mise à jour du
13 novembre 2005
1983; 80; 38-42
The role of dopaminergic receptors
in the behavioral effects
induced by lisuride in male rats
Giosué Baggio and Francesca Ferrari
Institute of Pharmacology, Chair of Pharmacology and Pharmacognosy
University of Modena, Italy


Abstract. Lisuride increased the incidence of stretching and yawning (SY) as well as of penile erection (PE) and elicited stereotyped behavior (SB), aggressive behavior and mounting in male rats, depending on the dose used. SY was prevented by two dopaminergic antagonists, haloperidol and sulpiride, but not by methysergide, a serotoninergic antagonist, while PE was antagonized by all three drugs. With regard to SB, aggressive behavior and mounting, all three were suppressed by haloperidol; sulpiride, while partially antagonizing aggressiveness, failed to affect SB and mounting; mcl hysergide did not significantly influence any of the three. This suggests that lisuride principally affects the dopaminergic system. Although further detailed studies are required to elucidate which type of the complex population of DA-receptors is involved in each kind of behavior, we suggest that SY at least is due to the activation by lisuride of presynaptic DAreceptors.

Biochemical and behavioral evidence suggests that lisuride, a semi-synthetic ergot derivative used mainly as a prophylactic agent in migraine, acts on 5-hydroxytryptamine (5-HT) and dopamine (DA) receptors (Votáva and Lamplová 1961; Horowski and Wachtel 1976; Pieri et al. 1977: Kehr 1977).
A central dopaminergic action has also been proposed for the other ergot derivatives (Corrodi et al. 1973: Johnson et al. 1973; Woodruff et al. 1974; Kehr 1977). Moreover, 2-bromo--ergocryptine is reported to induce stereotyped behavior (SB) (Johnson et al. 1974) and bromocriptine to induce repeated episodes of penile erection (PE) and stretching and yawning (SY) in rats (Bertolini et al. 1979). These modes of behavior are considered to be specific expressions of the stimulation of brain dopaminergic systems (Randrup and Munkvad 1968; Benassi-Benelli et al. 1979). The aim of our investigation was to assess whether lisuride also acted on DAreceptors, the stimulation of which evokes SY and increases PE, besides the other modes of behavior previously described, namely, SB (Horowski and Wachtel 1976; Horowski 1978), aggressive behavior (Podvalová and Dlabaé 1970) and mounting (Da Prada et al. 1977).
Our results show that lisuride elicits in male rats a number of different responses, according to the dose, and suggest that mainly DA-receptors are involved in these effects. Previous experiments with other well-known dopamine agonists, such as APO and NPA, have supported the hypothesis that SY. PE and SB are signs of activation of DA-receptors in the CNS (Menon et al. 1978: Benassi-Benelli and Ferrari 1979; Benassi-Benellj et al. 1979). Induction of SB by lisuride has already been reported (Horowski and Wachtel 1976; Horowski 1978), but the increase in SY and PE at very low doses to our knowledge has not. For SY, lisuride was as potent as NPA, and more so than APO (Benassi-Benelli and Ferrari 1979), but although these DA-agonists were also potent dose-dependent inducers of PE, the increase in sexual behavior caused by lisuride was small. Only the percentage of animals responding was significantly influenced, and not the mean number of PE per animal responding.
An effect of lisuride on male sexual behavior has already been described for the mating pattern in rats and 5HT involvement has been suggested to underlie the phenomenon (Ahienius et al. 1980). On the other hand, several similarities between lisuride and APO, such as the antagonism of reserpine-induced motor depression, hypothermia (Horowski and Wachtel 1976), aggressive behavior (Podvalovâ and Dlaba 1970), decrease in serum prolactin (Horowski et al 1975) and emesis in dogs, would support the concept that lisuride has mainly central DA-activity, as suggested by Horowski and Wachtel (1976). PE elicited by lisuride in rats was antagonized by both DA and 5-HT antagonists, rendering a simple interpretation difficult.
The antagonism might be non-specific and not exerted at the same receptor site, especially given the above mentioned, mild activation of PE by lisuride, in comparison with that obtained with other typical dopaminomimetics. On the other hand, the supposed dopaminergic nature of SY was confirmed by the clear antagonism obtained with haloperidol and sulpiride and by the failure of methysergide. Haloperidol, classically considered a dopamine antagonist drug, exerts its activity on pre- and post-synaptic DA-receptors (Long et al. 1975; Lokhandwala and Buckley 1977). Sulpiride seems also to be a specific DA-receptor antagonist with particular affinity for presynaptically located DA-receptors involved in the inhibition of DA-synthesis and release, the so-called autoinhibitor-receptors (Kehr et al. 1972; Carlsson 1975; Bunney and Aghajanian 1975; Di Chiara et al. 1976; Corsini et al. 1979; Spano et al. 1979). Although detailed studies must obviously be undertaken on the biochemical changes in neurotransmission correlated with SY, our data suggest that this behavior might be an expression of a preferential DAautoreceptor-stimulation. It must be stressed that we observed that the low doses of lisuride which elicitSYsimultaneously induced sedation (that is, a considerable reduction in spontaneous locomotor activity-data not reported). This is in agreement with the behavioral effects of low doses of typical DA-stimulants such as APO and N PA, which elicit SY (Benassi-Benelli and Ferrari 1979; Benassi-Benelli et al. 1979) and sedation both in animals and in man (Di Chiara et al. 1976; Corsini et al. 1977a, b; Spano et al. 1979), simultaneously inhibiting dopaminergic firing and DA-synthesis in the caudate nucleus and nucleus accumbens, presumably through preferential activation of presynaptic receptors, as assessed by changes in DOPAC levels (Serra et al. 1981). Moreover, lisuride is also reported to reduce DA turnover and synthesis at low doses (Kehr 1977).
In conclusion, our behavioural findings strongly support an effect of lisuride on dopaminergic mechanisms. At low doses it probably has a preferential affinity for presynaptic inhibitor receptors, the activation of which leads to SY and, probably, to PE enhancement. At higher doses it would appear to have chiefly an agonistic effect on the postsynaptic DA-receptors, thereby eliciting SB. 1f this hypothesis is confirmed by biochemical studies, induction of SY in addition to sedation could be used as a simple and sensitive behavioral model for testing drugs acting on presynaptic autoinhibitory DA-receptors. Whatever the type of receptor involved, we should like to stress that SY, specifically stimulated by dopamine agonists, would seem to be a parameter worthy of attention in studying animal behavior.