Addiction (1995) 90, 831-835

RESEARCH REPORT

The apomorphine test in heroin addicts

MIGUEL CASAS, JOSEP GUARDIA, GEMMA PRAT & JOANTRUJOLS

Unitat de Toxicomanies, Programa Sant Pau-CITRAN, FISP, Departament de Farmacologiai Psiquiatria, Facultat de Medidna, Universitat Autonoma de Barcelona, Hospital de la StaCreu i St Pau, Avda St Antoni M" Claret, 167, 08025-Barcelona, Spain

AbstractChronic administration of opiates to laboratory animals induces supersensitivity of the dopamine receptors inthe cerebral areas innervated by the mesotelencephalic dopamine pathways. In humans, the in vivo study ofthe sensitivity of the dopamine neurotransmitter system in Parkinson's patients can be done by means of theapomorphine test, which consists of measuring the number of yawns induced by the subcutaneous administra-tion of low doses of apomorphine (0.005 mg/kg). If chronic opiate use in humans, as in experimental animals,results in supersensitivity of the dopamine systems, the apomorphine test could differentiate between heroinaddicts and healthy volunteers, with the former showing greater number of yawns. In order to test thishypothesis we carried out the apomorphine test in two groups of subjects: a group of male heroin addictsattending our Addiction Treatment Centre for detoxification and the other group consisting of healthyvolunteer male university students. Results showed that subcutaneous apomorphine administration induced agreater number of yawns (p < 0.05) in the group of heroin addicts as compared with the group of healthyvolunteers, suggesting that heroin addicts present an enhanced sensitivity of the dopamine neurotransmittersystem.

IntroductionYawning is a common physiological reflexboth in animals and humans. Although thespecific neural mechanisms underlying yawninghave not been completely established, it isknown that in rodents and monkeys it canbe elicited by diverse pharmacologicalagents, including dopamine agonists, choli-nomimetics, serotonin agonists, centrally in-jected hormones such as ACTH, melanocytestimulating hormone, ^-lipotrophin and oxytocin

Correspondence to: M. Casas, Unitat de Toxicomanies,Hospital de la Sta Creu i St Pau, Avda St Antoni M' Claret, 167,08025-Barcelona, Spain.

0965-2140/95/060831-05

(Dourish & Cooper, 1990). In humans,dopamine-mediated yawning has been widelystudied through the administration of lowdoses of subcutaneous apomorphine in healthyvolunteers (Corsini et ah, 1981; Lai et al.,1987; Szechtman et al, 1988; Blin et al.,1988). Such studies led to the developmentof the "apomorphine test" used in the studyof the central nervous system (CNS) dopaminereceptor sensitivity (Lai, 1988; Blin et al.,1988; 1990) and in the prediction of dopa-minergic responsiveness in patients withParkinson's disease (Hughes, Lees & Stem,1988; Barker, Duncan & Lees, 1989; Gasser etal., 1992).

© 1995, Society for the Study of Addiction to Alcoholand other Drugs

832 Miguel Casas et al.

It is now well established that the mesothelen-cephalic dopamine neurotransmitter systems areinvolved, as a part of the brain reward mechan-ism, in the reinforcing properties of drugs ofabuse and consequently in the development andmaintenance of opiate addiction (Wise, 1987;Gardner, 1992). In animal studies, it has beenshown that the acute effect of opiates enhancesdopamine transmission (Chesselet et al., 1981;Pentney & Gratton, 1991) and, conversely,chronic opiate administration decreases do-pamine release (Acquas, Carboni & Di Chiara,1991), leading to a neuroadaptative process thatresults in a supersensitivity of dopamine recep-tors in the mesolimbic and mesostriatal do-pamine systems (Parenti et al., 1982; Nestler,1993),

If chronic opiate use in humans, as in exper-imental animals, results in supersensitivity of thedopamine systems the administration of lowdoses of subcutaneous apomorphine, followingthe 'apomorphine test' procedure proposed byBlin et al., (1988; 1990), could differentiate be-tween heroin addicts and healthy volunteers,with the former showing a greater number ofyawns.

To evaluate this hypothesis we compared theyawning response induced by low doses of apo-morphine (0,005 mg/Kg s.c) in two groups ofsubjects: a group of male heroin addicts attend-ing our Addiction Treatment Centre fordetoxification, and the other group consisting ofhealthy volunteer male university students.

appearance of withdrawal symptomatology(1000 ±450 mg). All subjects were previouslyinformed of the risk of the protocol. Testing wasdone individually in order to avoid group inter-actions, and subjects were not advised thatyawning was recorded.

General procedureAll subjects from both groups received NaCl orapomorphine on two different days. The order ofadministration of either NaCl or apomorphinewas decided at random on the first test day. Thepurpose of this procedure was to control theappearance of yawns induced by any initial with-drawal syndrome or the occurrence of yawns dueto a boring situation. In Group 1 both tests weredone while patients were stabilized with d-pro-poxiphene and before the pharmacologicaldetoxification process was started. On both testdays, all subjects had slept at least 7 hours andhad abstained from any drug or food consump-tion for between 10-12 hours. Between 9-11a.m, subjects received a subcutaneous adminis-tration of apomorphine (0.005 mg/Kg s.c.) orNaCl. Yawning was recorded continuously byindependent observers for a period of 45 minutesafter apomorphine or NaCl administration.Heart rate, temperature and blood pressure wererecorded every 15 minutes as a control measureof apomorphine-induced side-effects and in or-der to focus the attention of the subject on suchneurovegetative parameters.

MethodsSubjectsThirteen male inpatient heroin addicts (agerange: 18-35 years, mean: 25,9 ± 3,55) undergo-ing detoxification treatment in the AddictionTreatment Centre of our Medical School Gen-eral Hospital (Group 1) and 10 healthy non-ad-dict males (age range: 18-32 years, mean:21,7 ±3,31) (Group 2), very rarely consumingany legal psychoactive substances (maximum ofone cup of coffee, one cigarette and one al-coholic drink per week) were included in thestudy. Both groups showed normal vital signsand non-active organic or psychiatric diseases.Patients in Group 1 were withdrawn from heroinas of their admittance to the Addiction Treat-ment Centre and were stabilized for 3 days withd-propoxiphene at a dosage that prevents the

Statistical analysisThe number of yawns was analysed as a non-parametric variable. Differences between groupswere carried out with a Kruskall-Wallis one-wayanalysis of variance. The comparison betweenNaCl or apomorphine administration was madewith a Wilcoxon two-tailed test.

ResultsStatistical differences were obtained between thenumber of yawns induced by NaCl and apomor-phine in opiate addicts (Group 1), with thenumber of yawns induced by apomorphine beinggreater (p< 0,005) than that induced by NaCl.Group 2 did not show any statistical differencesbetween the number of yawns induced by apo-

Apomorphine test in heroin addicts 833

Table 1. Mean ± standard deviation of number of yawns in the twogroups of subjects

GroupApomorphine-induced

yawnsNaCl-induced

yawns

Heroin addictsNon addicts

10.1 ±8.43.4 ±3.8

2.5 ±3.30.6 ± 1.4

morphine or NaCl administration. The order ofapomorphine or NaCl administration did notinfluence the number of yawns. When compar-ing apomorphine-induced yawning betweengroups. Group 1 showed a greater number ofyawns (p<0.05) than Group 2. No statisticaldifferences were observed when comparingNaCl-induced yawning between the two groups.Results are shown as the mean and standarddeviation of the number of yawns per group togive an indication of variability (Table 1).

DiscussionOur results show that opiate addicts present agreater number of yawns (p<0.05) than a simi-lar group of non-addict healthy volunteers as aresult of the subcutaneous administration of0.005 mg/Kg s.c. of apomorphine. Apomor-phine-induced yawing is centrally mediated bythe action of apomorphine on the postsynapticD2 dopamine receptors (Stahle & Ungerstedt,1989; Dourisch & Cooper, 1990), with thestimulation of Dl receptors by apomorphineplaying a permissive-facilitating role (Longoni,Spina & Dichiara, 1987). As the apomorphinetest has recently been described as an easy, ethi-cal in vivo procedure to measure the dopaminesystem sensitivity in healthy volunteers (Blin etal., 1988; 1990) and Parkinson's patients(Gasser et al., 1992), our data suggest thatheroin addicts show an enhancement of the sen-sitivity of central dopamine systems, probably asa result of the development of a hypersensitivityof postsynaptic dopamine receptors afrer chronicopiate use.

Several reports on the neurochemical mechan-ism of drug addiction have pointed out that mostpsychoactive substances with high potentialabuse liability such as opiates, ethanol, cocaine,amphetamine and nicotine show a common ef-fect on the CNS dopamine systems. In labora-tory animals the acute administration of such

substances produces an increase in dopaminetransmission which has been related to the rein-forcing properties of such substances and withthe appearance of compulsive drug-taking behav-iour (Spanagel, Herz & Shippenberg, 1991;Brodie & Dunwiddie, 1992; Elverfors & Niss-brandt, 1992; Harsing et al., 1992; Yoshimoto etal., 1992). Conversely, in chronic use, a decreasein dopamine function has been observed (Ac-quas et al., 1991; Ackerman & White, 1992;Rossetti et al., 1992; Pitts et al., 1993), vidth thedevelopment of hypersensitivity of dopamine re-ceptors in the mesothelencephalic dopaminepathways (Parenti et al., 1982; Ujike et al., 1991;Rommelspacher et al., 1992; Alburges et al.,1993), possibly due to molecular mechanismsinvolving post-receptor intracellular messengers,such as G-proteins and the cyclic AMP system(Nestler, 1993).

In laboratory animals the hypersensitivity ofthe mesolimbic and mesostriatal dopamine re-ceptors facilitates the Pavlovian conditioningprocess of neutral environmental stimuli presentwhen such systems are drug-stimulated (Casas etal., 1989; Silverman, 1990). Such conditioningresults in undrugged responses similar to thoseelicited by the drug itself when animals are laterre-exposed to the conditioned environmentalcues (Schiff, 1982; Dietze & Kuschinsky, 1994).

In humans it is known that environmentalcues associated with drug withdrawal or drug-taking could become conditioned stimuli able totrigger conditioned withdrawal symptomatology,craving and drug-seeking behaviour when an ab-stinent patient is re-exposed to such dmg-relatedstimuli (Childress et al., 1992). Recently, hyper-sensitivity of the dopamine system has been pro-posed as a neural basis for conditionedwithdrawal syndrome and craving (Robinson &Berridge, 1993; Satel et al., 1993). This suggests,perhaps, that patients with a high drug-inducedhypersensitivity of the dopamine system may bemore easily condition drug-related environmen-

834 Miguel Casas et al.

tal cues, and consequently may be greatly at riskto relapse when re-exposed to these conditionedcues. If this were so, the apomorphine test couldbe a useful procedure to evaluate the level ofsensitivity of dopamine systems in opiate depen-dence, and might therefore be a simple in vivobiological marker for risk to relapse.

Before the apomorphine test can be intro-duced into the clinical routine many furtherstudies must be carried out, both in a greaternumber of subjects and in other substance usedisorders. Nevertheless, the increasing impli-cation of the sensitivity of dopaminergic systemin addictive behaviours, as proposed by bothclinical and neuroscience researchers (Nestler,1993; Robinson & Berridge, 1993; Satel et al.,1993) suggest that a simple test should be foundto measure the sensitivity of this neurotransmit-ter system in addict patients.

AcknowledgementsWe would like to thank A, J, Puech, Professor ofPharmacology, Departement de PharmacologieClinique, Hopital de la Pitie-Salpetriere, Paris,for introducing us in the methodology of theapomorphine test. We also thank A, Rubio andS. Lopez for their excellent technical assistanceand M. Lahoz for typing this manuscript. Worksupported by grants firom CITRAN (1990/1,1991/1, 1992/1) and FISS 90/0872.

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