Blockade of dopamine D3 receptors in frontal cortex, but not in sub-cortical structures, enhances social recognition in rats: Similar actions of D1 receptor agonists, but not of D2 antagonists

European Neuropsychopharmacology (2009) 19, 23–33

w w w. e l s e v i e r. c o m / l o c a t e / e u r o n e u r o

Blockade of dopamine D3 receptors in frontal cortex, but not in sub-cortical structures, enhances social recognition in rats: Similar actions of D1 receptor agonists, but not of D2 antagonists Florence Loiseau ⁎, Mark J. Millan Institut de Recherches Servier, Department of Psychopharmacology, 125 Chemin de ronde, 78290 Croissy-sur-Seine, Paris, France

Received 15 January 2008; received in revised form 25 July 2008; accepted 29 July 2008

KEYWORDS D3 receptor; D1 receptor; Social recognition; Frontal cortex; Nucleus accumbens; Striatum

Abstract Though D3 receptor antagonists can enhance cognitive function, their sites of action remain unexplored. This issue was addressed employing a model of social recognition in rats, and the actions of D3 antagonists were compared to D1 agonists that likewise possess pro-cognitive properties. Infusion of the highly selective D3 antagonists, S33084 and SB277,011 (0.04–2.5 µg/ side), into the frontal cortex (FCX) dose-dependently reversed the deficit in recognition induced by a delay. By contrast, the preferential D2 antagonist, L741,626 (0.63–5.0) had no effect. The action of S33084 was regionally specific inasmuch as its injection into the nucleus accumbens or striatum was ineffective. A similar increase of recognition was obtained upon injection of the D1 agonist, SKF81297 (0.04–0.63), into the FCX though it was also active (0.63) in the nucleus accumbens. These data suggest that D3 receptors modulating social recognition are localized in FCX, and underpin their pertinence as targets for antipsychotic agents. © 2008 Published by Elsevier B.V.

1. Introduction Dopaminergic innervation plays a major role in the control of mood and its perturbation is implicated in the pathogenesis of several psychiatric disorders, including schizophrenia and major depression (Millan, 2006; Nesler and Carlezon, 2006; ⁎ Corresponding author. Tel.: +33 1 55 72 21 91; fax: +33 1 55 72 20 82. E-mail address: [email protected] (F. Loiseau). 0924-977X/$ - see front matter © 2008 Published by Elsevier B.V. doi:10.1016/j.euroneuro.2008.07.012

Meisenzahl et al., 2007). Dopamine also plays an important role in the control of cognitive processes that are likewise disrupted in psychosis, depression and other CNS diseases (Neioullon, 2002; Robbins, 2003). Correspondingly, there is increasing interest in drugs that target dopaminergic mechanisms for the management of both the affective and cognitive symptoms of psychiatric states. Clearly, for optimal therapeutic exploitation of dopaminergic agents, it is essential to elucidate the roles of individual dopamine receptor subtypes.

24 Dopamine (DA) exerts its action via two subfamilies of Gprotein-coupled receptors: D1-like (D1 and D5) and D2-like (D2, D3 and D4) (Missale et al., 1998; Vallone et al., 2000). D1 receptors are expressed in many structures controlling cognitive function, including the frontal cortex (FCX) and hippocampus (Dubois et al., 1986; Köhler et al., 1991; Huang et al., 1992), and their participation in the modulation of cognitive processes has been extensively studied. Thus, D1 receptor agonists improve performance in a variety of cognitive models in rodents and primates (McGurk et al., 1992; Hersi et al., 1995; Steele et al., 1997; Hotte et al., 2005). In this regard, there is compelling evidence for a key role of the FCX since, over a critical range doses, activation of frontocortical population of D1 receptors exerts a facilitatory influence upon working memory and attentional processes (Sawaguchi and Goldman-Rakic, 1991; Cai and Arnsten, 1997; Seamans et al., 1998; Granon et al., 2000; Chudasama and Robbins, 2004, 2006). Other brain areas may also be involved in the pro-cognitive actions of D1 receptor activation. Indeed, D1 receptor agonists have been shown to improve attentional performance in a 5-choice serial reaction time task (5-CSRT) when infused into the nucleus accumbens (NAC) (Pezze et al., 2007). Further, in the hippocampus, D1 or, more likely, D5, receptors have been implicated in mechanisms underlying long-term spatial memory (Hersi et al., 1995; Seamans et al., 1998). While D2 receptors are widely expressed in the basal ganglia and many other brain areas, D3 receptors are principally localized in limbic structures, including the nucleus accumbens, olfactory tubercules and islands of Calleja, though they are also found in the FCX and other cortical structures (Sokoloff et al., 1990; Murray et al., 1994; Meador-Woodruff et al., 1996; Diaz et al., 2000). In line with their corticolimbic distribution, the role of D3 receptors in the control of motivation and affect has been intensively studied, together with their potential as targets for the treatment of drug abuse and schizophrenia (Heidbreder et al., 2005; Joyce and Millan, 2005; Sokoloff et al., 2006). Inasmuch as psychotic states are characterized by marked impairment of cognition, there is also increasing interest in the potential role of D3 receptors for the modulation of cognitive function. The highly potent D3 receptor agonist, 7-OH-DPAT, impaired passive avoidance performance in mice and disrupted object discrimination task in marmosets (Ukai et al., 1997; Smith et al., 1999). Further, several studies have raised the possibility that blockade of D3 receptors may facilitate cognitive function. Thus, the preferential D3 versus D2 receptor antagonist, nafadotride, attenuated the disruption of memory elicited by scopolamine in the passive avoidance test (Sigala et al., 1997), and the highly selective D3 antagonist, SB277,011, prevented scopolamine-induced impairment of spatial memory in a water maze (Laszy et al., 2005). Furthermore, specific (though not all) facets of cognitive performance were improved in mice genetically deprived of D3 receptors (Glickstein et al., 2002, 2005). In contrast to D3 sites, blockade or genetic inactivation of D2 receptors does not improve cognitive performance, but may rather exert a negative influence upon cognitive function (Wilkerson and Levin, 1999; Umegaki et al., 2001; Laszy et al., 2005, Glickstein et al., 2005). In line with the above findings, we recently demonstrated that systemic administration of selective D3 but not D2 receptor antagonists enhances social memory in rats (Millan

F. Loiseau, M.J. Millan et al., 2007, 2008a). That is, the ability of an adult rat to recognize a younger conspecific, a procedure incorporating components of visual and olfactory short-term working memory, as well as attention (Popik and van Ree, 1998, Ferguson et al., 2002; Millan and Brocco, in press). The location of D3 receptors involved in the effects of D3 antagonists upon social (and other forms of) cognition has not, as yet, been identified. To this end, the present work examined the potential significance of D3 receptors located in projection targets of the three main ascending (mesocortical, mesolimbic and nigrostriatal) dopamine pathways. Thus, we evaluated the influence upon social recognition of frontocortical infusion of two highly selective D3 receptor antagonists, S33084 (Millan et al., 2000a,b) and SB277,011 (Reavill et al., 2000; Heidbreder et al., 2005) (Table 1). The FCX is of particular interest in view of its broad role in the integration of cognitive processes, and its strong implication in the impairment of cognition in schizophrenia (Steckler et al., 1998; Dalley et al., 2004; Lee et al., 2006). Further, we compared the actions of S33084 in the FCX to its effects in first, the nucleus accumbens (NAC), a structure enriched in D3 receptors and involved in the modulation of affective components of mnemonic function, though not social memory, and second, the striatum, which is specifically implicated in procedural memory and possesses only a low density of D3 receptors (Dalley et al., 2004; Pezze and Feldon, 2004; Chudasama and Robbins, 2006). To elucidate the comparative roles of D3 versus D2 receptors, we also evaluated the influence of intra-FCX infusion of the preferential D2 receptor antagonist, L741,626 (Bristow et al., 1998; Millan et al., 2000a,b). Finally, inasmuch as systemic administration of D1 receptor agonists facilitates social memory (Di Cara et al., 2007), the effects of D3 antagonists were compared to those of the D1 receptor agonist SKF81297 (Arnt et al., 1988; Cussac et al., 2004; Mannoury La Cour et al., 2007), which has been shown to improve performance in object recognition and 5-CSRT procedures upon administration into the FCX (Chudasama and Robbins, 2004; Floresco, 2001). Finally, we also investigated the influence of D1 receptors blockade by SCH23390, a selective D1 receptor antagonist (Cussac et al., 2004; Mannoury La Cour et al., 2007), upon the action of intra-FCX SKF81297.

2. Materials and methods 2.1. Animals The experiments were conducted on male Wistar rats kept under standard laboratory conditions. Adult Wistar rats

Table 1

SB277,011 S33084 L741,626

←\\\pKi\\\→

← \\\pKi \\\→

←\\\pKB\\\→

rD3

rD2

hD3

hD2

hD3

hD2

8.0 8.7 6.5

5.6 6.8 7.5

8.0 9.6 7.2

6.0 7.5 8.4

8.4 9.6 7.4

6.5 7.7 8.7

Data for SB277,011 are from Reavill et al., 2000. Data for S33084 and L741,626 are from Cussac et al., 2000 (rat, r) and from Millan et al., 2000a (human, h). Affinities are expressed as pKi values and antagonist potencies as pKB values.

Blockade of dopamine D3 receptors in frontal cortex enhances social recognition in rats weighing 200–220 g (49–52 days old) and juvenile Wistar rats (21 days old) (Elevage Janvier, le Genest-Saint-Isle, France) were used. They were housed in sawdust-lined cages with unrestricted access to standard chow and water. Laboratory temperature was 21 1 °C and humidity 60 5%. There was a 12 h/ 12 h light/dark cycle (lights on at 7:30 a.m.). All animal use procedures conformed to international European ethical standards and to (86/609-EEC) decrees of the French National

25

Committee (décret 87/848) for the care and use of laboratory animals.

2.2. Social recognition procedure The procedure used was essentially that described elsewhere (Millan et al., 2004, 2007; Di Cara et al., 2007). Adult rats were individually housed for 2 days before testing. On the

Figure 1 Schematic illustration of the sites of bilateral microinjection into frontal cortex, nucleus accumbens and striatum, respectively. The cross-hatched area corresponds to the site of microinjection at coordinates indicated in the Methods. For the FCX, the zone perfused corresponds, as in previous studies (Loiseau et al., 2008), to the infralimbic and cingulate sub-territories. The zone of microinjection for the nucleus accumbens is equivalent to the “shell”.

26 test day, adults were placed in their home cages on the observation table. After 5 min habituation, a juvenile was placed into the home cage for a 5-min session. A second 5-min session was performed 120 min after the first one, in order to induce a spontaneous deficit of recognition: either with the same juvenile (for evaluation of promnesic actions of ligands) or with a different juvenile (to control for the specificity of drug actions). The time spent in active social investigation (i.e., the time spent by adult rat in sniffing, following, biting, jumping and crawling over or under the juvenile) during the first (T1) and the second (T2) session was monitored. Drugs (S33084, SB277,011, L741,626 or SKF81297) or their vehicle were administered by intracerebral route, 1 min after the first 5-min session. The difference “T2–T1” was calculated and dose–response curves for promnesic properties were analyzed by one-way ANOVA followed by Dunnett's test. Unpaired t-tests between treated and control rats were used when only one dose was tested (experiments conducted in the striatum). The specificity of drug effects was analyzed by two-way ANOVA with juvenile (same or different) and drug as between factors, followed, if significant, by Newman–Keuls test. Using the same procedure, the influence of SCH23390 upon SKF81297-induced improvement in social recognition was evaluated. SCH23390 (0.01 mg/kg, subcutaneously (s.c.)) or vehicle were administered 30 min before the first 5-min session, and SKF81297 (0.16 µg/side, FCX) or vehicle were administered 1 min after it. Interaction was analyzed by two-way ANOVA followed, if significant, by Newman– Keuls test. All data shown represent means ± SEMs.

2.3. Microinfusion procedure 2.3.1. Procedure This procedure is adapted from Chudasama and Robbins (2004) and was exactly as employed in our previous studies (Loiseau et al., 2008). 2.3.2. Surgery Adult rats were implanted with bilateral stainless steel guide cannulae above the FCX, the striatum or the NAC. Double guide

F. Loiseau, M.J. Millan cannulae consisted of two 22-gauge metal tubes (inner diameter: 0.39 mm) that were 1.5 mm apart, projecting 3 mm from the plastic square pedestal for the FCX; 5 mm apart, projecting 5 mm for the striatum or 2.0 mm apart, projecting 8 mm for the NAC (Plastics One, USA). Rats were deeply anesthetized by an intraperitoneal (i.p.) injection of chloral hydrate (400 mg/kg, in a volume of 10 ml/kg) and placed in a stereotaxic frame (David Kopf Instruments, Phymep, Paris). The scalp was retracted to expose the skull and holes were drilled directly above the target region of the brain. The guide cannulae were mounted on the arm of the stereotaxic frame and was lowered at the following coordinates from bregma: FCX: AP: + 3.0, L: ±0.7, DV: −2.3; NAC: AP: +1.7, L: ±2.0, DV: −5.8 and striatum: AP: +0.5, L: ±2.5, DV: −4.0 (Paxinos and Watson, 1994). The cannulae were then implanted and affixed with dental cement and stainless steel screws that served to hold the cannulae in place. Dummy stylets (Plastics One, USA) were introduced in the guide cannulae to prevent occlusion. Animals were housed individually and were allowed to recover for at least one week before the social recognition test. 2.3.3. Microinfusion Following postoperative recovery, rats were handled to minimize any stress associated with the infusion procedure. On the test day, rats were gently restrained while the dummy stylets were removed and replaced with a 28-gauge (inner diameter: 0.18 mm, outer diameter: 0.36 mm) stainless steel injector extending 1.0 mm beyond the tip of the guide cannulae (Plastics One, USA). The injectors were connected by tubing connector (Plastics One, USA) to two 10 μl precision syringes (Hamilton, Phymep, Paris) mounted in an infusion pump (Harvard Apparatus, Holliston, MA). Drug or vehicle was infused bilaterally in a volume of 1.0 μl over 2 min, 1 min after the first 5-min session. The injectors were left in place for a further 2 min before being removed. 2.3.4. Histology At the conclusion of the behavioural testing, the same procedure for verification of cannulae/injection loci was used as previously (Loiseau et al., 2008). Brains were removed and

Figure 2 Influence of local infusion of S33084 and SB277,011 into the FCX upon social recognition. Histograms represent dosedependant improvement of social recognition by S33084 and SB277,011 upon injection into the FCX (0.04–2.5 and 0.16–2.5 µg/side, respectively, same juvenile) as compared to a different juvenile. Data are means ± SEMs of differences in duration of social investigation between the two sessions (T2–T1). VEH = vehicle. N = 5–10 per group. Closed asterisks indicate significance of differences between drug and vehicle-treated groups in Dunnett's test following ANOVA (see Results). Open asterisks indicate the significance of differences in Newman–Keuls test following ANOVA (see Results) between same and different juvenile, receiving the same drug and dose. ⁎P b 0.05.

Blockade of dopamine D3 receptors in frontal cortex enhances social recognition in rats

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were as follows. SKF81297 [(±)-6-chloro-7,8-dihydroxy-1phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine] HBr and SCH23390 [(R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5phenyl-1H-3-benzazepine-7-ol] HCl were obtained from Sigma (Chesnes, France). L741,626 (4-(4-chlorophenyl)-1(1H-indol-3-ylmethyl) piperidin-4-ol) was purchased from Tocris (Cookson, Bristol, U.K.). S33084 (3aR,9bS)-N[4-(8cyano-1,3a,4,9b-tetrahydro-3H-benzo-pyrano[3,4-c]pyrrole-2-yl)-butyl]-(4-phenyl)benzamide) HCl and SB277,011 (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl) ethyl]cyclohexyl]-4-quinolininecarbox-amide) were synthesized by Servier Chemist (G. Lavielle).

3. Results Figure 3 Influence of local infusion of L741,626 into the FCX upon social recognition. Histograms represent the lack of effect of L741,626 (0.63–5.0 µg/side), infused into the FCX, upon social recognition. Data are means ± SEMs and represent the difference in duration of social investigation between the two sessions (T2– T1). VEH = vehicle. N = 7–15 per group.

frozen for histological verification of injection positions according to the method of Bert et al. (2004). Briefly, brains were coronally sectioned using a microtome, and photomicrographs taken for comparing cannulae tips to the atlas of Paxinos and Watson (1994). Thereafter, the overall zone of injection was determined across all subjects and depicted schematically in Fig. 1.

2.4. Chemicals and drugs All drug doses are expressed in terms of the base. SKF81297 and SCH23390 were dissolved in sterile water. S33084 and SB277,011 were dissolved in 10% hydroxypropyl-β-cyclodextrine (Sigma, Chesnes, France) and L741,626 in 5% dimethyl sulfoxyde (Riedel-de Haën, Germany) plus 5% cremophor EL (Sigma, Chesnes, France). Drug structures, salts and sources

3.1. Improvement of social recognition by intra-FCX administration of the D3 receptor antagonists, S33084 and SB277,011 The microinjection procedure permitted the precise introduction of drugs into the infralimbic and cingulate regions of the FCX, as schematically depicted in Fig. 1. Employing an intersession interval of 120 min, vehicle-treated animals spent equivalent time investigating a juvenile in the first and second sessions, suggesting that with this prolonged inter-session interval, there is a spontaneous loss of juvenile recognition. T1 values were 101 ± 3 s and 109 ± 6 s, and T2 values were 100 ± 10 and 111 ± 9 s, in experiments conducted with S33084 and SB277,011, respectively. Upon injection into the FCX, S33084 and SB277,011 (0.04–2.5 and 0.16–2.5 µg/side, respectively), dose-dependently and significantly (one-way ANOVAs, F3,23 = 3.9, P b 0.05 and F3,29 = 5.9, P b 0.01, respectively) reduced the time of investigation of the juvenile rat during the second session, revealing improved recognition (pronounced negative values for T2–T1). At maximally-effective doses, S33084 and SB277,011 (2.5 µg/side for each) did not modify the time devoted in the second session to interaction with a

Figure 4 Influence of local administration of S33084 into the NAC and the striatum upon social recognition. Histograms represent the lack of effect of S33084 injected into the NAC (0.16–2.5 µg/side) and the striatum (2.5 µg/side), upon the delay-induced deficit. Data are means ± SEMs and represent the difference in duration of social investigation between the two sessions (T2–T1). VEH = vehicle. N = 5–10 per group.

28 juvenile different from that presented during the first session. Two-way ANOVAs as follows: S33084, interaction, F1,19 = 8.1, P b 0.05; juvenile, F1,19 = 4.6, P b 0.05; drug, F1,19 = 1.9, P N 0.05 and SB277,011, interaction, F1,24 = 6.0, P b 0.05; juvenile, F1,24 = 10.8, P b 0.01; drug, F1,24 = 6.2, P b 0.05. These results suggest an influence of frontocortical administration of S33084 and SB277,011 specifically related to cognitive processes (Fig. 2).

3.2. Lack of enhancement of social recognition by intra-FCX administration of the D2 receptor antagonist, L741,626 Vehicle-treated animals spent equivalent time investigating a juvenile in the first and second sessions: T1 values were 99 ± 7 s and T2 values were 92 ± 9 s. In contrast to the D3 receptor antagonists, L741,626 (0.63–5.0 µg/side), did not reduce the time of investigation of the juvenile rat during the second session, revealing a lack of improved recognition (Fig. 3).

3.3. Lack of effect of S33084 administered into the nucleus accumbens or striatum upon social recognition Fig. 1 depicts the location of bilateral injection sites into either the shell (limbic component) of the NAC or into the central zone of the striatum. Vehicle-treated animals spent equivalent time investigating a juvenile in the first and second sessions in experiments conducted in the NAC and the striatum: T1 values were 122 ± 6 s and 114 ± 5 s and T2 values were 120 ± 8 and 107 ± 9 s, respectively. S33084 did not improve social recognition, either in the NAC (0.16–2.5 µg/side), or in the striatum (2.5 µg/ side) (Fig. 4).

F. Loiseau, M.J. Millan

3.4. Improvement of social recognition by intra-FCX administration of the D1 receptor agonist, SKF81297 In the presence of vehicle, T1 values were 108 ± 4 s and 120 ± 8 s, and T2 values were 114 ± 5 and 121 ± 12 s, in the experiments conducted with SKF81297 alone and the interaction study, respectively. Administered into the FCX, SKF81297 (0.04– 0.63 µg/side) dose-dependently and significantly (one-way ANOVA, F3,30 = 12.6, P b 0.01) reduced the time of investigation of the juvenile rat during the second session, revealing improved retention. At the maximally-effective dose of SKF81297 (0.63 µg/side), this influence upon retention was expressed specifically (two-way ANOVA as follows: interaction, F1,26 = 18.1, P b 0.01; juvenile, F1,26 = 15.6, P b 0.01 and drug, F1,26 = 15.2, P b 0.01). The D1 receptor antagonist, SCH23390 (0.01 mg/kg, s.c.), abolished the improvement of recognition induced by SKF81297 (0.16 µg/side, FCX), while it did not itself exert a significant effect. Two-way ANOVA was as follows: interaction, F1,18 = 7.8, P b 0.05; SKF81297, F1,18 = 5.3, P b 0.05 and SCH233390, F1,18 = 8.6, P b 0.01 (Fig. 5).

3.5. Differential effects of administration of SKF81297 into the NAC versus the striatum upon social recognition Vehicle-treated animals spent equivalent time investigating a juvenile in the first and second sessions: T1 values were 117 ± 8 s and 92 ± 7 s, and T2 values were 120 ± 8 s and 83 ± 11 s, in experiments conducted in the NAC and the striatum, respectively. Intra-NAC infusion of SKF81297 (0.16 and 0.63 µg/side) significantly (one-way ANOVA, F2,18 = 5.0, P b 0.05) and specifically (two-way ANOVA were as follows: interaction, F1,24 = 4.3, P b 0.05; juvenile, F1,24 = 7.6, P b 0.05 and drug, F1,24 = 2.6, P N 0.05) reversed the delay-induced deficit. By contrast, no

Figure 5 Influence of local infusion of SKF81297 into the FCX and interaction with SCH23390. Data are means ± SEMs of differences in duration of social investigation between the two sessions (T2–T1). VEH = vehicle. N = 5–10 per group. A. Histograms represent the dose–response improvement of recognition by SKF81297 injected into the FCX (0.04–0.63 µg/side, same juvenile) as compared to the control with a different juvenile. Closed asterisks indicate significance of differences between drug and vehicle-treated groups in Dunnett's test following ANOVA (see Results). The open asterisk indicates the significance of differences in Newman–Keuls test following ANOVA (see Results) between same and different juvenile, receiving the same drug and dose. B. Histograms represent the blockade by SCH23390 (0.01 mg/kg, s.c.) of the effect of SKF81297 (0.16 µg/side, FCX). The closed asterisk indicates significance of differences between vehicle/SKF81297 and vehicle/vehicle values and the open asterisk indicates significance of differences between SCH23390/SKF81297 and vehicle/SKF81297 values, in Newman–Keuls test following ANOVA (see Results). ⁎P b 0.01.

Blockade of dopamine D3 receptors in frontal cortex enhances social recognition in rats

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Figure 6 Influence of local administration of SKF81297 into the NAC and the striatum upon social recognition. Data are means ± SEMs and represent the difference in duration of social investigation between the two sessions (T2–T1). VEH = vehicle. N = 5–8 per group. A. Histograms represent the improvement of recognition by intra-NAC infusion of SKF81297 (0.16–0.63 µg/side). B. Histograms represent the lack of effect of SKF81297 (2.5 µg/side) in the striatum. The closed asterisk indicates significance of differences between drug and vehicle-treated groups in Dunnett's test following ANOVA (see Results). The open asterisk indicates the significance of differences in Newman–Keuls test following ANOVA (see Results) between the same and the different juvenile, receiving the same drug and dose. ⁎P b 0.05.

effect was found in the striatum with the maximally-effective dose of SKF81297 (0.63 µg/side) (Fig. 6).

4. Discussion Employing a low volume, low infusion rate microinjection technique widely used in previous work (Egashira et al., 2002; Passetti et al., 2002; Chudasama and Robbins, 2004, Pezze et al., 2007; Loiseau et al., 2008; Millan et al., 2008a) and permitting localized introduction of drugs into discrete cerebral regions, the present findings demonstrate that blockade of D3 receptors in the FCX, but not in the NAC or the striatum, reverses a delay-induced deficit of social recognition in rats. By analogy, stimulation of D1 receptors in the FCX likewise reinforced social recognition though, in contrast to D3 receptors, activation of D1 sites in the NAC was also effective.

4.1. Specific enhancement of social recognition by intra-FCX infusion of selective D3 antagonists The improvement of social recognition by infusion of D3 receptor antagonists into the FCX is unlikely to reflect nonspecific effects, such as an impairment in motor performance or the induction of anxiety. Accordingly, when a different juvenile was presented to the adult rat during the second test session, there was no decrease in investigation time. Further, it has been well-established that, in contrast to D2 antagonists, D3 receptor antagonists do not suppress motor behaviour, and they do not possess anxiogenic properties (Schwartz et al., 2000; Millan, 2003; Joyce and Millan, 2005). In addition, a specific influence upon social recognition has already been reported with systemic administration of D3 antagonists under conditions identical to those employed herein (Millan et al., 2007, 2008a). Finally, administration of D3 antagonists into the FCX did not

qualitatively affect the overall behaviour of adult rats, nor their behaviour towards juvenile conspecifics (unpublished observations). Since D3 antagonists were active when infused after the first session, it is likely that they act by improving memory consolidation, though further study would be necessary to determine their influence upon different stages of mnemonic processing. Underpinning the pharmacological specificity of FCX infusions of D3 receptor antagonists, similar dose-dependent and specific actions were observed with two chemically different ligands, S33084 and SB277,011, each of which possesses high selectivity (N 100fold) for D3 versus D2 receptors and all other classes of binding site examined (Table 1) (Cussac et al., 2000; Millan et al., 2000a,b; Reavill et al., 2000; Heidbreder et al., 2005). Moreover, evidence for a specific role of D3 versus D2 receptor in their pro-cognitive actions is provided by the lack of effect of intra-FCX infusion of L741,626, a potent and preferential D2 receptor antagonist (Bristow et al., 1998; Millan et al., 2000a,b). Furthermore, emphasizing the regional specificity of actions, S33084 had no influence upon infusion into the striatum or the NAC. Thus, it may be concluded that the enhancement of social recognition by S33084 and SB277,011 is indeed mediated by blockade of D3 receptors within the FCX.

4.2. Potential mechanisms of action of D3 receptor antagonists The present data are consistent with a key role of the FCX in the modulation of working memory and attentional processes, inasmuch as these components of memory are relevant to social recognition (Steckler et al., 1998; Dalley et al., 2004). Further, working memory and attentional processes are improved in primates by systemic administration of S33138, a preferential D3 versus D2 receptor antagonist (Millan et al., 2008a,b,c; Millan and Brocco, 2008). Indeed, at low doses (0.04–0.63 mg/kg, p.o.), S33138

30 attenuated the deficits of spatial working memory and visual attention induced by chronic treatment with MPTP in primates (Decamp et al., 2007; Millan and Brocco, 2008). Furthermore, S33138 improved attentional performance of aged monkeys on a delay matching to sample task (Millan and Brocco, 2008; Buccafusco, J., unpublished observation). Finally, supporting a role of frontocortical dopaminergic mechanisms, including D3 receptors, in the modulation of cognitive function, Glickstein et al. (2005) suggested that the improved performance of mice lacking D3 receptors in an attentional task correlates with the magnitude of prefrontal cortex activation. In addition, a PET study in primates showed that activation of D3 receptors by pramiprexole preferentially affects brain activity in prefrontal and limbic cortex (Black et al., 2002). These data in rodents and primates collectively provide evidence for a role of the FCX in the effects of D3 receptor blockade upon cognition. The FCX is intensely innervated by cholinergic fibres originating in the nucleus basalis magnocellularis (NBM) (Mesulam et al., 1983), which have been widely implicated in the modulation of cognitive function, including working memory, attention and social cognition (Soffié and Lamberty, 1988; Perio et al., 1989; Winslow and Camacho, 1995; Dalley et al., 2004; Robbins, 2005). Inasmuch as selective blockade of D3 receptors enhances the release of acetylcholine (ACh) in the FCX (Lacroix et al., 2006; Millan et al., 2007, 2008a), a relationship between the neurochemical and behavioural effects of D3 antagonists might be conjectured. D3 receptors are not located in the NBM. However, D3 receptor antagonists may act at the level of frontocortical cholinergic terminals, a hypothesis which remains to be directly examined. A role of frontocortical populations of D3 receptors in the modulation of cognition is of particular interest inasmuch as the FCX has been strongly implicated in the cognitive deficits of schizophrenia: notably perturbed working memory, attention and social cognition (Aleman et al., 1999; Kuperberg and Heckers, 2000; Weinberger et al., 2001; Manoach, 2003; Dalley et al., 2004; Gallese et al., 2004, Lee et al., 2006; Millan and Brocco, 2008). Thus, the present data support the pertinence of cortical populations of D3 receptors as targets for improved control of the poorly treated cognitive deficits of schizophrenia.

4.3. Actions of D1 receptor agonists in the FCX Administration of the D1 receptor agonist, SKF81297, into the FCX, mimicked D3 antagonists in dose-dependently enhancing social recognition. Support for a specific role of D1 receptors in the pro-cognitive effects of SKF81297 is provided by several lines of evidence. First, SKF81297 possesses high affinity for D1 receptors (pKi = 9.2) and is highly selective (N200-fold) for D1 receptors versus others binding sites (Arnt et al., 1988; Cussac et al., 2004; Mannoury La Cour et al., 2007). Second, the effect of SKF81297 administered into the FCX was abolished by systemic pre-treatment with a low dose of SCH23390 (0.01 mg/kg), a highly potent and selective D1 receptor antagonist (Bourne, 2001; Cussac et al., 2004; Mannoury La Cour et al., 2007). An important issue concerns a possible role of D5 receptors, since “selective” D1 receptor ligands fail to discriminate D1 receptors from the latter. In fact, some neurochemical studies have reported that the elevation of hippocampal ACh levels elicited by SKF38393, an analogue of SKF81297, is abolished by antisense probes

F. Loiseau, M.J. Millan directed against D5 but not D1 sites, and is absent in mice deprived of D5 receptors (Hersi et al., 2000; Laplante et al., 2004). However, the density of D1 receptors in the FCX is greater than that of D5 sites (Bergson et al., 1995; Ciliax et al., 2000), so the pro-cognitive actions observed with SKF81297 herein are unlikely to be mediated by D5 receptors. This question could be directly addressed in further studies, for example by FCX infusion of antisense oligonucleotides directed at the D5 receptor (Hersi et al., 2000). The present data are consistent with studies reporting that, over a critical range dose, activation of D1 receptors in FCX exerts a facilitatory influence upon working memory and attentional processes (Sawaguchi and Goldman-Rakic, 1991; Cai and Arnsten, 1997; Seamans et al., 1998; Chudasama and Robbins, 2004; Granon et al., 2000). A participation of frontocortical cholinergic mechanisms in the pro-cognitive action of FCX populations of D1 agonists could be hypothesized, inasmuch as, by analogy to D3 receptor blockade, activation of D1 receptors enhances cholinergic transmission in the FCX (Acquas et al., 1994; Steele et al., 1997; Di Cara et al., 2007). A potential role of the NBM, likewise enriched in D1 receptors (Huang et al., 1992; Zaborszky and Cullinan, 1996), was not directly addressed herein and requires further study.

4.4. Differential effect of D3 and D1 ligands in the NAC Despite the high density of D3 receptors in the NAC, infusion of the D3 receptor antagonist, S33084, did not modify social recognition, suggesting that its pro-cognitive actions are not mediated by this structure. It has previously been reported that NAC infusion of the antagonists, cis-flupentixol and sulpiride, both of which show equivalent affinity for D2 and D3 receptors, impairs attention and spatial memory (Himmelheber et al., 2000; Mele et al., 2004). Further, administration of cisflupentixol into the NAC blocked the enhancement of memory consolidation induced by intra-amygdala infusion of DA in an inhibitory avoidance task (LaLumière et al., 2007). Though these studies did not employ ligands differentiating D3 and D2 receptors, the present and previous studies collectively suggest that blockade of D2 rather than D3 receptor underlies these effects. Nonetheless, there is a need for further study of the roles of mesolimbic populations of D3 versus D2 receptors in the control of cognition, in particular in light of their opposite implication in the modulation of motor behaviour (Joyce and Millan, 2005; Sokoloff et al., 2006). Moreover, a further interesting question is the possible significance of D3 receptors in functionally distinct subterritories of the NAC (Di Chiara, 2002). In the present study, cannulae were implanted into a region corresponding to the shell of the NAC (Fig. 1), since this (limbic) sub-division contains a higher density of D3 receptor than the core (Diaz et al., 2000; Schwartz et al., 2000). Further, as shown there, injection of the D1 agonist, SKF82197, did improve social recognition supporting the functional relevance of this structure to social memory. Nonetheless, the possibility that the comparatively low concentration of D3 receptor in the NAC core may be involved in cognitive processes cannot be entirely excluded. As mentioned above, by contrast to D3 antagonists, D1 receptor stimulation in the NAC enhanced social recognition, consistent with a recent finding (Pezze et al., 2007) in which the intra-NAC administration of the D1 receptor agonist,

Blockade of dopamine D3 receptors in frontal cortex enhances social recognition in rats SKF38393, induced pro-attentional effects in a 5-CSRT procedure. Moreover, administration into the NAC of the D1 antagonist, SCH23390, impaired spatial memory (Mele et al., 2004). The present results provide novel evidence for the modulation of cognitive function by D1 receptors in the NAC. Interestingly, the NAC, a major source of GABAergic inputs to the NBM, has been suggested to regulate cortical cholinergic transmission (Zaborszky and Cullinan, 1992; Moore et al., 1999). Further, dopaminergic stimulation in the NAC was proposed to negatively modulate GABAergic projections and thereby to disinhibit frontocortical cholinergic projections. Day et al. (1994) suggested that mesolimbic dopamine contributes to the increased cholinergic transmission seen upon amphetamine administration. Blockade of D1 (but not D2) receptors in the NAC attenuated the enhancement in cortical ACh release produced by FG7142, a benzodiazepine receptor inverse agonist (Moore et al., 1999). On the other hand, intra-NAC infusion of D1 receptor antagonists attenuated the increase in release of ACh in the FCX induced by NMDA infusion in the NAC (Zmarowski et al., 2005). Thus, it could be hypothesized that stimulation of D1 receptor in the NAC results in an increase of ACh release in the FCX, participating in the improved social memory observed in this study. This remains to be directly elucidated.

4.5. Conclusion The present data provide the first demonstration that blockade of FCX-localized D3 receptors, like stimulation of FCX-localized D1 receptors, enhances social recognition in rat. These observations underpin the pertinence of D3 receptors as targets for the treatment of disorders like schizophrenia and Parkinson's disease, which are characterized by marked cognitive impairment involving a dysfunction of the FCX.

Role of the funding source This study was financially supported by Servier Pharmaceuticals.

Contributors F. Loiseau managed the behavioural experiments and analyses. F. Loiseau wrote the first draft and M.J. Millan wrote the final version of the manuscript. All authors have approved the final manuscript.

Conflict of interest No conflicts of interest exist.

Acknowledgement We thank Anne Dekeyne for rereading the manuscript.

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