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8 juillet 2004
Eur J Pharmacol
1987; 134; 2; 163-73

Permissive role of D1 receptor stimulation
by endogenous dopamine for the expression
of postsynaptic D2 mediated behavioural responses
Yawning in rats
R Longoni, L Spina, G Di Chiara
Institute of Experimental Pharrnacology and Toxicology,
University of Cagliari Italy


It is now well established on the basis of biochemical and pharmacological evidence that brain amine (DA) can act on at least two types of receptors, termed D1 and D2. Available evidence indicates that the two receptors are distinct molecular entities, utilize different transducing units and have a different distribrution the brain .
In spite of these differences, the behavioural roles of D1 and D2 receptors appear strikingly similar as deduced from the effects of their selective pharmacological blockade. Thus, in normal animals the central effects of SCH 23390, a selective D1 receptor antagonist,are similar to those of selective D2 antagonists. These properties include the ability to induce catalepsy, depress conditioned avoidance responses and block the hypermotility, stereotypy and the hypothermie effects of D1/D2 agonists like apomorphine and of specific D2 agonists like pergolide, LY 17155 and RU 24213 as well as yawning induced by apomorphine. In addition, SCH 23390, similarly to D2 antagonists, stimulates DA release in terminal dopaminergic areas as a result of stimulation of firing activity.
On the other hand clear-cut differences between D1 and D2 blockade can be shown for those effects which involve an action on DA autoreceptors; thus SCH 23390, in contrast with D2 antagonists, fails to antagonize the sedative actions and the in vitro inhibition of DA release elicited by D2 agonists. Other differences between the central effects of SCH 23390 and D2 antagonists refer to onset and duration of action, which are much shorter in the case of SCH 23390 and are best explained by pharmacokinetic differences.
From this evidence the furictions of central D1 receptors appear hardly distinguishable from those of central postsynaptic D2 receptors. Strangely enough, selective stimulation of central D1 receptors in normal rats by the reportedly selective D1 agonist SKF 38393 results in behavioural effects which are quite unlike those of selective stimulation of central D2 receptors. Thus, in normal rats, SKF 38393 induces grooming and rearing and upward sniffing but not the high intensity stereotypy items (confined downward sniffing, licking and gnawing) evoked by D1/D2 agonists or by pure D2 agonists. To further complicate this issue, D1 receptor stimulation in denervated animals is fully able to evoke the complete behavioural syndrome of D2 receptor stimulation including licking and gnawing. Moreover, after dopaminergic denervation, SCH 23390 loses the ability to block the behavioural stimulation elicited by central specific D2 agonists and acquires full D1 specificity. A tentative explanation for these results has been put forward by postulating that D1 and D2 receptors are 'coupled' in a reciprocally facilitatory manner in normal animals but become 'uncoupled' after DA denervation. Such coupling is not easily translated into molecular terms. The idea of a reciprocally facilitatory influence between D1 and D2 at the molecular level contrasts with the evidence that D1 and D2 receptors exert opposite, reciprocally inhibit effects on the production of cAMP. On the other hand, the interpretation of the mechanism of the results by Morelli and Di Chiara (1984) , Arnt (1985a,b) and Mueller (1985) is complicated by the fact that denervation could have resulted not only in interruption of DA transmission but also in supersensitivity of D1 and D2 receptors.
In order to circumvent these difficulties have reexamined the changes in sensitivity to SC 23390 blockade of D2-mediated effects after interruption of DA transmission. We selected conditions (6 h reserpine pretreatment) in which absence of supersensitivity to the agonist could documented and used an easily quantifiable behaviour like yawning as a behavioural index central D2 receptor activation. In the normal rat this behaviour appears to result from D2 recept activation .[...]
In agreement with previous studies, BHT 920, LY 171 555 and (+)3PPP elicited yawning in rats. While LY 171555 and (+)3PPP, as previously reported for apomorphine, showed a bell-shaped dose-response curve, BHT 920 showed a monophasic dose-response with a plateau at its maximum. These differences are clearly related to the emergence of competing behavioural stimulation induced by LY 171555 and by (+)3PPP which is absent after BHT 920. Such differences might be related to the nature of the interaction of LY 171555, (+)3PPP and BHT 920 with the receptors responsible for their ability to induce yawning. These receptors appear to be of the D2 type. In fact, available evidence indicates that BHT 920, LY 171555 and (+)3PPP are specific agonists of D2 receptors, as indicated by their low affinity for D1 receptors and lack of stimulatory influence on DA-sensitive adenylate cyclase compared to their high affinity for D2 receptors labeled by spiperone and their inhibitory effect on DA-sensitive adenylate cyclase.
Behavioural and biochermical evidence suggests that, while BHT 920 is a partial agonist, LY 171555 and (+)3PPP are full agonists at D2 receptors. Thus BHT 920 can stimulate in vivo postsynaptic DA receptors rendered supersensitive by 6-OHDA denervation, while in a normally innervated condition it elicits behavioural inhibition by stimulation of DA autoreceptors.
In contrast, LY 171555 and (+)3PPP elicit biphasic inhibitory-stimulatory behavioural effects in normal animals. Moreover, LY 171555 behaves as a full agonist of D2 receptors. Thus, the differences in the shape of the dose response curve for the yawning induced by LY 171555 and (+)3PPP as compared to that for BHT 920 are related to the fact that the first two are full agonists and the third is a partial agonist of D2 receptors.
Pretreatment with low doses of the specific D1 receptor antagonist SCH 23390 reduced the ability of BHT 920, LY 171555 and (+)3PPP to induce yawning in normal rats. This effect was dose-related but did not exceed a 50% reduction of the incidence of yawning. SCH 23390 at the doses which antagonized D2 agonist-induced yawning did induce catalepsy. We exclude a causal relation between these two effects since, for example, BHT 920 was fully effective to elicit yawning also when given in doses of 50-200mg/kg to reserpinized rats which are themselves fully cataleptic. On the other hand, apomorphine as well as LY 171555 after 16 h reserpine pretreatment was more potent to elicit yawning in spite of the fact that the animals were cataleptic. Finally, kainate lesions of file caudate, which aholish the ability of SCH 23390 to induce catalepsy, did not affected property to block the yawning induced by B 920.
We have previously reported that SCH 23 was capable of antagonizing yawning induced apomorphine. We then
concluded that this effect was not due to stimulation of DA autoreceptors. The present data confirm this suggestion and extend it to DA agonists specific for D2 receptors. Because apomorphine can act on both D1 and D2 receptors we suggested that yawning be mediated at least in part by stimulation of receptors by exogenously administered agonist.
Such an explanation cannot be applied to yawning induced by BHT 920, LY 171555 (+)3PPP since it is highly unlikely that these drugs interact with D1 receptors at the doses eliciting yawning. It is also unlik on the basis of binding studies, that SCH 2313 interacts with D2 receptors at the doses which were active against D2 agonist-induced yawing in the present study. We are therefore left with the possibility that SCH 23390 antagonizes a postsynaptic receptor-mediated effect by blocking D1 receptors, which are under tonic stimulation by endgenous DA.
Endogenous DA, by acting on D1 receptors would thus exert a permissive-facilitatory role for the expression of yawning induced by D2 receptor agonists. If this hypothesis is correct, abolition of endogenous DA transmission should exert effects on D2 agonist-induced yawning similar those of D1 blockade by SCH 23390, and abolish the effectiveness of D1 blockade by SCH23390 in reducing D2 agonist-induced yawing by a similar extent and this reduction is similar to that elicied by SCH 23390 pretreatment. Moreover, in reserpine-pretreated rats SCH 23390 loses the property od reducing D2 agonist-induced yawning.
One might argue that, since SCH 23392 is a potent antagonist of 5 HT2 receptors and reserpine is an effective depletor of 5HT. blockade of endogenous 5HT transmission might be the mechanisin by which SCH 23390 interferes with the behavioural expression by D2 receptor activation. This possibility is excluded by the fact that blockade of 5HT receptors by antagonists devoid of effects on D1 receptors, e.g. ketanserin and metergoline, fails to affect D2 agonist-induced yawning in normal rats.
Although reserpine depletes noradrenaline (NA) in addition to DA and 5HT, it seems unlikely that inhibition by SCH 23390 of DA agonist induced yawning is related to NA-receptor blockade since SCH 23390 is a very poor ligand of alpha-receptors both in vivo and in vitro.
Our finding that SCH 23390 loses the ability to block D2-mediated effects in reserpinized rats is line with the results of Morelli and Di Chiara. However, in contrast with these studies reserpine treatment now resulted in reduction rather than potentiation of responses to DA agonists. Indeed, the 6 h reserpine pretreatment in our experiments is quite different from the conditions in the other studies. Morelli used a 16 h reserpine pretreatt while Arnt and Breese and Mueller used chronic 6-OHDA lesions or repeated times daily reserpine pretreatment. Breese and ueller (1985) included an experiment performed after 24 h reserpine pretreatment in order to extende the role of supersensitivity. However evidence obtained by us shows that even 16 h reserpine pretreatment induces supersensitivity to agonist. Indeed, Breese and Mueller (1985) report that LY 55 elicits less hypermotility in animals thus pretreated than in normal animals, probably because of the expression of confined stereotypies (sniffng, licking and gnawing) which was indicative of an increased response to the agonis. As we have shown, there is no evidence of supersensitivitv after 6 h reserpine pretreatment reserpinized rats actually showed a reduction of yawning. This could not be explained by the emergence of competing behavioural items since the animals remained motionless in the intervals between yawns.
Arnt (1985a,b), having purposely induced a supersensitivity to the agonists and shown that in these conditions SCH 23390 loses the ability to block D2-mediated behavioural stimulation, postulated that D1 and D2 receptors are coupled in a normally innervated system and uncoupled as a result of denervation supersensitivity. We have now provided evidence that denervation itself, without receptor supersensitivity, is sufficient to abolish the relationship between D1 and D2 receptors. We therefore postulate that D1 and D2 receptors are located either on different neurons or on different areas of the same neurons or even in different areas but along the neural circuit mediating DA-agonist-induced yawning.
Whatever might be the specific neural mechanism by which endogenous DA input on to D1 receptors exerts a permissive-facilitatory role on the behavioural expression of D2 receptor stimulation, this hypothesis accounts not only for the results of the present study but also for certain observations reported in the literature which could not be explained convincingly in terms of current concepts. Thus, as pointed out in the Introduction, a D1 antagonist like SCH 23390 reduces most, if not all, the known behavioural effects of D2 agonists (e.g. hypermotility, stereotypy, hypothermia) attributable to an action on postsynaptic DA receptors. Moreover, a D1 antagonist like SCH 23390 produces a cataleptic state which appears both phenomenologically and pharmacologiçally similar to that induced by haloperidol or by pure D2 antagonists. This suggests that blockade of D1 receptors impairs D2 receptor stimulation not only by exogenous D2 agonists but also by endogenous DA.
On the other hand our hypothesis can explainthe observation that depletion of brain DA by short-term reserpine and a-methyltyrosine pretreatment abolishes the stimulant effects of bromocriptine., a D2 agonist devoid of intrinsic activity on D1 receptors. Since bromocriptine is devoid of DA-releasing properties in vivo, as estimated by brain dialysis in freely moving rats, it is unlikely that the DA dependence of its stimulant properties is due to some amphetamine- or cocaine-like property. On the other hand, bromocriptine-induced stimulant effects in DA-depleted rats can be reinstated by low doses of D1/D2 agonists like L-DOPA or apomorphine .
Whether these properties of bromocriptine extend to other ergot and non-ergot D2 agonists when hypermotility-stereotyped behaviour is taken as a measure of central postsynatic D2 receptor stimulation will be studied next.
-Morelli M et al Antagonism of apomorphine-induced yawning by SCH 23390: Evidence against the autoreceptor hypothesis Psychopharmacology 1986; 89; 259-260