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NEUROPHARMACOLOGY
Psychopharmacology Department (M.J.M., M.B., A.D.) and Chemistry B Department (J.-L.P.), Institut de Recherches Servier, Paris, France; Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland (M.P.); Biotrial, Rue Jean-Louis Bertrand, 35000 Rennes, France (C.D.L.R.); and University Department of Pharmacology, Oxford, United Kingdom (F.S., T.S.)
Received November 5, 2003; accepted February 12, 2004.
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2-adrenoceptor agonist S18616 [(S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2'-(1',2',3',4'-tetrahydronaphthalene)]]. In a learned helplessness paradigm, S32504 (0.08–2.5 mg/kg) suppressed escape failures. Furthermore, in a chronic mild stress model of anhedonia, S32504 (0.16–2.5 mg/kg) rapidly restored the suppression of sucrose consumption. S32504 inhibited marble-burying behavior in mice (0.04–0.16 mg/kg) and aggressive behavior in isolated mice (0.04–2.5 mg/kg): only higher doses of ropinirole mimicked these actions of S32504. In tests of anxiolytic activity, S32504 was more potent (0.0025–0.16 mg/kg) than ropinirole in suppressing fear-induced ultrasonic vocalizations, and S32601 was inactive. Furthermore, in contrast to ropinirole, S32504 modestly enhanced punished responses in a Vogel conflict procedure and increased open-arm entries in a plus-maze. At doses active in the above-described procedures, S32504 did not elicit hyperlocomotion. In the forced-swim, marble-burying, and ultrasonic vocalization models, actions of S32504 were blocked by the D2/D3 antagonists haloperidol and raclopride and by the D2 antagonist L741,626 [4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol], but not by the D3 receptor antagonist S33084
[GenBank]
[(3aR,9bS)-N-[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl]-(4-phenyl)benzamide. Finally, chronic administration of S32504 did not, in contrast to venlafaxine, modify corticolimbic levels of serotonin2A receptors or brain-derived neurotrophic factor. In conclusion, S32504 displays a broad and distinctive profile of activity in models of potential antidepressive and anxiolytic properties. Its actions are more pronounced than those of ropinirole and principally involve engagement of D2 receptors.
). These often anticipate onset of frank motor dysfunction and are, in general, poorly treated by the prototypical antiparkinsonian agent L-3,4-dihydroxyphenylalanine (Giladi et al., 2000; Rascol et al., 2003). A perturbation of adrenergic, serotonergic, and cholinergic transmission likely contributes to these interrelated features of Parkinson's disease, but the principal underlying deficit is a degeneration of nigrostriatal dopaminergic projections together with a (less pronounced) dysfunction of mesolimbic and mesocortical dopaminergic pathways (Rascol et al., 2003). Interestingly, as indicated by the following observations, a disruption of dopaminergic transmission is implicated in the depressed mood displayed both by Parkinson and by non-Parkinson patients (Willner, 1995; Lambert et al., 2000; Tremblay et al., 2002).
First, compromised nigrostriatal dopaminergic transmission is implicated in the etiology of psychomotor retardation, a symptom characteristic of depressive states (Paillère Martinot et al., 2001). Second, mesolimbic dopaminergic projections innervating the nucleus accumbens fulfill a critical role in the control of reward, mechanisms of which are disrupted in depression (Willner, 1995; Tremblay et al., 2002). In accordance, chronic stress and depressive states are associated with impaired limbic dopaminergic transmission (Gambarana et al., 1999; Shumake et al., 2003). This deficiency is, in turn, implicated in the cardinal symptoms of despair and anhedonia (Willner, 1995). Although antidepressant agents do not enhance mesolimbic release of dopamine (DA) per se, they sensitize mesolimbic dopaminergic pathways and "strengthen" dopaminergic signaling in the nucleus accumbens (Ainsworth et al., 1998; D'Aquila et al., 2000). Third, the activity of mesocortical dopaminergic projections is also compromised in depressive states (Willner, 1995; Drevets, 2000), and a common trend of clinically effective antidepressants, exerted by a variety of mechanisms, is an enhancement in extracellular levels of DA in frontal cortex (see Millan et al., 2001c).
In line with the above observations, agonists at closely related D2, D3, and D4 receptors, such as the antiparkinsonian agents ropinirole, pramipexole, and bromocriptine, are active in experimental models of potential antidepressant activity (Willner, 1995; Lehr, 2002). In clinical trials in Parkinson and non-Parkinson patients, D2/D3 receptor agonists have also shown antidepressant properties, both alone and in synergy with selective serotonin (5-HT) reuptake inhibitors (Weddell and Weiser, 1995; Corrigan et al., 2000). However, most dopaminergic agonists exert actions at diverse classes of 5-HT receptor and -adrenoceptor (Millan et al., 2002). Furthermore, experimental studies of the influence of selective antagonists discriminating D2 and D3 (and D4) sites upon their antidepressant actions have not been undertaken to date. Thus, the precise mechanisms underlying potential antidepressant actions of dopaminergic agonists remain unclear. Moreover, most studies have been limited to single drugs, doses, and/or procedures (Willner, 1995; see Discussion).
In addition to depressed mood, Parkinson patients frequently display anxious symptoms, including panic attacks and social phobia (Millan, 2003). Furthermore, clinical anxiety is associated with an enhanced activity of central dopaminergic pathways (Millan, 2003), whereas studies in rodents have shown that acute fear provokes a transient acceleration in the activity of mesolimbic and mesocortical dopaminergic pathways, which is inhibited by benzodiazepines (Millan, 2003). Certain reports have, interestingly, indicated that D2/D3 agonists exert anxiolytic properties, likely by moderating this stress-induced activation of dopaminergic pathways (Bartoszyk, 1998; Rogers et al., 2000; Millan, 2003). However, data remain fragmentary, and the respective roles of D2 and D3 receptors in the putative anxiolytic properties of dopaminergic agonists remain unknown.
In the accompanying papers (Millan et al., 2004a,b), we describe a novel naphtoxazine, (+)-trans-3,4,4a,5,6,10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth[1,2-b]-1,4-oxazine (S32504), which behaves as an efficacious agonist at dopamine D3 and, less potently, D2 receptors. In contrast to most other antiparkinsonian agents (Millan et al., 2002), S32504 is highly selective, showing only weak partial agonist activity at 5-HT1A receptors and low affinity for all other (>50) sites examined. In accordance, via engagement of D2/D3 autoreceptors, S32504 suppresses the activity of cortical and subcortical dopaminergic (but not serotonergic or adrenergic) pathways. Furthermore, reflecting stimulation of postsynaptic D2/D3 receptors, S32504 exerts robust antiparkinsonian properties in diverse rodent and primate models. Interestingly, although D2 receptors mediate the motor actions of S32504, D3 receptors participate in its neuroprotective properties (Millan et al., 2004a,b). In light of these observations, the present studies evaluated the actions of S32504 in diverse models of potential antidepressant and anxiolytic activity in rodents. As in the accompanying papers (Millan et al., 2004a,b), the actions of S32504 were compared with those of the structurally distinct indolinone, ropinirole. Although ropinirole also acts as a preferential D3 versus D2 receptor agonist, it is less selective and less efficacious than S32504 and shows lower potency in vivo (Rogers et al., 2000; Millan et al., 2002; Rascol et al., 2003; Millan et al., 2004a,b). Finally, employing the D2/D3 receptor antagonists haloperidol and raclopride, the selective D3 receptor antagonist (3aR, 9bS)-N [4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl]-(4-phenyl)benzamide (S33084
[GenBank]
), and the preferential D2 receptor antagonist 4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol (L741,626) (Millan et al., 2000), we also evaluated the role of D2 compared with D3 receptors in the antidepressant and anxiolytic actions of S32504.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Forced-Swim Test in Rats. On the first day of the experiment, rats were individually immersed for 15 min in glass cylinders (30-cm height x 20-cm diameter) filled to a depth of 16 cm with water at 25°C. The following day, rats were again placed in the water, and the duration of immobility was recorded over 5 min. The rat was considered immobile when it remained floating passively in the water in an upright position, making only the small movements necessary to keep its head above the surface. S32504, racemic (±)S31411, (-)S32601 [the less active enantiomer of (+)S32504], ropinirole, or vehicle were administered 30 min prior to the test on day 2. In antagonism studies, haloperidol, raclopride, L741,626, S33084 [GenBank] , or vehicle were administered 30 min before S32504 (0.63 mg/kg, s.c.) or vehicle. Data were analyzed by analysis of variance (ANOVA) followed by Dunnett's test, and ID50s were calculated. For antagonists, the percent inhibition of the actions of S32504 was computed as follows: 100 x [1 - [(antagonist + S32504) - (vehicle + vehicle)]/[(vehicle + S32504) - (vehicle + vehicle)].
Forced-Swim Test in Mice. The procedure employed was detailed previously (Millan et al., 2001b). Male CD mice (Charles River, Saint Aubin les Elbeuf, France) of 22 to 26 g were placed in individual glass cylinders (24-cm height x 12-cm diameter) containing 6 cm of water at 24 ± 0.5°C for 6 min. Duration (seconds) of immobility was measured during the last 4 min of the test. A mouse was judged to be immobile when it floated in an upright position and made only minimal movements to keep its head above water. S32504, ropinirole, or vehicle were administered 30 min before the test. In antagonism studies, raclopride, L741,626, S33084
[GenBank]
, or vehicle were given 30 min before S32504 (0.63 mg/kg, s.c.) or vehicle. Data were analyzed by ANOVA followed by Dunnett's test, and ID50s were calculated. For antagonists, the percent inhibition of the actions of S32504 was computed as follows: 100 x [1 - [(antagonist + S32504) - (vehicle + vehicle)]/[(vehicle + S32504) - (vehicle + vehicle)].
Inhibition of S18616-Induced Loss of Righting Reflex in Rats. The procedure employed was detailed previously (Millan et al., 2000b, 2001b). Rats were positioned on their backs on a lab surface prepared with paper wadding, and their ability to right themselves was evaluated as follows: score 0, normal, complete righting reflex (animal set itself on all four limbs); score 1, attempted righting reflex (turn of at least 90°); score 2, attempted righting reflex (turn of less than 90°); and score 3, total loss of righting reflex (no attempt to turn, animal remains lying on its back). S32504, ropinirole, or vehicle were administered 30 min before S18616 (0.63 mg/kg, s.c.), which was given 30 min prior to scoring of the righting reflex. All vehicle-treated animals that received S18616 displayed a score of 3, and the number of rats displaying a score of 2 or less following drug treatment was determined. The significance of drug actions was evaluated by use of the Fisher's exact test, and ED50s were calculated based on the percentage of rats presenting a score of 2 or less.
Learned Helplessness Test in Rats. This study employed male Wistar rats of 200 to 220 g (R. Janvier, Le Genest-Saint-Isle, France). The procedure was detailed previously (Millan et al., 2001b). In brief, on day 1 of testing, "nonstressed" and "stressed" ("helpless") rats were put in a small Plexiglas box (20 x 10 x 10 cm) equipped with a stainless steel grid floor for 1 h. Over this period, stressed rats were exposed every minute to a 15-s inescapable shock (0.8 mA) delivered from a constant current shocker (LE 10026; Letica, Barcelona, Spain). On days 3 to 5 of testing, both groups of rats were submitted to an avoidance task (sessions 1 to 3, respectively) in a shuttle box (LE 916; Letica). This box was made of two equal-sized compartments divided by a stainless steel partition fitted with a gate (7 x 7 cm). Following a 5-min free exploration period, there were 30 stimulus shock trials with a 24-s intertrial period. Each trial consisted of a 3-s light presentation, followed by a 3-s shock (0.8 mA) presentation. For each trial, the rat could avoid shock by crossing into the other compartment during the light stimulus (avoidance response) or terminate shock by escaping into the other compartment (escape response). It received the shock when it did not cross into the other compartment (escape failure). For each session, the number of escape failures, intertrial crossings (transfer from one compartment to the other during the intertrial period), and exploratory crossings (locomotion during the 5-min shock-free period commencing the session) were measured. Drug (S32504, s.c., and imipramine, i.p.), vehicle (stressed groups), or vehicle (nonstressed group) were given on day 1, 6 h after exposure to shocks, and twice a day on days 2 to 5 (half the dose, 30 min before the avoidance session and the other half, 6 h later). For each avoidance session, differences between control (vehicle) stressed and nonstressed rats were evaluated by Student's t test, which was also used to analyze the action of imipramine. Data obtained with S32504 in stressed rats were analyzed by ANOVA followed by Dunnett's test.
Chronic Mild Stress (CMS)-Induced Reduction in Sucrose Consumption in Rats. This study employed male Wistar rats of 220 to 250 g (Gorzkowska, Warsaw, Poland). They were brought into the laboratory 2 months before the experiment. The procedure was as detailed previously (Millan et al., 2001b). In brief, single-housed animals were trained to consume a 1% sucrose solution during 10 1-h baseline tests (twice weekly) in which sucrose was presented in the home cage following 14-h food and water deprivation. Sucrose intake was measured by weighing bottles containing the sucrose solution before and at the end of the test. Subsequently, sucrose consumption was evaluated under similar conditions at weekly intervals throughout the entire experiment. On the basis of sucrose intake in the final baseline test, animals were separated into two matched groups. One was exposed to the CMS procedure for 8 weeks. Each week, stress consisted of two periods each of water or food deprivation, 45° cage tilt, intermittent illumination (lights on and off every 2 h), soiled cage (250 ml of water in sawdust bedding), paired housing, low-intensity stroboscopic illumination (150 flashes/min), and no stress. All stressors lasted 10 to 14 h and were imposed individually and continuously, day and night. Control groups were kept in separate rooms. On the basis of sucrose intakes, following an initial 3 weeks of stress, both stressed and control animals were further subdivided into matched subgroups and for a further 5 weeks received daily injections (i.p.) of S32504, imipramine, or vehicle. Drugs were administered at 10:00 AM, and the weekly sucrose tests were carried out for 24 h following the final drug injection. Data were analyzed by multiple ANOVA with three between-subjects factors (stress/control, drug treatment, and successive sucrose tests) followed by Fisher's LSD test.
Marble-Burying Behavior in Mice. As previously reported (Millan et al., 2001b), mice of 22 to 26 g were individually placed in transparent polycarbonate cages (30 x 18 x 19 cm) containing a 5-cm layer of sawdust and 24 glass marbles (1.5 cm in diameter) evenly spaced along the cage wall. Thirty minutes later, animals were removed, and the number of marbles at least two-thirds buried in the sawdust was recorded. Mice were treated 30 min prior to the test with S32504, ropinirole, or vehicle. In antagonism studies, haloperidol, raclopride, L741,626, S33084
[GenBank]
, or vehicle were administered 30 min before S32504 (0.16 mg/kg, s.c.) or vehicle. Data were analyzed by ANOVA followed by Dunnett's test and ID50s calculated for the actions of S32504 and ropinirole.
Aggression in Preisolated Mice. As previously reported (Millan et al., 2001b), pairs of CD male mice of 22 to 26 g (Charles River) were isolated in black cages for 1 month and then exposed to each other weekly for 2 months by placement of one mouse (always the same, "intruder") in the cage of the other ("resident"). On the test day, the intruder mouse was placed in the cage of the resident mouse, and the total number and duration of fights were monitored. Fighting was defined as episodes of biting, emitted by either mouse. Both mice were treated 30 min prior to the test with S32504, ropinirole, or vehicle. Data were analyzed by ANOVA followed by Dunnett's test, and ID50s were calculated.
Ultrasonic Vocalizations (USVs) in Rats. As previously reported (Millan et al., 2001a), three experimental phases were performed at intervals of 24 h. In brief, on day 1 (training), rats were put in a chamber equipped with a grid floor and exposed to six shocks (800 µA and 8 s) over 7 min. On day 2 (selection), they were placed in the chamber for 2 min and received a single shock. They were returned to the chamber 30 min later, and USV was recorded over 10 min. Only rats emitting USV for at least 90 s were examined further. On day 3, the procedure was identical to day 2, but rats were treated with S32504, S31411
[GenBank]
, S32601, ropinirole, or vehicle just after the 2-min session. The total duration of USV was recorded over the 10-min session. In antagonism studies, haloperidol, raclopride, L741,626, S33084
[GenBank]
, or vehicle were administered 30 min before S32504 (0.04 mg/kg, s.c.) or vehicle. Data were analyzed by ANOVA followed by Dunnett's test, and ID50s were calculated for S32504 and ropinirole.
Vogel Conflict Test (VCT) in Rats. As previously reported (Millan et al., 2001a), studies were undertaken in polycarbonate cages (32 x 25 x 30 cm) with a grid floor and the spout of a water bottle located 6 cm above the floor. The grid and the spout were linked to an Anxiometer (Columbus Instruments, Columbus, OH) that recorded licks and delivered shocks. During the 3 days preceding testing, rats were housed in groups of four and restricted for 1 h per day to tap water (9:00–10:00 AM). On day 4, just after water delivery, they were isolated in cages with a grid floor. On day 5, rats were placed in the test cage and the session initiated after the animal had made 20 licks and received a first, mild shock (a single, 0.5-s constant current pulse of 0.3-mA intensity) through the spout. Thereafter, a shock was delivered every 20th lick for 3 min. Animals that did not initiate the session within 5 min were removed. The number of licks emitted by the animal during the 3-min session was recorded. Certain control (vehicle) animals did not receive shocks during the session and were used to evaluate free drinking. S32504, ropinirole, or vehicle were given 30 min prior to testing. Drug effects were analyzed employing ANOVA followed by Dunnett's test (nonshocked animals were not included in the analysis). The percentage of drug effect was computed as: [(drug - vehicle)/(vehicle, nonshocked - vehicle)].
Elevated Plus-Maze Test in Rats. As previously reported (Millan et al., 2001a), studies were performed in a white mat-painted, plus-maze made of wood and placed at a height of 50 cm. The apparatus comprised two open arms (50 x 10 cm) and two enclosed arms of the same dimensions, with walls 40 cm high. Open arms were opposite each other. Rats were administered S32504, ropinirole, or vehicle and placed, 30 min later, in the central square of the maze facing one of the enclosed arms. The number of entries and time spent in open and enclosed arms was recorded by an observer situated 2 m from the maze. An entry was counted when the rat had all four limbs in an individual arm. Data analyzed were the total number of entries, the percent entries in open arms, and the percent time spent in open arms. Drug effects were analyzed employing ANOVA followed by Dunnett's test.
Locomotor Activity in Mice and Rats. As described in previous studies (Millan et al., 2001b; Brocco et al., 2002), the influence of S32504 compared with ropinirole upon locomotor activity was evaluated in mice and rats: 1) exposed to an unfamiliar environment and 2) prehabituated to the environment. In the studies performed in an unfamiliar environment, S32504, ropinirole, or vehicle were given 30 min before placing mice for 10 min, or rats for 12 min, in individual activity chambers. Mice activity chambers were white Plexiglas cages (27 x 27 x 27 cm) equipped with two rows of four photocells 2 cm above the floor and 6 cm apart connected through an interface to a microcomputer (Hesperid, Loiron, France). Rat activity chambers were transparent polycarbonate cages (35 x 24 x 19 cm) equipped with two infrared beams 4 cm above the floor and 22 cm apart, connected through Lablinc System interface (Coulbourn Instruments, Allentown, PA) to a microcomputer. In the studies performed with mice or rats prehabituated to the environment, animals were placed in the activity chambers just after drug or vehicle injection, and locomotor activity was recorded 30 min later for 10 min (mice) or 1 h (rats). In both procedures, data were locomotion counts, with one count corresponding to the consecutive interruption of two infrared beams. Data were analyzed by ANOVA followed by Dunnett's test.
Long-Term Influence upon Cerebral 5-HT2A Receptors and Brain-Derived Neurotrophic Factor (BDNF). Rats were treated once daily with S32504 (2.5 mg/kg, s.c.), venlafaxine (10.0 mg/kg, s.c.), or vehicle for 14 days. One day following the final injection, the cerebral density of 5-HT2A receptors was quantified as detailed elsewhere (Burnet et al., 1999) in sections of the cortex by autoradiography employing the radioligand, [3H]-ketanserin. Furthermore, as also described elsewhere (Zetterström et al., 1999), mRNA levels encoding BDNF were quantified throughout corticolimbic structures by in situ hybridization. The influence of drugs was expressed relative to control (vehicle-treated) values (defined as 100%).
Drugs. Dose-response curves were performed for all behavioral studies of agonists, with the exception of S32601, for which supplies were limited. Regarding the antagonists used to examine the role of D2 compared with D3 receptors in the actions of S32504, their essential properties may be briefly summarized as follows. The substituted benzamide, raclopride, presents high and balanced affinity for dopamine D2 and D3 receptors, and it behaves as a potent antagonist of cerebral populations of these sites in vivo: it is virtually devoid of other receptor interactions (Millan et al., 1998). The butyrophenone derivative, haloperidol, shares the potent and equilibrated antagonist properties of raclopride at dopamine D2 and D3 receptors in vitro and in vivo, although it is also possesses high affinity for dopamine D4 receptors (Bartoszyk, 1998; Campbell et al., 1999). Finally, the benzopyrollidine, S33084
[GenBank]
, is a potent and highly selective antagonist at dopamine D3 sites, whereas L741,626 behaves, in an opposite fashion, as a preferential antagonist at dopamine D2 versus D3 receptors (Millan et al., 2000; Silverdale et al., 2002). For antagonists, the doses used correspond to those defined as selective in previous studies (Millan et al., 1998, 2000; Silverdale et al., 2002). Racemic (±)S31411 and the less active enantiomer of (+)S32504, (-)S32601, were evaluated in key tests of antidepressant (forced swim) and anxiolytic (USV) activity, respectively. All drug doses are in terms of the base. Drugs were dissolved in sterile water, if necessary, plus a few drops of lactic acid, and pH was adjusted to as close to normality (> 5.0) as possible. Unless otherwise specified, drugs were injected s.c. in an injection volume of 1 ml/kg. Drug structures, sources, and salts were as follows: haloperidol, imipramine HCl, raclopride tartrate (Sigma, Quentin St. Fallavier, France), and L741,626 (Tocris Cookson Inc., Bristol, UK). S33084
[GenBank]
was synthesized by G. Lavielle (Servier, Paris, France), and S18616 HCl was synthesized by A. Cordi (Servier). Ropinirole HCl, venlafaxine, WAY100,635 [N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohexane carboxamide], S32504, its (-)-entantiomer S32601, and racemic (±)S31411 were synthesized by J.-L. Peglion (Servier).
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Influence of S32504 upon the Motor-Suppressant Properties of S18616. The 2-adrenoceptor agonist S18616 (0.63 mg/kg, s.c.) elicited a complete loss of righting reflex in all vehicle-treated rats (score = 3, see Materials and Methods). S32504 and, less potently, ropinirole dose-dependently blocked the loss of righting reflex elicited by S18616. Administered alone, they were without effect (not shown) (Fig. 3; Table 1).
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Activity of S32504 in the Learned Helplessness Test. Compared with control, nonstressed animals, subjects exposed to inescapable shock ("helpless") manifested a significantly higher number of escape failures (Fig. 4; Table 1). In analogy to imipramine (the internal, positive control), on each of the three avoidance task sessions, at doses of 0.08, 0.64, and 2.5 mg/kg, s.c., S32504 elicited a significant reduction in escape failures. Compared with control, nonstressed animals, the "helpless" animals showed a significantly lower number of intertrial crossings. In analogy to imipramine, S32504 significantly increased intertrial crossings at doses of 0.64 and 2.5 mg/kg in each session. However, the lowest dose tested (0.08) did not, in contrast to escape failures, elicit a significant effect, and intertrial crossings were only weakly affected during the first session. In session 1, compared with control, nonstressed animals, the "helpless" animals showed no significant change in the number of crossings during the free exploration period. Both S32504 and imipramine significantly reduced the number of exploratory crossings. In an opposite fashion, in sessions 2 and 3, compared with control, nonstressed animals, exploratory crossings were significantly reduced in "helpless" animals. S32504 significantly increased these crossings at the doses of 0.64 (session 3) and 2.5 (sessions 2 and 3) mg/kg, whereas the lowest dose tested of S32504 (0.08) and imipramine did not elicit a significant effect.
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Influence of S32504 upon the Reduction in Sucrose Consumption Induced by CMS. Following exposure to CMS for a period of 3 weeks, animals displayed a pronounced reduction in sucrose intake relative to control, nonstressed rats (Fig. 5; Table 1). Daily administration of S32504 was associated with a pronounced dose (0.16–2.5) and time-dependent augmentation of sucrose consumption toward normal, control levels in stressed subjects. Indeed, the highest dose of S32504 (2.5 mg/kg, s.c.) was significantly active after only 1 week of treatment. Imipramine (the internal, positive control) also displayed an enhancement in sucrose consumption at the dose of 10.0 mg/kg, i.p., although it was significantly active only after 4 weeks administration. In control, nonstressed animals, only the highest dose of S32504 (2.5 mg/kg, s.c.) significantly modified sucrose consumption relative to vehicle: F(1,84) = 7.8, P < 0.01. In a post hoc Fisher's LSD test, its effect was significant relative to vehicle only on week 3, and, across the 5 weeks of testing, there was no significant difference between S32504 (2.5) and basal values in control animals. Other doses of S32504 had no significant effect on sucrose consumption in nonstressed rats compared with either vehicle-treated or basal values: 0.04 mg/kg, F(1,84) = 1.6, P > 0.05; 0.16 mg/kg, F(1,84) = 1.8, P > 0.05; and 0.63 mg/kg, F(1,84) = 0.7, P > 0.05. No dose of S32504 significantly modified body weight in either stressed or control animals (not shown).
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Influence of S32504 upon Marble-Burying Behavior. S32504 dose-dependently reduced marble-burying behavior in mice, an action likewise seen with ropinirole, although over a higher dose range (Fig. 6; Table 1). Haloperidol, raclopride, and L741,626 all significantly attenuated the influence of S32504 upon marble-burying behavior, whereas its actions were not significantly affected by S33084 [GenBank] . None of the antagonists significantly affected marble-burying behavior alone at the doses administered, although L741,626 elicited a nonsignificant tendency toward a reduction. The selective 5-HT1A receptor antagonist WAY100,635 (0.16 mg/kg, s.c.) did not modify the actions of S32504: n = 8 per group, vehicle/vehicle, 19.5 ± 0.8 hidden marbles; WAY100,635/vehicle, 17.0 ± 1.3 hidden marbles; vehicle/S32504 (0.16 mg/kg, s.c.), 7.4 ± 1.7 hidden marbles; and WAY100,635/S32504, 9.0 ± 2.1 hidden marbles, no significant effect of WAY100,635 (P > 0.05).
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Influence of S32504 upon Aggressive Behavior. In pairs of preisolated, familiar mice, placement of the "intruder" mouse into the cage of the "resident" mouse elicited aggressive behavior. S32504 dose-dependently attenuated aggressive behavior, as shown by a reduction in the number and duration of attacks (Fig. 7; Table 1). This action of S32504 was reproduced (less potently) by ropinirole.
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Activity of S32504 in the USV Procedure. S32504 dose-dependently reduced the duration of USV in rats re-exposed to an environment in which they had previously received an aversive stimulus (Fig. 8; Table 1). Over the same dose-range, (±)S31411 was also active, and, although (-)S32601 tended to decrease USV, this effect did not attain statistical significance. The action of S32504 was mimicked, although less potently, by ropinirole. In the presence of haloperidol, raclopride, or L741,626, the inhibitory influence of S32504 upon USV was significantly reduced, whereas S33084 [GenBank] was ineffective in this regard. These antagonists were inactive alone. The selective 5-HT1A receptor antagonist WAY100,635 (0.16 mg/kg, s.c.) did not modify the action of S32504 (0.04 mg/kg, s.c.), n = 6 per group: vehicle/vehicle, 296.3 ± 59.5 s; WAY100,635/vehicle, 308.3 ± 61.1 s; vehicle/S32504, 14.3 ± 5.7 s; and WAY100,635/S32504, 26.3 ± 12.3 s, no significant effect of WAY100,635 (P > 0.05) (Table 2).
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Activity of S32504 in the VCT. S32504 elicited a significant, modest, and dose-dependent increase in punished responses in the VCT: the percent increase in punished responses was 4%, 10%, 19%, and 25% for the doses of 0.16, 0.63, 2.5, and 5 mg/kg, respectively. In distinction, ropinirole was ineffective (Fig. 9; Table 2).
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Activity of S32504 in the Plus-Maze Test. Administered over a broad dose range, S32504 evoked a significant increase in percent entries in open arms of the plus-maze, although its dose-response curve was biphasic (Fig. 10; Table 1). A similar profile was obtained for percent time in open arms, although statistical significance was not reached. S32504 did not suppress total arm entries at any dose examined. Over the same dose range, ropinirole did not significantly modify the percent number of open arm entries nor time spent in open arms. It significantly decreased the total number of arm entries at doses of 0.16 and 10.0 mg/kg (Table 2).
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Influence of S32504 upon Motor Behavior. S32504 did not significantly affect motor behavior of rats habituated to the activity chamber, although there was a clear tendency to a decrease at 0.16 mg/kg (Fig. 11). In nonhabituated rats, S32504 significantly reduced locomotion over a broad range of doses. In mice either habituated or nonhabituated to the environment, S32504 significantly reduced locomotion at doses of 0.16 to 10.0 mg/kg. Thus, S32504 did not increase motor activity in either rats or mice. Ropinirole significantly increased locomotion in rats habituated to the environment at a high dose (10.0), although lower doses tended to decrease locomotion. Moreover, a marked reduction was seen in nonhabituated rats. In mice either habituated or nonhabituated to the environment, ropinirole dose-dependently decreased locomotion at doses of 0.04 to 0.63 mg/kg, although the curve inflected at higher doses.
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Influence of S32504 upon Cerebral Levels of 5-HT2A Receptors and mRNA Encoding BDNF. Chronic administration of the serotonin/noradrenaline reuptake inhibitor and antidepressant agent venlafaxine, employed as an internal positive control, provoked a robust reduction in the density of 5-HT2A receptors in the cingulate and frontal cortex (Fig. 12). In contrast, their levels were unaffected by S32504. Venlafaxine markedly elevated the level of mRNA encoding BDNF in cingulate (although not frontal) cortex and in the CA3 and dentate gyrus regions of the hippocampus. In contrast, S32504 did not modify levels of BDNF in any of these structures.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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; Maj et al., 1997), actions which can be dissociated from their influence upon motor function (Borsini et al., 1988; Maj et al., 1997). In accordance, S32504 dose-dependently and stereospecifically suppressed immobility over a dose range that did not stimulate locomotion. Consistent with a study employing the D2/D3 antagonist sulpiride and the agonist apomorphine (Borsini et al., 1988), haloperidol and raclopride abolished the actions of S32504. Importantly, L741,626 also blocked the reduction in immobility elicited by S32504, whereas S33084
[GenBank]
was ineffective, suggesting a key role for D2 versus D3 receptors (Figs. 1 and 2). Increases in immobility provoked by high doses of D2 antagonists in the forced-swim model likely reflect motor dysfunction (Borsini et al., 1988; Drago et al., 2000). On the other hand, sustained administration of low doses of amisulpride and raclopride elicited antidepressant actions, presumably via preferential blockade of D2/D3 autoreceptors inhibitory to DA release (Drago et al., 2000). Inasmuch as L741,626 increases mesolimbic DA release (Millan et al., 2004a), it would be interesting to evaluate its long-term actions (and those of S33084
[GenBank]
) in this paradigm. Although we did not examine the site of action of S32504, studies of other D2/D3 agonists suggest that postsynaptic D2 sites in the nucleus accumbens are implicated (Muscat et al., 1992; Willner, 1995; D'Aquila et al., 2000).
Reduction of Resignation and Psychomotor Retardation. Antidepressant actions in the learned helplessness procedure reflect their influence upon both resignation and "psychomotor retardation," as reflected in a decrease in escape failures and an increase in intertrial crossings ("disinhibition"), respectively (Martin et al., 1990; Willner, 1995; Millan et al., 2001b). Notably, then, S32504 potently reduced escape failures and increased intertrial crossings although, by analogy to a study of apomorphine (Geoffroy and Christensen, 1993), S32504 preferentially influenced escape failures. A further parallel to this study was the progressive increase in intertrial crossings upon repeated testing with S32504, perhaps reflecting motor sensitization. Indeed, potential motor effects of D2/D3 agonists invite caution in interpreting their antidepressant effects. Nevertheless, a dissociation was seen on session one where the reduction in escape failures by S32504 was accompanied by a decrease in exploratory crossings (a measure of motor performance). Moreover, for all sessions, the lowest dose of S32504 suppressed escape failures without affecting exploratory crossings. Actions of S32504 in this procedure appear, therefore, to be specific.
A further empirical indication of the specific influence of S32504 (and ropinirole) upon psychomotor retardation is provided by their ability, like monoamine reuptake inhibitors, to block the motor-suppressant effects of the 2-adrenoceptor agonist S18616 at doses that do not enhance locomotor activity (Millan et al., 2001b). Furthermore, S32504 and ropinirole also specifically alleviate reserpine-induced akinesia (Millan et al., 2004b), a model likewise relevant to the psychomotor retardation of depressive states (Willner, 1995).
Antianhedonic Properties. CMS is characterized by antidepressant-reversible changes in dopaminergic transmission in the nucleus accumbens (Muscat et al., 1992; Papp et al., 1994; Willner, 1995; Di Chiara et al., 1999), and sucrose consumption is associated with alterations in DA release in this structure (Hajnal and Norgren, 2001). Intermittent administration of D2/D3 agonists restored suppressed sucrose consumption in stressed subjects (Muscat et al., 1992). However, the positive effects of pramipexole were complicated by weight loss and enhanced sucrose intake in nonstressed subjects (Willner, 1995; 1997). It is of importance, thus, that S32504 exerted a robust, rapid, and dose-dependent elevation in sucrose consumption in CMS-exposed rats in the absence of an influence upon body weight. Furthermore, with the exception of a single time-point at the highest dose, it did not elevate sucrose intake in controls. These data provide compelling evidence for specific anti-anhedonic actions of S32504 and could instructively be complemented by other measures of reward, such as self-stimulation (Willner, 1997). At doses active in the CMS model, S32504 suppresses mesolimbic release of dopamine via activation of D2 (D3) autoreceptors (Millan et al., 2004a). Thus, stimulation of postsynaptic populations of these sites is clearly involved in its antianhedonic properties. Although the role of D3 compared with D2 receptors remains to be determined, it is interesting to note that raclopride blunts the antianhedonic actions of quinpirole and imipramine in the CMS paradigm (Muscat et al., 1992).
Inhibition of "Impulsive" and Aggressive Behavior. Marble-burying behavior is suppressed by selective 5-HT reuptake inhibitors and tricyclics (Millan et al., 2001b), both of which are clinically effective in treating obsessive-compulsive disorders, although marble burying cannot be considered a model of this behavior per se (De Boer and Koolhaas, 2003). Via interactions with serotonergic networks, dopaminergic pathways are implicated in mechanisms controlling impulsive behavior (Harrison et al., 1997; Campbell et al., 1999). Furthermore, although DA exerts a diversity of effects upon impulsivity, activation and blockade of D2 receptors can, respectively, improve and worsen performance in rodent models of impulsive behavior (Campbell et al., 1999; Wade et al., 2000). Notably, then, S32504 potently reduced marble burying via actions at D2 rather than D3 receptors.
By analogy to marble burying, blockade of aggressive behavior in isolated adult mice is an empirical model of potential antidepressant properties inasmuch it is responsive to diverse classes of antidepressant agent (Millan et al., 2001b). Notably, long-term isolation modifies dopaminergic transmission (Ahmed et al., 1995; Gendreau et al., 2000), and corticolimbic release of DA is altered both before and following aggressive encounters (Isovich et al., 2001; Ferrari et al., 2003). It is, thus, of interest that S32504 inhibited aggressive behavior, an effect mimicked by ropinirole and other D2/D3 receptor agonists (Gendreau et al., 2000). Unfortunately, the role of D3 versus D2 receptors could not be deciphered since D2 (and D2/D3) antagonists themselves nonspecifically (motor disruption) suppress aggressive behavior (Gendreau et al., 2000; M. Brocco, unpublished observations).
Anxiolytic Properties. Although Gendreau et al. (2000) speculated that antiaggressive actions of D2/D3 ligands reflect increased fearfulness, there is evidence suggesting anxiolytic actions of D2/D3 agonists under other conditions (Millan, 2003). In the plus-maze model, D2/D3 agonists have generally proven inactive, although ropinirole (Rogers et al., 2000) biphasically increased open arm time in rats upon administration i.p., possibly explaining the difference to the present work where it was inactive s.c. Contrariwise, S32504 (biphasically) elevated open arm entries, whereas total entries were not modified, suggesting a specific anxiolytic action. In the punishment-based VCT, S32504 revealed modest anxiolytic properties over a comparable dose range. Although ropinirole again proved inactive, other D2/D3 agonists such as apomorphine are effective in this paradigm, and their effects have been shown not to reflect an influence upon water intake or nociceptive thresholds (see Millan, 2003). The VCT incorporates a component of conditioning, and in a model in which this element is more prominent, induction of USV, both S32504 and ropinirole were potently active corroborating work with other D2/D3 agonists (Bartoszyk, 1998; Sanchez, 2003). Interestingly, the USV paradigm may reflect a panic-like state that has been ascribed to excessive activation of corticolimbic dopaminergic pathways (Millan, 2003). Supporting a role of presynaptic D2/D3 sites in the anxiolytic actions of dopaminergic agonists, the preferential autoreceptor agonist preclamol is active in the USV and VCT procedures, whereas introduction of D2/D3 agonists into the ventrotegmental area suppresses conditioned fear and the accompanying activation of dopaminergic projections (Gifkins et al., 2002; Millan, 2003). Inasmuch as S32504 potently suppresses corticolimbic DA release at doses active in the present procedures (Millan et al., 2004b), its actions at D2/D3 autoreceptors on ventrotegmental dopaminergic neurones likely contribute to its anxiolytic properties. In line with this possibility, the control of DA released by S32504 is predominantly mediated by D2 receptors that were shown to mediate the suppression of USV by S32504 (Fig. 8).
Lack of Modulation of 5-HT2A Receptors and BDNF Levels. Tricyclic antidepressants decrease cortical levels of 5-HT2A receptors upon long-term administration with a time course paralleling onset of clinical efficacy (Maes and Meltzer, 1995; Yatham et al., 1999). Extending our report of a venlafaxine-induced decrease of 5-HT2A sites in cortex (Millan et al., 2001c), the present autoradiographical approach localized this effect to cingulate and frontal territories. In contrast, chronic administration of S32504 did not modify levels of 5-HT2A receptors, supporting the contention that their down-regulation characterizes long-term effects of certain classes of antidepressant only (Maes and Meltzer, 1995; Yatham et al., 1999). Venlafaxine also enhanced BDNF expression in cortex and hippocampus, mimicking studies with other 5-HT and/or noradrenaline reuptake inhibitors (Duman et al., 1999). BDNF promotes synaptic transmission and may restore neurogenesis in depressed states, although its precise significance to actions of antidepressant agents awaits clarification (Duman et al., 1999; Coppell et al., 2003; Shimizu et al., 2003). The significance of the lack of BDNF induction by S32504 for its antidepressant profile remains, therefore, unclear. In any case, these neurochemical findings emphasize the distinctive profile of action of S32504 in models of potential antidepressant activity.
D2 and D3 Receptors in the Expression of Antidepressant Properties. In line with the present findings indicating that D2 receptors mediate antidepressant actions of S32504 (and other D2/D3 agonists, unpublished observations), chronic stress reduces the limbic density and functional status of D2 receptors, whereas long-term treatment with antidepressant agents exerts opposite effects (Dziedzicka-Wasylewska et al., 1997). However, other studies have demonstrated that the density of D3 receptors is up-regulated by chronic exposure to antidepressants (Dziedzicka-Wasylewska et al., 1997; Maj et al., 1998; Lammers et al., 2000). Thus, a potential role of D3 receptors in the long-term antidepressant—and anxiolytic—actions of S32504 remains to be more fully explored.
Conclusions. S32504 displays a broad-based and distinctive pattern of activity in models predictive of antidepressant and anxiogenic properties, actions principally mediated via D2 receptors. An improvement of mood would clearly be beneficial in Parkinson patients. However, the genuine utility of S32504 to the wider management of depressive and anxious states clearly requires clarification. Finally, the studies described in the present and accompanying papers (Millan et al., 2004a,b) comprise a (uniquely) comprehensive characterization of: first, the functional profile of a novel and selective D2/D3 receptor agonist, S32504; and second, the role of D3 compared with D2 receptors in the expression of antiparkinsonian, neuroprotective, antidepressant, and anxiolytic properties. S32504 clearly offers an instructive tool for further exploration of the significance of D3 and D2 receptors to the etiology and treatment of psychiatric and neurological disorders.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: DA, dopamine; 5-HT, 5-hydroxytryptamine (serotonin); S32504, (+)-trans-3,4,4a,5,6,10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth[1,2-b]-1,4-oxazine; S33084 [GenBank] , (3aR,9bS)-N-[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl]-(4-phenyl)benzamide; L741,626, 4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol; ANOVA, analysis of variance; S18616, (S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2'-(1',2',3',4'-tetrahydronaphthalene)]; CMS, chronic mild stress; LSD, least significant difference; USV, ultrasonic vocalization; VCT, Vogel conflict test; BDNF, brain-derived neurotrophic factor; WAY100,635, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohexane carboxamide; S32601, (-)-trans-3,4,4a,5,6,10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth-[1,2-b]-1,4-oxazine.
Address correspondence to: Dr. Mark J. Millan, Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125 chemin de Ronde, 78290 Croissy/Seine, France. E-mail: mark.millan{at}fr.netgrs.com
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5 per value. ANOVA as follows: panel A, S32504, F(4,34) = 28.9, P < 0.001; (±)S31411, F(5,30) = 19.4, P < 0.001; (-)S32601, P > 0.05 (Student's two-tailed t test); and ropinirole, F(4,20) = 22.9, P < 0.001. Panel B, influence of haloperidol versus S32504, F(3,15) = 53.7, P < 0.001; and effect of haloperidol alone, F(3,12) = 2.0, P > 0.05. Panel C, influence of raclopride versus S32504, F(3,20) = 48.0, P < 0.001; and effect of raclopride alone, F(3,19) = 4.2, P < 0.05. Panel D, influence of L741,626 versus S32504, F(4,29) = 26.2, P < 0.001; and effect of L741,626 alone, F(4,28) = 1.8, P > 0.05. Panel E, influence of S33084
