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mise à jour du
15 décembre 2007
Psychopharmacology (Berl)
The mode of action of bromocriptine
following pretreatment
with reserpine and alpha-methyl-p-tyrosine in rats
Ushijima I, Mizuki Y, Yamada M.
Department of Neuropsychiatry, Yamaguchi University, Ube, Japan


The ability of bromocriptine (BRC), a selective dopamine D-2 receptor agonist, to induce yawning responses was studied in rats pretreated with reserpine and alpha-methyl-p-tyrosine (alpha-MPT). BRC (1 20 mg/kg IP) evoked yawning responses, which were pronounced at 2.5 mg/kg and characterized by the head moving downward. Higher doses of BRC (5 20 mg/kg) dose-dependently delayed the onset and peak time of yawning.
A low dose of the selective D-1 dopamine receptor agonist SK&F38393 did not induce yawning but enhanced the BRC-induced response. Pretreatment with reserpine (1 and 5 mg/kg SC), alpha-MPT (100 and 300 mg/kg IP) and reserpine (1 mg/kg) plus alpha-MPT (100 mg/kg) was able to significantly reduce BRC-induced yawning.
The inhibitory effects were prevented by a low dose of SK&F38393 (0.5 mg/kg IP). In particular, combined treatment with reserpine (5 mg/kg) and BRC (10 and 20 mg/kg) elicited upright fighting and jumping behaviors which were inhibited by haloperidol (1 mg/kg IP), a non-selective D-1 and D-2 receptor antagonist, SCH23390 (0.05 mg/kg SC). a selective D-1 receptor antagonist, or sulpiride (20 mg/kg IP), a potent D-2 receptor antagonist, and were potentiated by SK&F38393 (0.5 mg/kg). SCH23390 (0.05 mg/kg) decreased BRC-induced yawning and the apomorphine (low doses)-induced potentiation of BRC yawning, and prevented the apomorphine (high doses)-induced reduction of BRC yawning. SCH23390 also inhibited apomorphine-induced stereotypy and BRC-induced potentiation of apomorphine stereotypy.
Furthermore, haloperidol (0.02 and 1.0 mg/kg IP), sulpiride (20 mg/kg IF) or scopolamine (0.5 mg/kg IP) inhibited BRc-induced yawning, but prazosin (1.0 and 3.0 mg/kg IP), an Œ-1 receptor antagonist, did not affect this behavior These results suggest that BRC-induced yawning may be mediated via presynaptic dopaminergic neuron activity and that BRC, in addition to the stimulation of dopamine D-2 receptors, appears to require endogenous dopamine or receptor activation by another dopamine agonist (D-1 agonist) for the induction of yawning, stereotypy and upright fighting responses. The ability of dopamine agonists to induce these behaviors seems to depend apon the potency and ratio of D-2 versus D-1 receptor activity.
It has been reported that yawning occurred in rats after administration of relatively small doses of various dopamine agonists which are known to stimulate dopamine receptors either directly (apomorphine) or indirectly (amphetamine, nomifensine) (Mogiinicka and Klimek 1977; Yamada and Furukawa 1980). Since low and high doses of haloperidol, sulpiride (a selective dopamine D-2 antagonist) and scopolamine inhibit BRC-induced yawning, a dopaminergic-cholinergic link is thought to be involved in BRCinduced yawning. As was the case with apomorphine-induced yawning, BRC-induced yawning may also be mediated by cholinergic activation secondary to the inhibition of dopamine transmission. Furthermore, BRC-induced yawning is characterized by the head moving downward, which is similar to the effects produced by apomorphine (Ushijima et al. 1985). The neuronal mechanism involved in BRC yawning seems to be similar to that of low doses of apomorphine.
In this study, the ability of reserpine and oc-MPT to potentiate yawning at high doses of BRC is a reflection of an overall shift to the right of the inverted U doseresponse curve for BRC-induced yawning which, in turn, might be due to receptor blockade produced by the dopamine depletion. Reserpine plus -MPT completely inhibited BRC-induced yawning. The prevention of BRC-induced yawning by reserpine, as well as by -MPT, suggests that intact neurotransmitter function (dopamine, noradrenaline) is necessary for the action of BRC to appear. Noradrenergic stimulation, however, has to be excluded because a noradrenergic antagonist, prazosin, did not abolish BRC-induced yawning.
A low dose of SK&F38393 (0.5 mg/kg), a dopamine D-1 agonist, prevented the inhibition of BRCinduced yawning by reserpine, oc-MPT or reserpine plus x-MPT. On the other hand, the yawning and stereotyped behaviors induced by apomorphine, a dopamine receptor (both D-1 and D-2 receptors) agonist are markedly potentiated by pretreatment with reserpine, x-MPT or reserpine plus -MPT (Morelli et al. 1986; Ushijima et al. 1987; Kishimoto et al. unpublished observation).
The mode of action of BRC is different from that of apomorphine. BRC, but not apomorphine, appears to require endogenous dopamine or receptor activation by another dopamine agonist (D-1 agonist) for the induction of yawning. While SK&F38393 or BRC alone does not induce stereotyped behavior, combined treatment with BRC (2.5-20 mg/kg) and high doses of SK&F38393 (Sand 10mg/kg) is followed by stereotyped behaviors such as sniffing, licking and biting in a dose-dependent manner (Ushijima et al. 1988). Most recently, Arnt et al. (1987) has reported that D-1 receptors are functionally relevant, since SK&F38393 facilitates the expression of oral stereotyped behavior (licking and biting) after combination with quinpirole, a D-2 agonist. Furthermore, it appears that D-1 receptors also contribute to the yawning response, since this action of BRC alone is partially offset by SCH23390. Indeed, it appears that in most cases, SCH23390 can reduce the apomorphine (low doses)induced potentiation of BRC yawning and BRC-induced potentiation of apomorphine stereotypy. Conversely, SCH23390 can prevent the apomorphine (high doses)-in-
duced reduction of BRC yawning. These results suggest that dopamine receptors mediating stereotypy as well as yawning may include not only D-1 but probably also D-2 receptors. It is probable that yawning is produced by relatively weaker stimulation of D-1 and D-2 receptors, whereas stereotypy is due to stronger stimulation of these receptors. The ability of dopamine agonists to induce yawning and stereotypy seems to be based on the ratio and potency of D-2 versus D-1 receptor stimulation.
When high doses of BRC (10 and 20 mg/kg) were administered after a high dose of reserpine (5 mg/kg), paroxysmal, violent upright fighting and sudden jumping behavior appeared in addition to typical behavioral symptoms such as stereotypy and hyperlocomotion. The episodic behaviors were inhibited by dopamine receptor antagonists (either D-1, D-2 or non-specific dopamine receptor antagonist), suggesting that dopaminergic activation (both D-1 and D-2 receptor activation) was involved in the behaviors.
It is likely that newly synthetized dopamine, released in the synaptic cleft, may be sufficient to induce these symptoms approximately 24 h after reserpine treatment, partly because supersensitivity has probably developed at postsynaptic dopamine receptors. L-Dopa in combination with Ro4-4602, a peripheral decarboxylase inhibitor and reserpine has been reported to induce the bizarre behaviors, which are reminiscent of certain psychotic states seen in man, for which neuroleptic, but not antianxiety drugs are the drugs of choice (Benkert et al. 1973; Lammers and Van Rossum 1968). These results suggest that the mode of action of BRC in producing yawning, stereotypy and upright fighting responses requires both ongoing dopamine synthesis and/or release in addition its own (presumably D-2) receptor stimulation, and seems to result in the potency and ratio of D-2 versus D-1 receptor activity.