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.
