., 1996; Bristow et al., 1998; Millan et al., 2000b). Inasmuch as the PD128,907 cue is resistant to selective D3 receptor antagonists, potent blockade by S33138 was unexpected. Nonetheless, potent antagonism of S33138 at presynaptic D3/D2 sites is underpinned by electrophysiological studies (see below), and S33138 is a potent antagonist at D3/D2 heterodimers, which may form in dopaminergic neurones (Millan et al., 2007).
Antagonist Properties of S33138 at D3/D2 Autoreceptors. Attenuation of the inhibitory influence of PD128,907 upon VTA firing by acute S33138 at doses as low as 0.004 mg/kg i.v. mimics findings with selective D3 antagonists; this action probably reflects blockade of D3 autoreceptors, activation of which phasically inhibits DA release and neuronal firing (Millan et al., 2000a,c,d, 2004a; Reavill et al., 2000; Drescher et al., 2005; Roberts et al., 2006). Conversely, full blockade of PD128,907 by higher doses of S33138 presumably reflects additional occupation of D2 receptors (Usiello et al., 2000). A comparable degree of "resolution" cannot be achieved in dialysis studies, but blockade by S33138 of the PD128,907-induced reduction of DA release in FCX, nucleus accumbens, and striatum (Millan et al., 2000c, 2004a; Reavill et al., 2000; Roberts et al., 2006) corroborates its antagonist properties at D3 (and D2) autoreceptors. Mimicking selective D3 antagonists, and in contrast to D3/D2 and preferential D2 antagonists, S33138 neither activated the VTA nor elevated extracellular levels of DA (Millan et al., 2000c,d; Roberts et al., 2006). There are several possible explanations. First, D3 autoreceptors are not tonically active. Furthermore, even when occluded by low doses of S33138, DA has access to inhibitory D2 autoreceptors (Millan et al., 2000c,d; Sokoloff et al., 2006). Second, extinction of "spontaneous" coupling at constitutively active D2 autoreceptors may account for activation of dopaminergic projections by haloperidol, an inverse agonist (Nilsson et al., 1996; Millan et al., 2000d); the possibility that S33138 behaves as a neutral antagonist is under exploration. Third, at high doses, antagonism by S33138 of excitatory, VTA-localized 5-HT2A receptors may dampen disinhibition of dopaminergic cell bodies via D2 receptor blockade (Millan et al., 2000d; Minabe et al., 2001). Regardless of the underlying reasons, this observation is intriguing because increased mesolimbic DA release provoked by haloperidol may interfere with concurrent antagonism of postsynaptic D2/D3 receptors and underlie patient resistance.
Lack of Antagonist Properties of S33138 at D1 Receptors. In rats sustaining a unilateral lesion of the SNPC, D1 receptor agonists elicit contralateral rotation, principally via supersensitive striatal D1 receptors, although D1 sites in the substantia nigra pars reticulata may also be involved (Asin and Montana, 1988; Gulwadi et al., 2001; Gerfen et al., 2002). This response is abolished by D1 antagonists such as SCH23390. Although S33138 possesses mild affinity for D1 receptors (Millan et al., 2007), it is >100-fold less potent than SCH23390 and did not influence SKF81297-induced rotation. Accordingly, D1 antagonism is unlikely to be an important component of its pharmacological properties.
Influence of S33138 upon Noradrenergic Neurones: Blockade of 2C-ARs. Although S33138 excited noradrenergic perikarya (Millan et al., 2000d; Invernizzi and Garattini, 2004), D3/D2 receptors are unlikely to be involved because active doses were substantially higher than those blocking the influence of PD128,907 on dopaminergic neurones. In addition, selective D3 receptor antagonists do not excite the LC (Millan et al., 2000c). Rather, antagonist properties of S33138 at 2C-AR autoreceptors may be implicated inasmuch they inhibit adrenergic cell firing (Arima, 1998; Millan et al., 2000d; Owesson et al., 2003). Nonetheless, the response of the LC to agonists is mainly transduced via 2A-ARs (Mateo and Meana, 1999; Pudovkina et al., 2001). Accordingly, the lack of affinity of S33138 for 2A-ARs accounts for its inability, in distinction to idazoxan, to prevent the suppressive influence of clonidine upon LC firing. These electrophysiological data provide a "surrogate" measure of the ability of S33138 to block postsynaptic populations of 2C-ARs inhibitory to motor function, mood, and cognition (Svensson, 2003; Marcus et al., 2005).
Antagonist Properties of S33138 at 5-HT2A and 5-HT7 Receptors. Because D3 receptor antagonists do not affect DOI-induced HTW, the modest antagonist properties of S33138 at 5-HT2A receptors (Millan et al., 2007) account for its inhibition of DOI-evoked HTW, which are abolished by selective 5-HT2A receptor antagonists, such as MDL100,907 (Schreiber et al., 1995). 5-HT2A sites mediating HTW are localized in the FCX (Willins and Meltzer, 1997), a structure implicated in the mood and cognitive deficits of schizophrenia, and 5-HT2A receptor blockade contributes to the atypical profile of certain antipsychotics, including their low extrapyramidal symptom potential (Meltzer et al., 2003). Activation of hypothalamic 5-HT7 sites elicits hypothermia, an effect blocked by the selective antagonist, SB269,970 (Hagan et al., 2000; Guscott et al., 2003). In relation, prevention of 5-CT-induced hypothermia by S33138 supports its abrogation of h5-HT7 receptor-coupled cAMP formation (Millan et al., 2007). Whereas blockade of 5-HT7 receptors is unlikely to control psychosis per se (Pouzet et al., 2002; Meltzer et al., 2003), it may exert a beneficial effect on comorbid symptoms, such as depressed mood and poor sleep (Hedlund and Sutcliffe, 2004).
Conclusions. In line with cellular studies (Millan et al., 2007), these data demonstrate modest antagonist properties of S33138 at central 2C-ARs, 5-HT2A receptors and 5-HT7 receptors. Most importantly, in line with antagonist properties at human D3 and D2L/D2S receptors, they demonstrate that S33138 blocks cerebral populations of presynaptic and postsynaptic D3 and D2 receptors. Furthermore, mimicking in vitro studies, the present in vivo observations support preferential actions of S33138 at D3 versus D2 receptors in the central nervous system. Thus, doses of S33138-inducing c-fos in the D3 receptor-rich IOC were 16-fold lower than those elevating c-fos in striatum, and a similar ratio was seen for doses of S33138 that reduced motor actions of ropinirole in Parkinsonian primates versus those that facilitated its actions. Although comparisons are less easy to make, the more potent inhibition by S33138 of the spontaneous firing of neurons in the VTA versus SNPC is also consistent with more marked D3 receptor antagonism. A limitation of these analyses is, of course, the contrasting routes, species, and treatment-durations employed, all inherent to the various procedures. Furthermore, whereas PET studies of S33138 in man show dose-dependent (10–70 mg p.o.) occupation of [11C]raclopride-labeled D2/D3 sites in basal ganglia (unpublished observations), radiolabeled antagonists differentiating D3 and D2 receptors are unavailable. Studies in mice genetically lacking D3 or D2 receptors would be useful in further characterizing the roles of D3 versus D2 receptors in the actions of S33138. However, certain procedures cannot be performed in this species; "knock-out" mice have their own limitations; and information on novel drugs from nongenetically modified animals is most relevant to their potential actions in man. Finally, it would be interesting to evaluate the actions of other antipsychotics at cerebral D3 versus D2 receptors in the procedures employed herein.
Thus, further study of the roles of D3 and D2 receptors in the actions of S31338 would be instructive, but the present in vivo and in vitro studies collectively suggest that it acts as a preferential and not selective antagonist of D3 versus D2 receptors. These observations provide an instructive framework for interpreting its potential antipsychotic properties in experimental studies and in ongoing (Phase II) clinical trials in man.
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ABBREVIATIONS: S33138, N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide; h, human; AR, adrenoceptor; CT, core temperature; 5-CT, 5-carboxytryptamine; DA, dopamine; DOI, 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane; DRN, dorsal raphe nucleus; DS, discriminative stimulus; FCX, frontal cortex; 5-HT, serotonin, 5-hydroxytryptamine; HTW, head twitches; IOC, Isles of Calleja; LC, locus coeruleus; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NA, noradrenaline; 7-OH-DPAT, (+)-7-dihydroxy-2-(di-n-propylamino)-tetralin; 8-OH-DPAT, (+)-8-dihydroxy-2-(di-n-propylamino)-tetralin; SNPC, substantia nigra, pars compacta; VTA, ventral tegmental area; WAY100,635, ((N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclo-hexanecarboxamide)fumarate; SKF81297, (±)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; SB269,970, (R)-1-{2-[1-(3-hydroxy benzensulfonyl) pyrrolidin-2-yl] ethyl}-4-methylpiperidine; SCH23390, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; PD128,907, (+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]-benzopyrano-[4,3-b]-1,4-oxazin-9-ol; SB-277,011, trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide; MDL100,907, (S)-(–)-4-[1-hydroxy-1(2,3-dimethoxyphenyl)methyl]N-2-4-fluorophenylethyl)piperidine; L741,626, 4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol; AP, anterior-posterior; L, lateral; DV, dorsal-ventral.
Address correspondence to: Dr. Mark J. Millan, Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125, Chemin de Ronde, 78290 Croissy-sur-Seine, France. E-mail: mark.millan{at}fr.netgrs.com
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