mise à jour du
15 août 2002
1986; 25; 7; 783-786
Desipramine induces yawning behaviour in rats
E. Mogilnicka, K. Wedzony, V. Klimek and A. Czyrak
Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland


Much evidence shows that the tricyclic antidepressant, desipramine, apart front its potent property of inhibiting the uptake of noradrenaline (NA) (Iversen, 1975), also exhibits an influence on central dopaminergic systems. Desipramine enhances depletion of dopamine (DA) in the striatum by a -methyl-m -tyrosine, a finding that suggests an increase in utilization of DA (Waldmeier, 1982), produces significant elevation of the net efflux of endogenous DA from the hypothalamus and striatum (Myers and Tessel, 1984), inhibits the uptake of DA into the corpus striatum (Randrup and Braestrup, 1977; Koe, 1979). However, concentrations of desipramine 100-1000-fold greater are required to inhibit the uptake of DA than of NA.

Enhancement of the release of DA and inhibition of the uptake of DA by desipramine can be expected to result in an increase in the amount of DA in the synaptic cleft, which, in turn, should affect behaviour that is dependent on dopaminergic stimulation. Agents that stimulate DA systems directly, such as apomorphine or indirectly, such as amphetamine, produce characteristic stereotyped behaviour, hypermotility or induce sedation and yawning behaviour in rats. The latter effect, however, is induced by relatively small doses of DA agonists (Mogilnicka and Klimek, 1977; Dubuc, Protais, Colboc and Costentin, 1982). Desipramine, even in large doses, fails to provoke stereotypy but according to biochemical findings, it does affect dopaminergic systems. Therefore, in the prescrit study it was decided to investigate the effect on yawning. Additionally, the effect of some other typical and atypical antidepressants on yawning were tested. [...]

Discussion : The main finding of this study was that desipramine and some other antidepressants provoked yawning in rats. As has been pointed out in the introduction, yawning occurred in rats after administration of relatively small doses of various DA agonists that stimulate DA receptors either directly (apomorphine) or indirectly (amphetamine, nomifensine; Mogilnicka and Klimek, 1977; Yamada and Furukawa, 1980). Reduction of the yawning induced by desipramine by the DA-ergic blockers (haloperidol, spiperone, pimozide) points to the involvement of DA receptors in phenomenon observed.

As desipramine is a potent inhibitor of the uptake of NA, it can be expected that NA-ergic stimulation plays a role in the induction of yawning. This possibility, however, has to be excluded because the NA-ergic antagonists, prazosin and phenoxybenzamine, did not abolish yawning induced by desipramine and, on the other hand, another selective and potent inhibitor of the uptake of NA, the active enantiomer of (±)oxaprotiline - (+)oxaprotiline (Waldmeier, Baumann, Hauser, Maître and Storni, 1982) did not provoke yawning.

Furthermore, the prevention of yawning by reserpine, as well as by a-MT, points to the presence of neurotransmitters (DA, NA) being necessary for the action of desipramine to appear. It seems, therefore, in the light of above finding that desipramine might induce yawning by releasing DA from nerve endings. A dopaminergic-cholinergic link bas been shown to be involved in yawning (Yamada and Furukawa, 1980; Dubuc et al., 1982). Indeed, as was the case with apomorphine-induced yawning, scopolamine also blocked yawning provoked by desipramine. However, cholinergic stimulation is brought about indirectly, by DA-ergic activation (which scems to be a primary effect), since yawning induced by desipramine was blocked by DA blockers. It must bc added that haloperidol did not affect yawning induced by cholinomimetie drug physostigrnine (Dubuc et al., 1982).

Among drugs that induce yawning to a lesser extent than desipramine, are the tricyclics imipramine and clomipramine, atypical antidepressant trazodone and its metabolite m-chlorophenylpiperazine, as well as neuroleptics of the benzamine group sulpiride. Imipramine induced yawning episodes of lesser intensity, which suggests that it affects DA-ergic systems to a smaller degree than does desipramine. As imipramine is metabolized to desipramine (Rickel and Weder, 1968; Daniel, Adamus, Melzacka, Szymura and Vetulani, 1981), its pharmacological effects can also be brought about by its metabolite. Interestingly, trazodone which blocks 5-HT receptors, as well as m-chlorophenylpiperazine, which stimulates them (Fuller and Snoddy, 1977, Maj, Palider and Rawlôw, 1979) each provoked the occurrence of yawning. It can, however, be argued that yawning is due solely to stimulation of 5-HT receptors as trazodone is metabolized to m-chlorophenylpiperazine (Melzacka, Boksa and Maj, 1979), a 5-HT agonist. However, lack of inhibition of yawning induced by m-chlorophenylpiperazine by the specific 5-HT-ergic blocker, metergoline excludes this possibility. Therefore, it is not surprising that no yawning episodes were observed after administration of the strong and specific inhibitor of the uptake of 5-HT citalopram (Hyttel, 1982). The fact that haloperidol prevented yawning induced by m-chlorophenylpiperazine indicates a DA-ergic action of m-chlorophenylpiperazine.

It is noteworthy that all the compounds which induced yawning can influence the DA-ergic system. As demonstrated with various methods, clomipramine, trazodone and m-chlorophenylpiperazine increase the turnover of DA (Fuller and Snoddy, 1977; Waldmeier, 1982, 1984). Clomipramine, trazodone, m-chlorophenylpiperazine and sulpiride increase the turnover of DA in brain, probably by blocking DA receptors (Fuller and Snoddy, 1977; Keller, Burkard and Da Prada, 1980; Montanare, Dall'Olio, Gandolfi and Vaccheri, 1982; Waldmeier, 1982, 1984). The open question is how to explain the presence of yawning if DA receptors are blocked. Omitting at the moment the speculation concerning the kind of DA receptors responsible for yawning (pre- and postsynaptic receptor mechanism?) it is assumed that, in spite of the blockade of these receptors, their stimulation is possible. Following the speculation of Bunney (1984) referring to the mechanism of action of antipsychotic drugs, one can imagine that receptor blockade is not very effective after acute administration of antipsychotics or neuroleptic-like drugs. A single dose of such a drug would result, in an increase in release of DA into the synaptic cleft, and due to the consequential flooding of the cleft with DA molecules and their competition with drug molecules for the receptor, the DA receptors can be stimulated. This mechanism could explam the appearance of yawning after clomipramine trazodone and sulpiride.

From the above findings it is concluded that desipramine and some other antidepressant drugs induce yawning behaviour and that a DA-ergic mechanism is involved in this behavioural manifestation.

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