haut de page

mise à jour du
8 mars 2010
Brain Res Bull
Atypical neuroleptic-like behavioral effects of neurotensin
Jolicoeur FB, Gagné MA, Rivest R, Drumheller A, St-Pierre S.
Department of Psychiatry, Faculty of Medicine, University of Sherbrooke, Quebec, Canada.


To better characterize the neuroleptic-like properties of neurotensin, the dose-related effects of the peptide on the following behavioral phenomena were examined: a) the yawning-penile erection syndrome induced by small doses of the dopamine agonists apomorphine and N-propylnorapomorphine (NPA); b) yawning produced by the anticholinesterase physostigmine, and c) stereotyped climbing and sniffing produced by a larger dose of apomorphine. Several doses of the peptide were injected intraventricularly 30 min prior to drug administration. Results indicate that neurotensin markedly decreased yawning and penile erections produced by both apomorphine and NPA. These effects were seen with relatively small doses (0.9-3.75 micrograms). Neurotensin also potently decreased physostigmine-induced yawning with the initial inhibitory effect seen with 50 ng of the peptide. Apomorphine-induced climbing was significantly attenuated with 30.0 and 60.0 micrograms neurotensin, whereas stereotyped sniffing was unaffected, even by doses as large as 120.0 micrograms. These findings suggest that neurotensin might antagonize dopamine autoreceptors and indicate that the peptide possess central anticholinergic activity. Furthermore, these results lend support to the hypothesis that neurotensin's profile of central actions resemble that of atypical neuroleptics.

Many neurobehavioral effects of the tridecapeptide neurotensin resemble those of neuroleptics. These effects include decreases in body temperature, motor activity, muscular tone, and rates of self-stimulation (10,17,21). Also, similarly to neuroleptics, neurotensin attenuates the behavioral hyperactivity induced by a variety of substances known to stimulate dopaminergic transmission (6,11,14). On the other hand, contrary to typical neuroleptics, the peptide does not induce catalepsy in rats and faits to decrease stereotyped sniffing elicited by dopamine stimulating drugs (Il). Because of this, it has been suggested that the profile of neurotensin's neurobehavioral effects is more akin to that of so-called atypical neuroleptics such as sulpiride and clozapine (12). These drugs, while capable of producing all of the aforementioned behavioral eñècts of typical neuroleptics, also display weak cataleptogenic properties and are relatively impotent in reducing stereotyped sniffing induced by dopaminergic stimulation (30).
The examination of drug effects on behaviors induced by small and large doses of apomorphine has been shown to be a simple and reliable procedure to detect potential neuroleptics and to differentiate between typical and atypical neuroleptics (5,23). Among other effects in rats, relatively small doses of apomorphine (25-200 g kg) induce yawning and penile erections, two responses often attributed to the activation of dopamine autoreeeptors (27,31). Larger doses produce stereotyped behaviors that are thought to be mediated by the activation of dopa-
mine postsynaptic receptors (2). Whereas typical neuroleptics antagonize apomorphine-induced yawning, penile erections, and stereotypies at similar doses, atypical neuroleptics are markedly more potent to inhibit yawning and penile erections than to attenuate stereotyped behaviors (23). Also, while typical neuroleptics decrease both stereotyped climbing and oro-facial stereotypies at similar doses, atypical neuroleptics are markedly more potent in reducing the former than the latter stereotyped behavior (7.18). Furthermore, as stereotypies produced by large doses of the dopamine agonist gradually dissipate, yawning responses begin to be emitted by the animals. Such emergence of yawning following disappearance of stereotypy is maintained with typical but is inhibited by atypical neuroleptics (23).
The purpose of the present study was to better characterize the atypical neuroleptic-like nature of neurotensin. We examined the effects of several doses of the peptide on yawning and penile erections induced by 100 ag/kg of apomorphine as well as on stereotyped climbing and sniffing produced by 600 big/kg of the dopamine agonist. The possible appearance of yawning after administration of the larger dose of apomorphine was also closely monitored. The effects of neurotensin on yawning and erections produced by a small dose of N-propylnorapomorphine (NPA) were also assessed. The inclusion of this second dopamine agonist was prompted by the report that the peptide specifically and markedly reduces the binding of NPA to neuronal membranes (1). To determine the specificity of the effects of neurotensin on yawning produced by dopamine agonists, and because a dopamine-cholinergic link has been implicated in yawning behavior (3!), the effects of the peptide on physostigmine-induced yawning were also examined. Finally, to verify the possible implication of cholinergic transmission in penile erections produced by dopamine agonists, the effects of atropine on erections induced by 100 pg/kg apomorphine were also studied. Some preliminary results of the present study have been presented previously .
Together, the results of the present study extend previous findings that suggested that neurotensin has a profile of neurobehavioral effects similar to that of atypical neuroleptics (12). The peptide significantly decreased both yawning and erections induced by a relatively small dose of apomorphine. Compared to yawning, penile erections were significantly decreased with a smaller dose of neurotensin (Fig. I; Table 1). Neurotensin also decreased both yawning and penile erections induced by NPA (Fig. 1: Table 1), The peptide was equipotent in inhibiting these behaviors induced by both NPA and apomorphine. It has been reported that neurotensin decreases the affinity of NPA for DA receptors in vitro (1), If this action constitutes the mechanism responsible for our in vivo results with NPA, then it might be generalized to other DA agonists, such as apomorphine. In any case, a direct action of neurotensin on the D2 receptors thought to mediate yawning (32) can be ruled out, because NT has only a weak affinity for the this subtype of receptor (20).
As mentioned earlier, the inhibition of the yawning-penile erection syndrome is a common effect of both typical and atypical neuroleptics (3,5,23). However, contrary to typical neuroleptics. neurotensin failed to reduce stereotyped sniffing induced by the larger dose of apomorphine (Table 3), thus confirming previous findings (11). Sniffing remained unaffected even with 120 ig of the peptide, the largest subtoxic dose we could utilize. The differential influence of the peptide on the penile-erection syndrome and on stereotypy thus seems to be more pronounced than that of atypical neuroleptics which can attenuate apomorphine-induced sniffing, albeit at much larger doses than those required to inhibit yawning and erections. It is noteworthy that yawning was not seen in animals injected with the peptide (Table 3). Again, the inhibition of yawning, a behavior which typically appears as stereotypy dissipates, is a characteristic effect of atypical neuroleptics.
The results also demonstrate that neurotensin can antagonize apomorphine-induced climbing. This effect cannot be attributed to a nonspecific motor impairment effect of the peptide because we have shown previously that 60.0 zg of neurotensin, the most effective dose in reducing climbing, does not affect motor activity or muscle tone of animals (10). Also, careful observation of the animals during the course of this study did not reveal any behavioral abnormalities. Finally, the maintenance of oral stereotypies in the experimental animals is further indication that inhibition of climbing is not due to a generalized sedative effect of the peptide.
The present results demonstrate for the first time that neurotensin can affect stereotyped behavior induced by a dopamine agonist. Until now examination of the possible influence of the peptide on stereotypy induced by dopaminergic stimulation has been limited to oro-facial stereotypies, and the inability of neurotensin to decrease these behaviors has been reported frequently (6.11). This was confirmed in the present study. The selective inhibitory effect of the peptide on stereotyped climbing is, therefore, interesting, although the exact mechanism underlying this action is difficult to explain at the present time. The neuronal substrates of apomorphine-induced climbing in rats are unknown but they do not seem to be located in either the striatum or the nucleus accumbens. as lesions of these regions do not alter climbing (24). The dopamine receptors implicated in this behavior also remain to he clearly identified (7.18). However, thc fact that neurotensin affected climbing but not oro-facial movements indicates that distinct receptors and/or ncurophysiological processes underhc these different apomorphine-induced stereotyped behaviors.
Yawning and penile erections induced by small doses of dopamine agonists are generally thought to he mediated by activation of dopamine autoreceptors (4,27.3 1,32). although data inconsistent with this hypothesis have been presented (19,28). If autoreeeptors do underlie yawning and climbing induced by small doses of dopamine agonists, then our results constitute behavioral evidence that neurotensin might act as an antagonist of dopamine autoreeeptors.
Neurotensi n also markedly antagonized physostigm inc-induced yawning. The effect was first seen with 50 ng of the peptide. indicating that neurotensin is approximately 37 times more potent in reducing yawning produced by cholinergic stimulation than that elicited by a dopamine agonist. To our knowledge. this prominent finding constitutes the first evidence that neurotensin might possess central anticholinergic properties. In agreement with this hypothesis. we have observed recently that neurotensin reduces both tremors and muscular rigidity in an animal model of Parkinson's disease, two effects that could possibls be attributed to an anticholincrgie action of the peptide (15).
As discussed above, a dopamine-cholinergic fink has been demonstrated for yawning responses induced by dopamine agonists (31). Such a link for penile erections produced by these drugs has been suggested but, as yet, has not been clearly established (9). Our results with atropine confirm that an anticholinergic agent can inhibit effectively yawning induced by small doses of apomorphine (Table 2). However, as can he seen in this table, atropine did not affect the frequency of erections induced by the dopamine agonist. Therefore, the inhibition by neurotensin of' apomorphine- or NPA-elicited erections cannot solely he attributed to an anticholinergic property of the peptide.
The behavioral findings of this study are in agreement with our recent ncurochemical data that demonstrate that, contrary to the typical neuroleptics haloperidol and perphenazine whose increasing effects on striatal DOPAC levels are amplified hy the dopamincrgic stimulant amfanehic acid, the elevation oistriatal levels of the dopamine metabolite produced by clozapine, thioridazine, and neurotensin were actually decreased h amfonehic acid (25).
In conclusion, neurotensin shares many central properties with atypical neuroleptics. More specifically, our data suggest that the actions of neurotensin resemble more closely those of clozapine because, compared to other atypical neuroleptics such as sulpiride and thioridazine. this compound is the only antipsychotic capable of antagonizing with similar potency yawning induced by both dopamine agonists and by physostigmine (5). This finding is important and warrants further research because it has been reported that clozapine, a drug rapidly being recognized as the treatment of choice in the pharmacological management of schizophrenia, does not produce extrapyramidal side effects in man (8). However, this drug is known to produce agranulocytosis in some patients, limiting it's clinical usefulness. Therefore, the development of pharmokinetically viable neurotensin derivatives could hold promise for treating this debilitating disease,