mise à jour du
14 octobre 2004
Behavioural manifestations elicited by apomorphine, influence of the route of administration
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, Brazil


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. administration.
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 stereotypy.
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.
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