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mise à jour du
23 septembre 2007
Pharmacol Biochem Behav.
2000;67(3):637-645
Intra-accumbens infusion of D(3) receptor agonists reduces spontaneous and dopamine-induced locomotion
Ouagazzal AM, Creese I.
Pharmaceuticals Division, F. Hoffmann-La Roche,Basel, Switzerland
Yawning and D3 receptors

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The present study investigated whether PD 128907 and 7-OH-DPAT, described as preferential dopamine (DA) D(3) receptor agonists, produce hypolocomotion by acting at postsynaptic dopaminergic receptors within the nucleus accumbens. Bilateral infusion of PD 128907 (1.5 and 3 microg/0.5 microl) induced a dose-dependent hypolocomotion, whereas its enantiomer, PD 128908, was inactive. Local infusion of 7-OH-DPAT and the preferential DA autoreceptor agonist, B-HT 920, at the same dose range also decreased spontaneous locomotion. In addition, both drugs induced yawning with B-HT 920 producing the greatest effect. In the second experiment, the ability of these agonists to reduce the locomotor activity induced by intra-accumbens injection of DA (10 microg/0.5 microl) was studied. Pretreatment with either PD 128907 or 7-OH-DPAT (3 microg) reduced DA-induced hyperactivity. Local infusion of B-HT 920 (3 microg) failed to antagonise the locomotor effects of DA. Altogether these findings suggest that PD 128907 and 7-OH-DPAT induce hypolocomotion by acting in part at postsynaptic DA receptors. The possible role of D(2) and/or D(3) receptors in the mediation of these effects is discussed.
 
1. Introduction
 
Among the newly discovered dopamine (DA) receptors, the D3 receptor subtype has been of particular interest, in part because of its distinctive pattern of localisation in the brain. The D3 receptor is predominantly expressed in limbic regions of the brain (e.g.; nucleus accumbens,, island of Calleja, and hippocampus) known to be associated with cognitive and emotional functions [9,2I,23,} This neuroanatomical distribution together with its high affinity for antipsychotic drugs suggests that D3 receptors may be important targets for the development of therapeutic treatments for schizophrenia and drug abuse [32,36,37]. In the past few years, several existing compounds were reported to display a greater selectivity for D3 receptors as compared to D2 receptors. For instance, both PD 128907 and 7-OH-DPAT were characterised as D3-preferring receptor agonists in both binding and cellular studies, with the former compound being the most selective [5,23,33,35]. However, given systematically, both PD 128907 and 7OH-DPAT were found to produce behavioural changes (e.g., hypolocomotion and yawning) comparable to those observed with other DA receptor agonists such as apomorphine. Interestingly, unlike apomorphine or other related agonists, the sedative effects induced by systemic administration of 7-OH-DPAT have been reported to occur independently from changes of DA release or synthesis [40]. Similarly, PD 128907 was also found to inhibit amphetamine-induced hyperactivity at doses that had no effect on the increase of extracellular DA levels induced by amphetamine in the ventral striatum [10]. On the basis of these observations, it has been suggested that the hypolocomotion induced by the PD 128907 and 7-OHDPAT may be mediated via D3 postsynaptic DA receptors [10,40]. In line with these findings, subsequent studies have shown that PD 128907 could also reduce stereotypies induced by direct DA receptor agdu.ist, apomorphine, and the NMDA receptor antagonist, MK 801. Furthermore, the effects of PD 128907 on MK 801-induced stereotypies could be prevented by coadministration of the selective D3 antagonist, NGB 2900 [43].
 
Although there is strong evidence that PD 128907 and 7OH-DPAT suppress locomotion by acting at postsynaptic DA receptors, there have been few attempts to explore the neuroanatomical substrate underlying such action. To address this issue we studied the effects of direct infusion of PD 128907 and 7-OH-DPAT to the nucleus accumbens, a brain structure where D3 receptors are highly expressed [39]. For comparison we also studied the DA D2 agonist, BHT 920 [35]. This compound has been described as a preferential presynaptic DA autoreceptor agonist on the basis of behavioural and neurochemical studies in intact animals [6,28,34]. For instance, B-HT 920 produces hypolocomotion over a wide dose range. Furthermore, unlike direct dopaminergic agonists (e.g., apomorphine and lisuride), high doses of B-HT 920 fail to increase locomotion, suggesting that this compound has only weak agonistic actions at postsynaptic D2 receptors [3,28]. This apparent selectivity for presynaptic autoreceptors has been related to the difference of receptor reserves in dopaminergic neurones and their target neurones [14,25].
 
The first part of the study was designed to characterise the behavioural effects induced by local infusion of PD 128907, 7-OH-DPAT, and B-HT 920 into the nucleus accumbens. To further investigate the possibility that a population of postsynaptic DA 1ceptàrs might mediate suppression of locomotion, we have studied the ability of these agonists to reduce the hyperactivity induced by bilateral intra-accumbens infusions of DA. Since the hyperlocomotor activity induced by DA is mediated by postsynaptic DA receptors, suppression of DA's effect would suggest that D3-preferring agonists act via postsynaptic mechanisms to reduce locomotion.
 
4. Discussion
 
The present behavioural study shows that all three DA agonists, PD 128907, 7-OH-DPAT, and B-HT 920, injected into the nucleus accumbens reduced spontaneous locomotor activity. However, only 7-OH-DPAT and B-HT 920 increased the incidence of yawning. More importantly, these three agonists differentially suppressed the locomotor hyperactivity induced by local infusion of DA into the nucleus accumbens. Whilst both PD 128907 and 7-OHDPAT markedly reduced DA-induced locomotor hyperactivity, local infusions of the putative DA autoreceptor agonist, B-HT 920, failed to antagonise the effects of DA. These findings indicate that the nucleus accumbens is one of the brain areas mediating yawning and hypolocomotion induced by systemic administration of low doses of dopaminergic agonists. Furthermore, they suggest that a population of postsynaptic DA receptors within the nucleus accumbens may be involved in mediating the locomotor suppression induced by PD 128907 and 7-OH-DPAT.
 
Previous studies have shown that low doses of 7-OHDPAT injected into the nucleus accumbens reduced the locomotor activity of rats tested in a novel environment [13,19]. Our study confirms these previous findings and
 
further demonstrates that local injection of the D3-preferring agonist, PD 128907, as well as the preferential DA autoreceptor agonist, B-HT 920, can also induce hypolocomotion. Interestingly, we have found that the three agonists tested showed a marked difference in their ability to induce yawning. Indeed, a clear increase in the incidence of yawning was seen after both injections of 7-OH-DPAT and B-HT 920, with the latter inducing the greatest effect. However, microinjection of PD 128907 at the same dose range failed to elicit yawning (but the possibility exists that a higher dose might be effective). Thus, in the yawning test 7-OH-DPAT displayed a behavioural profile more comparable to B-HT 920 than PD 128907. It is unlikely that this behavioural difference between PD 128907 and 7-OHDPAT reflects differences in bioavailability or intrinsic activity. In fact, at the higher dose tested (3 rig) both drugs induced a comparable reduction of locomotor activity (during the first 30 mm, PD 128907 reduced locomotor activity by 39% and 7-OH-DPAT by 42% relative to the control). The present finding would suggest that the differential effects of PD 128907 and 7-OH-DPAT on yawning might be due to an action on distinct receptors. Several binding and functional in vitro studies have shown that 7-OH-DPAT has a modest selectivity for D3 versus D2 receptors than PD 128907 [12,35]. It is therefore possible that populations of presynaptic D2 receptors may mediate yawning induced by 7-OH-DPAT. In support of this suggestion the autoreceptor agonist B-HT 920, which had the greatest effect on yawning, was shown to display a higher functional selectivity toward D2 receptor subtypes [35]. However, we cannot exclude the possibility that 7-OH-DPAT and B-HT 920 may induce yawning by acting on other receptors. For instance, B-HT 920 has also high affinity for a1-adrenergic receptors, which have been implicated in the modulation of yawning [18].
 
To further investigate the possibility that a population of postsynaptic DA receptors may mediate suppression of locomotion, we have studied the ability of PD 128907, 7OH-DPAT, and B-HT 920 to reduce the hyperactivity induced by bilateral intra-accumbens infusion of DA. In Iine with previous studies, local infusion of DA into the nucleus accumbens caused a marked locomotor hyperactivity in rats [2,29,31,41]. Interestingly, both PD 128907 and 7OH-DPAT markedly reduced the lcomotor activity induced by intra-accumbens injection of IA; in contrast, the putative DA autoreceptor agonist, B-HT 920, was ineffective. The lack of effect of B-HT 920 suggests that (1) the suppression of DA-induced locomotor hyperactivity is not due to a potential nonspecific effect resulting from combined injection of the drugs and (2) that the D3-preferring agonists reduce DA effects by acting at postsynaptic rather than presynaptic receptors. Consistent with this finding, systemic administration of PD 128907 was found to inhibit amphetamine-induced locomotor hyperactivitiin rats at doses that had no effect on the increase of extracellular DA level induced by amphetamine in the ventral striatum [10]. More importantly, PD 128907 also reduced the hyperactivity induced by the D1 receptor agonist SKF 81297, as well as stereotypies induced by the direct DA receptor agonist apomorphine, and the NMDA receptor antagonist MK 801 [27,43]. Furthermore, the effects of PD 128907 on MK 801induced stereotypies could be prevented by coadministration of selective D3 antagonist NGB 2900 [43]. Given that PD 128907 possesses a higher affinity for the D3 versus D2 receptors, it is conceivable that its suppressive effect on DAinduced hyperactivity may be due to the stimulation of postsynaptic D3 receptors. In line with this suggestion, It was recently shown that the ontogeny of motor inhibition induced by low doses of PD 128907 coincides in time with the developmental expression of DA D3 receptors within the nucleus accumbens [15,36]. Further evidence for the role of D3 receptors in the inhibition of locomotor activity is also provided by several studies using more selective strategies such as the antisense knockdown approach. Indeed, intracerebroventricular infusion of an antisense oligodeoxynucleotide directed against D3 receptor subtypes mRNA reduced D3 receptor density in the nucleus accumbens and increased spontaneous locomotor activity in rat [11,45]. Furthermore, D3 antisense oligodeoxynucleotide treatment increased locomotor activity induced by apomorphine in DA-depleted rats [26], thus revealing the role of postsynaptic D3 receptors in the inhibition of locomotor activity. It is important to stress that these effects were observed with different sequences of D3 antisense oligodeoxynucleotides, thus confirming the selectivity of the antisense knockout approach. Moreover, we found that the D2 antisense oligodeoxynucleotide induces an opposing effect on locomotion [45]. Altogether, these findings strongly suggest that D2 and D3 receptors regulate the expression of locomotor behaviour in rat in an opposing direction.
 
It should be noted, however, that recent data from gene knockout studies have questioned the role of D3 receptors in the suppression of locomotion. While some authors have reported increased locomotion in mice lacking the D3 receptor gene [1,44], others failed to observe these effects [8]. Furthermore, only mice lacking D2, but not D3 receptor genes were found to be nonresponsive to the. hypolocomotion induced by 7-OH-DPAT and PD 128907, thus suggesting that these compounds may be rather acting on D2 receptors to inhibit locomotion [7]. As recently demonstrated by Levin [22], D3 receptors are differentially expressed in certain brain regions in mice and rats, and it is thus possible that they may also differentially regulate certain behaviours in these two species. It should be also stressed that there are clear phenotypic differences between D3 mutant mice generated in different laboratories [1,8,38,44], and this seems also the case for D2 mutant mice [4,7,17]. These discrepancies strongly suggest that the behavioural phenotypes of the mutants are not due only to the loss of the targeted receptors but also to several other factors including developmental adaptations and genetic background [17]. As such, it cannot be excluded
 
that these factors might also influence drug responses [16,24], and thus contribute to the discrepant results obtained in rats and mice.
 
Finally, it was recently shown that 7-OH-DPAT and PD 128907 act as partial agonist at both D2 and D3 receptors [42], but see Ref. [35]. It is therefore possible that these ligands might behave as D2 receptor agonists or antagonists depending on the level of the dopaminergic tone. For instance, the suppression of spontaneous locomotion may be due to the stimulation of presynaptic D213 receptors, whereas the blockade of DA-induced locomotor hyperactivity may be related to an antagonism of postsynaptic D2 receptors. However, this hypothesis seems unlikely, especially for PD 128907. Firstly, in functional assays unlike 7OH-DPAT, PD 128907 was found to behave as a partial agonist that lacks antagonist properties [42]. Furthermore, pretreatment with the selective D3 receptor antagonist NGB 2900 was shown to prevent PD 128907-induced blockade of stereotypies evoked by MK 801 [43], which strongly suggests that PD 128907 acts via stimulation of D3 receptors.
 
In conclusion, our findings confirm previous studies showing that 7-OH-DPAT and PD 128907 reduce spontaneous and DA agonist-induced locomotion. Furthermore, they suggest that this suppression of locomotion can be mediated via at least two independent mechanisms within the nucleus accumbens: (1) a presynaptic mechanism involving inhibition of DA release, probably via stimulation of D2 receptor subtypes [20], and (2) a postsynaptic mechanism involving activation of D2-like receptors. Further studies using intra-accumbens infusions of highly selective D2 and D3 receptor ligands are clearly needed to confirm whether the postsynaptic receptors are of D2 or D3 subtype.