mise à jour du
11 décembre 2003
The apomorphine test in heroin addicts
Miguel Casas, Josep Guardia, Gemma Prat, Joan Trujols
Unitat de Toxicomanies, Departament de Farmacologia i Psiquiatria, Facultat de Medicina, Universitat Autonoma de Barcelona Spain


A new model for the apomorphine test as a biological marker for cocaine-dependent patients
Roncero C, Fuste G, Grau-López L, et al.
Yawning as a dose-dependent side effect of treatment with escitalopram
Roncero C, Mezzatesta-Gava M,
Grau-López L, Daigre C.
Neurologia (spanish) 2012
The apomorphine test: a biological marker for heroin dependence disorder?
Guardia J, Casas M, et al
Addict Biol

Introduction Yawning is a common physiological reflex both in animals and humans. Although the specific neural mechanisms underlying yawning have not been completely established, it is known that in rodents and monkeys it can be elicited by diverse pharmacological agents, including dopamine agonists, cholinomimetics, serotonin agonists, centrally injected hormones such as ACTH, melanocyte stimulating hormone, b-lipotrophin and oxytocin (Dourish & Cooper, 1990). In humans, dopamine-mediated yawning has been widely studied through the administration of low doses of subcutaneous apomorphine in healthy volunteers ( Lal et al., 1987; Blin et al., 1988).
Such studies led to the development of the apomorphine test used in the study of the central nervous system (CNS) dopamine receptor sensitivity and in the prediction of dopaminergic responsiveness in patients with Parkinson' s disease It is now well established that the mesothelencephalic dopamine neurotransmitter systems are involved, as a part of the brain reward mechanism, in the reinforcing properties of drugs of abuse and consequently in the development and maintenance of opiate addiction. In animal studies, it has been shown that the acute effect of opiates enhances dopamine transmission and, conversely, chronic opiate administration decreases dopamine release, leading to a neuroadaptative process that results in a supersensitivity of dopamine receptors in the mesolimbic and mesostriatal dopamine systems.
If chronic opiate use in humans, as in experimental animals, results in supersensitivity of the dopamine systems the administration of low doses of subcutaneous apomorphine, following the apomorphine test procedure proposed by Blin et al., could differentiate between heroin addicts and healthy volunteers, with the former showing a greater number of yawns.
To evaluate this hypothesis we compared the yawning response induced by low doses of apomorphine (0.005 mg/Kg s.c.) in two groups of subjects: a group of male heroin addicts attending our Addiction Treatment Centre for detoxication, and the other group consisting of healthy volunteer male university students.
Discussion Our results show that opiate addicts present a greater number of yawns (p , 0.05) than a similar group of non-addict healthy volunteers as a result of the subcutaneous administration of 0.005 mg/Kg s.c. of apomorphine. Apomorphine- induced yawing is centrally mediated by the action of apomorphine on the postsynaptic D2 dopamine receptors, with the stimulation of D1 receptors by apomorphine playing a permissive-facilitating role. As the apomorphine test has recently been described as an easy, ethical in vivo procedure to measure the dopamine system sensitivity in healthy volunteers and Parkinson' s patients, our data suggest that heroin addicts show an enhancement of the sensitivity of central dopamine systems, probably as a result of the development of a hypersensitivity of postsynaptic dopamine receptors after chronic opiate use.
Several reports on the neurochemical mechanism of drug addiction have pointed out that most psychoactive substances with high potential abuse liability such as opiates, ethanol, cocaine, amphetamine and nicotine show a common effect on the CNS dopamine systems. In laboratory animals the acute administration of such substances produces an increase in dopamine transmission which has been related to the reinforcing properties of such substances and with the appearance of compulsive drug-taking behaviour. Conversely, in chronic use, a decrease in dopamine function has been observed, with the development of hypersensitivity of dopamine receptors in the mesothelencephalic dopamine pathways, possibly due to molecular mechanisms involving post-receptor intracellular messengers, such as G-proteins and the cyclic AMP system.
In laboratory animals the hypersensitivity of the mesolimbic and mesostriatal dopamine receptors facilitates the Pavlovian conditioning process of neutral environmental stimuli present when such systems are drug-stimulated. Such conditioning results in undrugged responses similar to those elicited by the drug itself when animals are later re-exposed to the conditioned environmental cues.
In humans it is known that environmental cues associated with drug withdrawal or drugtaking could become conditioned stimuli able to trigger conditioned withdrawal symptomatology, craving and drug-seeking behaviour when an abstinent patient is re-exposed to such drug-related stimuli. Recently, hypersensitivity of the dopamine system has been proposed as a neural basis for conditioned withdrawal syndrome and craving. This suggests, perhaps, that patients with a high drug-induced hypersensitivity of the dopamine system may be more easily condition drug-related environmental cues, and consequently may be greatly at risk to relapse when re-exposed to these conditioned cues. If this were so, the apomorphine test could be a useful procedure to evaluate the level of sensitivity of dopamine systems in opiate dependence, and might therefore be a simple in vivo biological marker for risk to relapse.
Before the apomorphine test can be introduced into the clinical routine many further studies must be carried out, both in a greater number of subjects and in other substance use disorders. Nevertheless, the increasing implication of the sensitivity of dopaminergic system in addictive behaviours, as proposed by both clinical and neuroscience researchers suggest that a simple test should be found to measure the sensitivity of this neurotransmitter system in addict patients.