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 .
DISCUSSION
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,
