manifestations elicited by apomorphine,
influence of the route of
HMT Barros, S Braz, EA Carlini
Department of Psychobiology,
Escola Paulista de Medicina, São Paulo,
and Discipline of Pharmacology,
Fundaçâo Facuidade Federal de
Ciências Médicas de Porto Aiegre,
Apomorphine (APO) is a dopamine receptor
agonist frequently used in behavioural studies
to evaluate dopaminergic activity of animals
submitted to cerebral lesions, sleep deprivation
or pharmacological receptor activation. The
administration of small doses of APO produces
decreased locomotor activity, yawning and penile
erection. These effects seem to be related to
the presynaptic action of APO. Higher doses of
the drug, that operate on postsynaptic
receptors, produce stereotypy which is defined
as the performance of an invariant sequence of
movements with repetitive rearing and enhanced
locomotor activity. The behavioural
manifestations elicited by APO reported by
several studies are difficult to compare, since
they have employed different routes of
administration. It has been suggested that the
drug is more potent by the subcutaneous (s.c.)
route because, when injected by the
intraperitoneal (i.p.) route, it suffers
first-pass metabolism. The relative potency of
each route has not yet been established.
In this investigation we studied the effect
of increasing doses of APO injected s.c. or i.p.
on the intensity of stereotypy and on the
occurrence of sedation, yawning, grooming,
penile erection and rearing. Dose-response
curves for each behavior were calculated and the
potency ratio between the routes was determined.
The results show a great difference in the
effective doses of APO between i.p. and s.c.
administration. APO is more potent when
administered after s.c. than after i.p.
injection. Depending on the effect considered,
the potency ratio between s.c. and i.p.
injections varied from 4.6 to 11.8. With the
range of the APO doses used, it was possible to
detect two different behavioural syndromes: (1)
stereotypy or (2) sedation, grooming, yawning
and penile erection after i.p. and s.c.
Stereotypy and rearing, which have been
described as effects due to a postsynaptic
dopaminergic action were produced by higher
doses. The drug was 10 times more potent to
produce stereotypy by the s.c. than by the i.p.
route. Doses to produce rearing were similar for
both routes. In contrast to observations by Fray
et al., who were not able to detect any
relationship between APO doses and rearing, we
found that APO enhances rearing with an ED50
higher than that for inducing stereotypy. It may
be that rearing is not a component of the
APO-induced stereotypy syndrome.
Several additional mechanisms can be
proposed to explain such conflicting results.
First of all, it is possible that the
differences in effects can be due to the
different strains of rats used or to the
differences in the cages employed. It can also
be presumed that the drug concentrates in
different brain areas, depending either on the
route of administration or on the different
speed of its penetration into the brain.
Finally, it could be proposed that there
might be differences in the sensitivity of the
dopaminergic receptors, which mediate different
behaviours. Stereotypy is mediated by both D1
and D2 receptors, but the D2 receptors play a
more important role.
Studies show that some behavioural
components of stereotypy, like sniffing, are
related to D1 receptors while D2 receptors
modulate the expression of rearing, initiated by
D1 stimulation .
After administration of lower doses of APO,
sedation, yawning and penile erection could be
observed. These effects seem to be determined by
presynaptic dopaminergic effects, and are
reduced by higher doses. Similarly to yawning,
penile erection and sedation, grooming is
enhanced by dopamine agonists . In this study,
grooming occurred in the same dose range which
produced sedation, yawning and penile erection;
a biphasic dose-response curve could also be
delineated and this behaviour did not occur when
stereotypy was present. These effects could be a
consequence of the action of APO at the same
synapses or receptors.
The decrease of APO-induced presynaptic
effects was similar for each route of
administration, since the potency ratios for the
behaviours considered were not significantly
different. It could also be verified that either
the i.p. or s.c. ED 50 for stereotypy induction
was similar to the same route of administration
ED 50 which caused decreasing of sedation,
yawning, penile erection and grooming. These
observations are similar to those of Protaiset
al., showing that sedation, yawning, penile
erection and grooming are associated with
In summary, it was verified that APO
administration, either i.p. or s.c, produces
similar behavioural effects (with the exception
of rearing). However, the s.c. dose necessary to
produce the behavioural effects was much lower
than the i.p. dose. This knowledge of the
potency ratios between the s.c. and i.p. routes
will facilitate the comparison of studies on
behavioural effects by apomorphine.
Himes CS Apomorphine produced more yawning
in Sprague-Dawley rats than in F344 rats: a
pharmacological study Eur J Pharmacol 1995; 284;