Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior
Collins G et al`

mise à jour du
1 septembre 2003
Pharmacol Biochem Behav 1988;29(1):59-62

Prolactin-induced yawning behavior requires an intact nigro-striatal dopamine system
Laping NJ, Ramirez VD
Department of Physiology and Biophysics, University of Illinois, Urbana, Illinois


-Laping NJ, Ramirez VD Prolactin-induced yawning behavior requires an intact nigro-striatal dopamine system Pharmacol Biochem Behav 1988;29(1):59-62
-Laping NJ, Ramirez VD Prolactin induces yawning and the stretching yawning syndrome in young adulte male rats. Hormones & Behavior 1986;20:49-59
-Laping NJ, Ramirez VD.Yawning behavior in male rats is associated with decreases in in vivo DOPAC efflux from the caudate nucleus. Behav Brain Res. 1990;36(1-2):65-72.
YAWNING behavior, a discrete event with a low spontaneous occurrence, appears to be a well suited model to study behaviors linked to dopaminergic systems such as the nigro-striatal dopamine system. Yawning is also of clinical interest since it has been reported that psychotics rarely yawn, and yawning is symptomatic in a wide range of central nervous system disorders such as brain lesions, chorea, and encephalitis. It has been shown that a variety of substances, such as dopamine (DA) agonists, cholinergic agonists, as well as peptide hormones, induce yawning behavior.
A prevalent view of the regulation of yawning considers that cholinergic neurons which stimulate yawning are under inhibitory control by dopaminergic neurons. Yawning evoked by cholinomimetics, such as physostigmine or pilocarpine, are thought to be mediated by central muscarinic receptors, since yawning induced in this manner is blocked by scopolamine hydrobromide. Furthermore, it is known that the striatal cholinergic system can be inhibited by dopamine. In light of this, it is not surprising that agents which inhibit central dopamine systems induce yawning behavior as well. For example, low doses of dopamine agonists, such as apomorphine (APO) or piribedil (which are thought to be preferentially stimulate dopamine autoreceptors at low doses, and thereby inhibit the dopamine system) can induce yawning behavior as well as the stretch yawning-syndrome. Interestingly, scopolamine also blocks yawning, when induced with APO or piribedil. In terms of dopaminergic agents, yawning behavior is thought to be evoked by compounds which activate dopamine autoreceptors, as illustrated when autoreceptor-selective drugs are used such as 3-PPP or TL-99.
However, yawning behavior is also induced by protein hormones from the pituitary, such as ACTH, oxytocin, and alpha MSH. We have shown that low doses of ovine prolactin (PRL) [0.25 1µg/kg] injected systemically induce yawning in young adult male rats. In spite of the initial release of dopamine by PRL from the striatal terminals, we have hypothesized that the initial release of dopamine eventually will bind to dopamine autoreceptors and then induce yawning behavior. Since there was an indication that infusions of prolactin into the caudate nucleus can induce yawning as well, and that 6OH-Dopamine (6-OH-DA) lesions of the striatum abolished APO induced yawning in rats, it was of interest to investigate if the nigro strital dopamine system is involved in prolactin as well as Apo induced yawning behavior. Herein , we report the effect of bilatreal 6-OH-Da lesions of the substantia nigra on physostigmine, apomporphine and prolactin induced yawns. [...]


Our results indicate that physostigmine-induced yawning is not reduced by a bilateral lesion of the substantia nigra, whereas both APO- and PRL-induced yawning are. Physostigmine most likely mimics cholinergic system involvement in yawning stimulation. However, the present results show that physostigmine does reduce DA concentrations in the caudate nucleus in intact as well as lesioned rats. This reduction may be due to cholinergic activation of GABA, which can inhibit dopamine neurons. In any event, different sites of action appear to be responsible for physostigmine-induced yawning versus APO- and PRLinduced yawning.

Also in the intact animals, both DA and DOPAC concentrations in the caudate nucleus were lower in the APO-30' and PRL groups as compared to those of saline controls, at times that were temporally related te the yawning display. It has been proposed that one site in the central nervous system where APO and PRL act to induce yawning behavior is the nigro-striatal dopamine system. In support of this hypothesis is evidence indicating that not only do infusions of APO within the caudate nucleus decrease striatal neuron firing rates, but that a local infusion of APO is also capable of inducing yawning. The concentrations of APO used in the present experiment could act on the nigro-striatal dopamine autoreceptors, given that APO at these low doses binds prefèrentially to dopamine autoreceptors. Activation of these autoreceptors could inhibit synthesis and/or decrease release of dopamine thereby lifting dopaminergic inhibition of cholinergie systems which have been demonstrated to activate yawning.

With regard to PRL, intra-striatal but not intraaccumbens infusions of PRL can induce yawning (, unpublished observations). It is proposed that PRL induces yawning by a similar mechanism to that of APO. However, this mechanism is probably secondary to its initial releasing action of DA as indicated by the longer latency of PRLinduced yawning. In this way small doses of PRL can release small amounts of DA from the caudate nucleus, and ultimately decrease dopaminergic activity through autoreceptors after a certain latency period. In support of the temporal differences between APO- and PRL-induced yawning is the finding that DA and DOPAC concentrations had recovered by 60 minutes in the intact APO group but not in the intact PRL group.

It can be speculated that in the lesioned animals the remaining intact neurons must increase their output to compensate for the loss of functional dopamine neurons. This could be accomplished in part by a decrease in dopamine auto-receptors which leads to a decrease in feedback inhibition and/or by an increase in receptors at the postsynaptic site leading to hypersensïtivity. The results of the APO30' groups suggest that the number of functional autoreceptors have decreased in the lesioned condition because in this group the DA and DOPAC concentrations were not significantly lower than the lesioned saline controls. In the lesioned APO-60' group the DA and DOPAC concentrations were much higher than the lesioned saline controls. A lesion of the nigro-striatal dopamine system can induce postsynaptic hypersensitivity, which was observed in these experiments by the display of stereotyped behavior in the majority of lesioned animals. However, such hyperactivity could also be the result of DA release from degenerating nerve terminals as well as decreased DA reuptake. In the lesioned condition low doses of APO may in fact stimulate postsynaptic receptors. The activation of postsynaptic receptors could inhibit the GABA-ergic inhibitory feedback loop, resulting in an increased impulse flow of the nigro-striatal dopamine neurons. It has been shown that the increased impulse flow of dopaminergic neurons can result in an increase in DA synthesis. Thus as it was the case one could expect higher DA and DOPAC concentrations 60 minutes after the APO injection.

PRL releases DA and with the decreased number of functional autoreceptors less effective feedback inhibition would be observed. Again, the transient release of dopamine caused by PRL could have inhibited the GABA-ergic feedback loops, resulting in increased impulse flow of dopamine neurons. This could contribute to the greater DA concentrations observed in the lesioned PRL group compared to the lesioned saline group. However, in this group no increase in DOPAC concentration was observed.

In summary, physostigmine-induced yawning does not require an intact nigro-striatal dopamine system. In contrast, APO- and PRL-induced yawning behavior requires an intact nigro-striatal dopamine system. But, the mechanism of action of these two substances appear to be different. The findings that PRL in addition to other pituitary hormones such as ACTH, MSH, and oxytocin, can induce yawning behavior, suggests that the nigro-striatal dopamine system may be an important site where pituitary hormones modulate behaviors.

-Sato F et al. Suppressive effects of chronic hyperprolactinemia on penile erection and yawning following administration of apomorphine to pituitary-transplanted rats Journal of Anthology 1997; 18; 1; 21-25