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Could the inter-individual variability in cocaine-induced psychotic effects influence the development of cocaine addiction?
Medical Hypotheses 75 (2010) 600–604
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Could the inter-individual variability in cocaine-induced psychotic effects influence the development of cocaine addiction? Towards a new pharmacogenetic approach to addictions G. Brousse a,b,c,⇑, F. Vorspan a, K. Ksouda a, V. Bloch a, K. Peoc’h a, J.L. Laplanche a, S. Mouly a, J. Schmidt b, P.M. Llorca c, J.P. Lepine a a
Inserm U705, UMR CNRS 8206, Neuropsychopharmacologie des Addictions, Université Paris Diderot, Hôpital Fernand Widal Assistance Publique des Hôpitaux de Paris, 200, Rue du Fg Saint-Denis, 75 475 Paris Cedex 10, France b Université Clermont 1, Faculté de Médecine, CHU Clermont Ferrand, Service Accueil Urgences, Rue Montalembert 63003 Clermont-Ferrand Cedex 01, France c Université Clermont 1, Faculté de Médecine, CHU Clermont Ferrand, Service Psychiatrie de l’adulte CMP B Rue Montalembert 63003 Clermont-Ferrand Cedex 01, France
a r t i c l e
i n f o
Article history: Received 26 May 2010 Accepted 27 July 2010
s u m m a r y Cocaine addiction is a chronic disease marked by relapses, co-morbidities and the importance of psychosocial consequences. The etiology of cocaine addiction is complex and involves three types of factors: environmental factors, factors linked to the specific effects of cocaine and genetic factors. The latter could explain 40–60% of the risk for developing an addiction. Several studies have looked for a link between cocaine addiction and the genes of the dopaminergic system: the genes DRD2, COMT, SLC6A3 (coding for the dopamine transporter DAT) and DBH (coding for the dopamine beta hydroxylase) but unfortunately very few well established results. Pharmacogenetic approach could be an interesting opportunity for the future. The gene DBH has particularly been linked with the psychotic effects caused by cocaine. This so-called cocaine-induced psychosis (CIP) or cocaine-induced paranoia may influence the development of cocaine addiction. Indeed, these psychotic symptoms during cocaine exposure could cause an aversive effect limiting the development of an addiction. Several functional alterations caused by different mutations of the genes involved in dopaminergic transmission (principally-1021C > T of the gene DBH, but also Val158Met of the gene COMT, TaqI A of the gene DRD2 and VNTR 9 repeat of the DAT) could result in a cocaineinduced psychosis prone phenotype. We are hypothesising that the appearance of CIP during the first contact with cocaine is associated with a lower risk of developing cocaine addiction. This protective effect could be associated with the presence of one or more polymorphisms associated with CIP. A pharmacogenetic approach studying combination of polymorphism could isolate a sub-group of patients at risk for CIPs but more favorably protected from developing an addiction. This theory could enable a better understanding of the protective factors against cocaine addiction and offer new therapeutic or preventive targets in vulnerable sub-groups exposed to cocaine. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction Cocaine addiction is a chronic disease, marked by relapses, frequent co-morbidities and heavy psychosocial consequences. The National Survey on Drug Use and Health found, in 2002, 19.5 million illegal drugs users in the American population [1]. Cocaine is the second most consumed illegal substance in the United States and Europe after cannabis. It is very often consumed in combination ⇑ Corresponding author at: Inserm U705, UMR CNRS 8206, Neuropsychopharmacologie des Addictions, Hôpital Fernand Widal, 200, Rue du Fg Saint-Denis, 75 475 Paris Cedex 10, France. Tel.: +33 01 40 05 48 81; fax: +33 01 40 05 43 42. E-mail address: [email protected] (G. Brousse). 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.07.043
with other psychoactive substances (i.e. alcohol and heroin). Among North-Americans, 2.5 million are regular cocaine users [2] 1.5 millions of which are dependent [1]. In 2007, 4.5 million Europeans were identified as users [3]. In France, in 2005, a general population study numbered 1.1 million users and 250,000 regular users [4,5]. One of the major issues raised by addictions is to understand why only a moderate percentage of exposed individuals will become dependent. This is especially interesting in conditions of repeated exposure, knowing the addictive properties of cocaine, and knowing the addictive proneness of subjects that are exposed to cocaine, some of them being already dependent on other drugs [6,7]. The vulnerability factors (extrinsic and intrinsic) associated with the development of a cocaine addiction are still
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not well understood, neither the protective factors that may protect against it. We generally acknowledge that three types of factors are involved in the development of an addiction: environmental factors, factors linked to the pharmacological effects of the substance (e.g. neurochemical effects at the neuronal level) and genetic factors. Individual vulnerability factors, may concern all type of addictions of be specific to one substance [7]. Individual vulnerability is composed of genetic and environmental factors and their interaction [8]. If social factors contribute to or protect against the development of addictions, it is clear that genetic factors are also widely involved [9]. They may, according to the studies, explain 40–60% of vulnerability to drugs [10–12]. In fact, addictions, like others human disorders that display both genetic and environmental contribution, are complex polygenic disorders which involved allelic variation in a number of a genes. In cocaine dependence, the genetic vulnerability has been estimated from around 65–78%. The physiopathological basis underpinning this hereditary factor and the totality of implied genes [13] are yet to be described. The human genome has about 40,000 genes [14]. Genetic studies classically consist in linkage-based approaches or genetic association studies. Linkage-based approaches examine the way in which disease vulnerability and genomic markers (loci on chromosome) move together through families. They have been particularly used in studies focusing on alcohol and tobacco and have product modest results [12]. Association studies do not require family member participation. They allow the identification of smaller chromosomal regions than linkage-based approaches, examining the way in which disease vulnerability and genomic markers move together through population samples. This approach is focused particularly on single nucleotide polymorphisms (SNPs) which reflect human genes inter-individual variability (around 0.1%). They have been used to describe inter-individual differences in the development of a broad spectrum of addictions [15]. Several genes coding for peptidergic (GABA, glutamate) and monoaminergic systems have been looked at [7]. For cocaine dependence, knowing that cocaine effects consists essentially of blocking the reuptake of dopamine by the DAT (membrane transporter) [17], the genes coding for the proteins involved in dopaminergic transmission [16] (pharmacodynamics, transduction of the signal, dopaminergic metabolism) could be particularly implicated. The genes which have been mostly studied in this domain are the gene (DRD2) coding for the D2 dopaminergic receptor [18–22], the gene (SLC6A3) coding for the dopamine transporter (DAT) [23–32], the gene (COMT) coding for the Cathecol-O-methyltransferase (COMT)
[33–35] and the gene (DBH) coding for dopamine beta hydroxylase (dopamine metabolization enzyme) Table 1 [16]. Despite a great number of genetic association studies in the last decade, few results have emerged in the field of addiction [36]. This could be explained particularly by the high number of candidates genes tested in studies with non rigorous approaches and statistical analyses. Gene-environment interaction studies especially lead to test multiple candidate genes for most behavioral phenotype without a priori knowledge of functionally consequences of their polymorphisms. Another frequent limitation of genetic studies in the field of addiction is that they are control case study where the control subjects are generally not exposed [37]. Doing so, they mix the risks for drug initiation and for drug dependence. An original approach could consist in genetic comparison between dependent subjects and exposed subjects who did not develop the addiction despite repeated exposure. This last approach is pharmacogenetic, i.e. modeled on the study of the variation of the interindividual reaction of organisms to xenobiotics [38]. It may consist of studying the response (acute or chronic) to exposure to the drug and its involvement in the development of addiction. The phenotype of interest could be a specific ‘‘response” when the substance is consumed in subjects bearing a specific SNP. This response could determine the development of the addiction (individual product interaction). For example the ‘‘aversive” phenotype is interesting to study as it may determine the development of the addiction [39] and it is in certain cases the operational expression of a genic alteration. This is the case for alcohol consumption and the gene coding for aldehyde dehydrogenase [9]. This could also be the case for the occurrence of psychotic symptoms under cocaine (or cocaine-induced psychosis or CIP), which are known to display a between-subject variability, and which may have an aversive effect limiting the development of cocaine addiction [40]. The aim of this article is to propose an original pharmacogenetic approach for studying the implication of genes of dopaminergic system in the development of cocaine addiction by focusing on a phenotype of interest (cocaine-induced psychosis) reflecting a functional mutation (DDH) and contributing to a protection (or a vulnerability) to addiction.
Study of a phenotype of interest: cocaine-induced psychosis (CIP) The appearance of psychotic and in particular paranoid symptoms (or cocaine-induced psychosis: CIP, or cocaine-induced
Table 1 Polymorphisms that alter neurochemical responses to psychostimulants (According to Haile et al. 2007). Gene
Polymorphism (s)
Biochemical effect
Clinical finding
References
Dopamine B hydroxylase (DBH)
DBH*50 -ins/del
Associated with levels of
Cocaine-induced paranoia
Cubells et al. [47]
DBH*444 g/a 1021C ? T
DßH in CSF Low plasma DßH activity
N/A Cocaine-induced paranoia
Dopamine transporter (DAT) SLC6A3
+1603C ? T
Low plasma DßH activity
N/A
Cubells et al. [57] Zabetian et al. [58] Kalayasiri et al. [48] Tang et al. [60]
G2319A VNTR 9 and 10 repeat
Influences DAT gene expression in vitro
Cocaine-induced paranoia (9/9, 9/10 repeat)
Gelernter et al. [28]
Increased binding of SPECT DAT radioligand in healthy subjects (9/9, 9/10 repeat)
Jacobsen et al. [31]
Decreased therapeutic and subjective response to methylphenidate and amphetamine (9/9)
Van Dyck et al. [23] Lott et al. [24] Stein et al. [25]
D2 Dopamine receptor (DRD2)
TaqIA, TaqIB
Deficient receptor binding in vitro
957T
Decreased translation efficiency
Associated with polysubstance abuse and cocaine dependence
O’Hara et al. [20] Persico et al. [21] Duan et al. [22]
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paranoia) when taking cocaïne is a common phenomenon although not systematic, generally resolved by abstinence. Its most frequent phenomenology is a delirious and hallucinatory context [41], with irrational fears about the fact that somebody or something may threaten or harm the patient despite the fact that no real danger exists [40]. These manifestations have clinical implications involving visits to emergency departments and sometimes violent psychobehavioural symptoms [42]. Fifty to Eighty percent of cocaine users experiment these symptoms [43,44]. The appearance of CIP is not linked to the plasma levels of cocaine [45], but dependent upon the dose taken [40]. The associated risk factors are an early age of onset of cocaine use [42], being a male and age [46]. Route of administration especially smoking cocaine is also a risk factor [40].
Polymorphisms of interest in CIP The existence of a genetic vulnerability in the development of CIPs has been documented [47,48]. Cubells et al. were the first to report, in a retrospective work, on American Caucasian patients who were cocaine abusers, a connection between haplotype Dela (polymorphisms DBH*5-ins/del and DBH*G444A), a reduced activity of DßH and the appearance of psychotic symptoms under cocaine [47]. The enzyme DßH (Dopamine beta Hydroxylase) transforms dopamine into noradrenalin [49]. It is stored in the synaptic vesicles and is released with the catecholamine. The involvement of the variation of plasma levels of DßH in the occurrence of mental illnesses has been the subject of several investigations in particular on mood disorders, with conflicting results [50–53]. A reduction in activity of the DßH has been demonstrated in certain antisocial, hostile and impulsive behaviors which are frequently associated with substance abuse [54,55]. Familial studies on twins have shown that the levels of DßH were under the marked influence of a hereditary factor [56]. Several polymorphisms located at the level of the gene (DBH) coding for DßH or indeed near to it have been identified and associated with differences in circulating levels of DßH [57]. So the polymorphisms DBH*5-ins/del [47], DBH*G444A [57], C-1021T [58,59] and +1603C > T [60] appear linked with variations in the plasma levels of DßH. Therefore, variations in the level of the enzyme DßH, linked with different genotypes of DBH, were clearly linked with the appearance of psychotic symptoms under cocaine (Cocaine-induced psychosis). This link between the reduction of activity of the DßH and the CIPs was particularly found in the presence of polymorphism C-1021T [48]. Thus, in a prospective study Kalayasiri and Coll. assessed pharmacogenetic interaction between cocaine and this polymorphism in 31 cocaine users during three cocaine self-administration sessions (8, 16 and 32 mg/70 kg) [48,61]. The patients who were homozygote for allele T showed greater sensitivity to the induction of psychotic disorders under cocaine compared with patients CT and CC. The polymorphism C-1021T (1021C > T) is a SNP (in 50 of the gene in the promoter region) located around 1 KB before the codon of initiation of the gene DBH [59]. This polymorphism is involved in the alteration of the transcription of DBH (reduction of the transcription) and functionally leads to modifications of the plasma levels of DßH [47,57–59,62]. The individuals who are homozygotes for allele T present a very low activity of DßH [58,62,63]. This reduction of activity associated with polymorphism C-1021T is found in different populations (North American Caucasians, Afro-Americans, Indians, Japanese) and had been associated to nearly 52% of the variability of the levels of DßH [37,58,62]. As regards the study of polymorphisms C-1021T, Hess et al. [64] demonstrated a link between this polymorphism and ‘‘impulsive” and ‘‘novelty-seeking” personality traits which are frequently found in cocaine abusers or dependent.
As regards the other genes of the dopaminergic system studied in the field of addictions, other studies have reported a link between the presence of psychotic symptoms during cocaine abuse and the presence of a polymorphism of the gene SLC6A3 coding for the DAT (G2319A VNTR 9/9 and 9/10 repeat) [28]. As regards the D2 dopamine receptor in a recent publication Ujike et al. showed that the genotype A1/A1 of the gene DRD2 could constitute a protection as regards the psychotic symptoms induced by psychostimulants [65]. As regards COMT, several studies have suggested that the allele Val 158 is involved in certain mental illnesses such as schizophrenia or psychotic disorders in Alzheimer’s disease [66,67]. To our knowledge no study has looked for an association between this polymorphism and the appearance of psychotic symptoms under cocaine. Combination of polymorphisms So it could be relevant to study the phenotype CIP by focusing on a combination of a restricted number of polymorphisms of interest regarding the genes involved in dopaminergic transmission such as DBH, SLC6A3 (DAT), DRD2, COMT, some of which have also been linked to the appearance of CIP. This approach by combination of polymorphism was used in the pharmacogenetic study of the response to atypical neuroleptic treatment in schizophrenia [68]. Genes coding for proteins involved in the dopaminergic route relies on the one hand on the involvement of this route both in the physiopathology of dependence [7] and in the physiopathology of psychotic symptoms in other mental disorders [69,70]. We still do not know if the vulnerability to trigger psychotic symptoms plays a role such as an aversive protective factor against cocaine dependence in cocaine users. We can suggest such a hypothesis by relying on the neurobiological data from animals studies [71] but also on clinical findings in man [39]. The absence of DßH activity in Knockout Mice animal models results in hypersensitivity to the reward of low dose cocaine and the appearance of aversive effects at higher doses [71]. In man, the occurrence of CIPs can have interesting therapeutic consequences. Several authors have reported that cocaine-induced psychotic symptoms promote more rapid access to the care system and additional motivation to stop taking cocaine [43,72]. This aversive property of the CIPs is used during treatment with disulfiram [73]. Treatments with disulfiram cause aversive effects in cocaine-addict patients. These effects which they describe as ‘‘paranoiac” are accompanied by a reduction in cocaine-taking [74,75]. The data from clinical studies indicate that disulfiram, whose mode of action relies in particular on inhibition of activity of the DßH, results in reduced cocaine consumption by increasing the phenomena of CIP [73]. Polymorphism 1021C > T is involved in the response to treatment of cocaine addiction with Disulfiram which would be more effective in carriers of the mutated form of polymorphism 1021C > T, linked with reduced activity of the DßH. Hypothesis It could be assumed that the appearance of an aversive psychotic effect during the first intakes of cocaine, limits the development of the addiction to this substance. Subjects bearing a combination of polymorphisms of genes involved in dopaminergic transmission may be more prone to this aversive effect. In other words we could speculate that the dependent patients are less often presenting with CIP during their first contact with cocaine. However the involvement of the aversive effect in the development of an addiction is still under discussion. First and foremost this would be more favorably the positive hedonic factors linked to the first experience which would determine the appearance of
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the addiction rather than the aversive symptoms as for cannabis [76]. In addition, one of the rare studies which looked to demonstrate a link between the first negative experience under cocaine and development of an addiction found a positive relationship between the fact of having experienced unpleasant sensations during first taking cocaine and later development of an addiction [77]! This study was conducted on Vietnam veterans and may be hard to generalize. So it seems that the appearance of CIPs are equally subject to environmental vulnerability strongly determining development of the addiction despite the product’s aversive effects [41,43], which could be the case in situations of major stress such as that of war veterans. Study proposal and anticipated results A work aiming to confirm this hypothesis should demonstrate a greater early vulnerability to CIPs in patients exposed to cocaine and not dependent compared with patients exposed who have become addicted. It should also demonstrate a relationship between the occurrence of CIPs and a greater frequency of a combination of polymorphisms in particular allele T of the polymorphism 1021C > T of the gene DBH but also polymorphisms Val158Met of the gene COMT, TaqI A of the gene DRD2 and VNTR 9 repeat of the DAT this in patients not dependent on cocaine compared with dependent subjects. In a group of patients exposed during their lives to cocaine we will search for the existence of the occurrence of CIP during periods of consumptions. The type of misuse of the product will be documented using MINI (at risk use, abuse, dependence) [78]. The other addictions will be assessed (MINI) and documented as well as psychiatric disorders of axis I (DSM IV) [79]. The validation of this hypothesis, in lifetime cocaine exposed subjects, could enable better understanding of the protective factors to cocaine addiction, and thus the definition of new preventive or therapeutic targets in vulnerable sub-groups. The challenge of such research is also to approach the genetics of addictions in accordance with the product/gene/environment interaction model i.e. from the group exposed to a specific product to initiation and further to dependence. Moreover this pharmacogenetic original approach responds to recent recommendations focusing on criteria which must be respected for genetic studies. First candidates genes should be selected on the basis of known neurobiology, secondly polymorphisms should be selected only if they have known functional consequences, thirdly the total number of genes and polymorphism and the total number of phenotypes investigated should be reported [36]. This heuristic approach considers the risk of development of the illness in an interactional perspective, by studying the body’s response (physical and psychological) to the product, which determines in part the development of the addiction, and no longer the genetic terrain alone. This approach requires the definition and/or demonstration, by way of therapeutic or animal models for example, of phenotypes of interest reflecting an interaction between the product and the person. These interactions could result in positive reinforcements (hedonic effects) and/or negative reinforcement (relief of tension) which, as we know, encourage the development of an addiction.
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[23]
[24]
[25]
[26]
[27] [28]
Conflicts of Interest Statement
[29]
None declared. [30]
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Could the inter-individual variability in cocaine-induced psychotic effects influence the development of cocaine addiction? Towards a new pharmacogenetic approach to addictions G. Brousse a,b,c,⇑, F. Vorspan a, K. Ksouda a, V. Bloch a, K. Peoc’h a, J.L. Laplanche a, S. Mouly a, J. Schmidt b, P.M. Llorca c, J.P. Lepine a a
Inserm U705, UMR CNRS 8206, Neuropsychopharmacologie des Addictions, Université Paris Diderot, Hôpital Fernand Widal Assistance Publique des Hôpitaux de Paris, 200, Rue du Fg Saint-Denis, 75 475 Paris Cedex 10, France b Université Clermont 1, Faculté de Médecine, CHU Clermont Ferrand, Service Accueil Urgences, Rue Montalembert 63003 Clermont-Ferrand Cedex 01, France c Université Clermont 1, Faculté de Médecine, CHU Clermont Ferrand, Service Psychiatrie de l’adulte CMP B Rue Montalembert 63003 Clermont-Ferrand Cedex 01, France
a r t i c l e
i n f o
Article history: Received 26 May 2010 Accepted 27 July 2010
s u m m a r y Cocaine addiction is a chronic disease marked by relapses, co-morbidities and the importance of psychosocial consequences. The etiology of cocaine addiction is complex and involves three types of factors: environmental factors, factors linked to the specific effects of cocaine and genetic factors. The latter could explain 40–60% of the risk for developing an addiction. Several studies have looked for a link between cocaine addiction and the genes of the dopaminergic system: the genes DRD2, COMT, SLC6A3 (coding for the dopamine transporter DAT) and DBH (coding for the dopamine beta hydroxylase) but unfortunately very few well established results. Pharmacogenetic approach could be an interesting opportunity for the future. The gene DBH has particularly been linked with the psychotic effects caused by cocaine. This so-called cocaine-induced psychosis (CIP) or cocaine-induced paranoia may influence the development of cocaine addiction. Indeed, these psychotic symptoms during cocaine exposure could cause an aversive effect limiting the development of an addiction. Several functional alterations caused by different mutations of the genes involved in dopaminergic transmission (principally-1021C > T of the gene DBH, but also Val158Met of the gene COMT, TaqI A of the gene DRD2 and VNTR 9 repeat of the DAT) could result in a cocaineinduced psychosis prone phenotype. We are hypothesising that the appearance of CIP during the first contact with cocaine is associated with a lower risk of developing cocaine addiction. This protective effect could be associated with the presence of one or more polymorphisms associated with CIP. A pharmacogenetic approach studying combination of polymorphism could isolate a sub-group of patients at risk for CIPs but more favorably protected from developing an addiction. This theory could enable a better understanding of the protective factors against cocaine addiction and offer new therapeutic or preventive targets in vulnerable sub-groups exposed to cocaine. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction Cocaine addiction is a chronic disease, marked by relapses, frequent co-morbidities and heavy psychosocial consequences. The National Survey on Drug Use and Health found, in 2002, 19.5 million illegal drugs users in the American population [1]. Cocaine is the second most consumed illegal substance in the United States and Europe after cannabis. It is very often consumed in combination ⇑ Corresponding author at: Inserm U705, UMR CNRS 8206, Neuropsychopharmacologie des Addictions, Hôpital Fernand Widal, 200, Rue du Fg Saint-Denis, 75 475 Paris Cedex 10, France. Tel.: +33 01 40 05 48 81; fax: +33 01 40 05 43 42. E-mail address: [email protected] (G. Brousse). 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.07.043
with other psychoactive substances (i.e. alcohol and heroin). Among North-Americans, 2.5 million are regular cocaine users [2] 1.5 millions of which are dependent [1]. In 2007, 4.5 million Europeans were identified as users [3]. In France, in 2005, a general population study numbered 1.1 million users and 250,000 regular users [4,5]. One of the major issues raised by addictions is to understand why only a moderate percentage of exposed individuals will become dependent. This is especially interesting in conditions of repeated exposure, knowing the addictive properties of cocaine, and knowing the addictive proneness of subjects that are exposed to cocaine, some of them being already dependent on other drugs [6,7]. The vulnerability factors (extrinsic and intrinsic) associated with the development of a cocaine addiction are still
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not well understood, neither the protective factors that may protect against it. We generally acknowledge that three types of factors are involved in the development of an addiction: environmental factors, factors linked to the pharmacological effects of the substance (e.g. neurochemical effects at the neuronal level) and genetic factors. Individual vulnerability factors, may concern all type of addictions of be specific to one substance [7]. Individual vulnerability is composed of genetic and environmental factors and their interaction [8]. If social factors contribute to or protect against the development of addictions, it is clear that genetic factors are also widely involved [9]. They may, according to the studies, explain 40–60% of vulnerability to drugs [10–12]. In fact, addictions, like others human disorders that display both genetic and environmental contribution, are complex polygenic disorders which involved allelic variation in a number of a genes. In cocaine dependence, the genetic vulnerability has been estimated from around 65–78%. The physiopathological basis underpinning this hereditary factor and the totality of implied genes [13] are yet to be described. The human genome has about 40,000 genes [14]. Genetic studies classically consist in linkage-based approaches or genetic association studies. Linkage-based approaches examine the way in which disease vulnerability and genomic markers (loci on chromosome) move together through families. They have been particularly used in studies focusing on alcohol and tobacco and have product modest results [12]. Association studies do not require family member participation. They allow the identification of smaller chromosomal regions than linkage-based approaches, examining the way in which disease vulnerability and genomic markers move together through population samples. This approach is focused particularly on single nucleotide polymorphisms (SNPs) which reflect human genes inter-individual variability (around 0.1%). They have been used to describe inter-individual differences in the development of a broad spectrum of addictions [15]. Several genes coding for peptidergic (GABA, glutamate) and monoaminergic systems have been looked at [7]. For cocaine dependence, knowing that cocaine effects consists essentially of blocking the reuptake of dopamine by the DAT (membrane transporter) [17], the genes coding for the proteins involved in dopaminergic transmission [16] (pharmacodynamics, transduction of the signal, dopaminergic metabolism) could be particularly implicated. The genes which have been mostly studied in this domain are the gene (DRD2) coding for the D2 dopaminergic receptor [18–22], the gene (SLC6A3) coding for the dopamine transporter (DAT) [23–32], the gene (COMT) coding for the Cathecol-O-methyltransferase (COMT)
[33–35] and the gene (DBH) coding for dopamine beta hydroxylase (dopamine metabolization enzyme) Table 1 [16]. Despite a great number of genetic association studies in the last decade, few results have emerged in the field of addiction [36]. This could be explained particularly by the high number of candidates genes tested in studies with non rigorous approaches and statistical analyses. Gene-environment interaction studies especially lead to test multiple candidate genes for most behavioral phenotype without a priori knowledge of functionally consequences of their polymorphisms. Another frequent limitation of genetic studies in the field of addiction is that they are control case study where the control subjects are generally not exposed [37]. Doing so, they mix the risks for drug initiation and for drug dependence. An original approach could consist in genetic comparison between dependent subjects and exposed subjects who did not develop the addiction despite repeated exposure. This last approach is pharmacogenetic, i.e. modeled on the study of the variation of the interindividual reaction of organisms to xenobiotics [38]. It may consist of studying the response (acute or chronic) to exposure to the drug and its involvement in the development of addiction. The phenotype of interest could be a specific ‘‘response” when the substance is consumed in subjects bearing a specific SNP. This response could determine the development of the addiction (individual product interaction). For example the ‘‘aversive” phenotype is interesting to study as it may determine the development of the addiction [39] and it is in certain cases the operational expression of a genic alteration. This is the case for alcohol consumption and the gene coding for aldehyde dehydrogenase [9]. This could also be the case for the occurrence of psychotic symptoms under cocaine (or cocaine-induced psychosis or CIP), which are known to display a between-subject variability, and which may have an aversive effect limiting the development of cocaine addiction [40]. The aim of this article is to propose an original pharmacogenetic approach for studying the implication of genes of dopaminergic system in the development of cocaine addiction by focusing on a phenotype of interest (cocaine-induced psychosis) reflecting a functional mutation (DDH) and contributing to a protection (or a vulnerability) to addiction.
Study of a phenotype of interest: cocaine-induced psychosis (CIP) The appearance of psychotic and in particular paranoid symptoms (or cocaine-induced psychosis: CIP, or cocaine-induced
Table 1 Polymorphisms that alter neurochemical responses to psychostimulants (According to Haile et al. 2007). Gene
Polymorphism (s)
Biochemical effect
Clinical finding
References
Dopamine B hydroxylase (DBH)
DBH*50 -ins/del
Associated with levels of
Cocaine-induced paranoia
Cubells et al. [47]
DBH*444 g/a 1021C ? T
DßH in CSF Low plasma DßH activity
N/A Cocaine-induced paranoia
Dopamine transporter (DAT) SLC6A3
+1603C ? T
Low plasma DßH activity
N/A
Cubells et al. [57] Zabetian et al. [58] Kalayasiri et al. [48] Tang et al. [60]
G2319A VNTR 9 and 10 repeat
Influences DAT gene expression in vitro
Cocaine-induced paranoia (9/9, 9/10 repeat)
Gelernter et al. [28]
Increased binding of SPECT DAT radioligand in healthy subjects (9/9, 9/10 repeat)
Jacobsen et al. [31]
Decreased therapeutic and subjective response to methylphenidate and amphetamine (9/9)
Van Dyck et al. [23] Lott et al. [24] Stein et al. [25]
D2 Dopamine receptor (DRD2)
TaqIA, TaqIB
Deficient receptor binding in vitro
957T
Decreased translation efficiency
Associated with polysubstance abuse and cocaine dependence
O’Hara et al. [20] Persico et al. [21] Duan et al. [22]
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paranoia) when taking cocaïne is a common phenomenon although not systematic, generally resolved by abstinence. Its most frequent phenomenology is a delirious and hallucinatory context [41], with irrational fears about the fact that somebody or something may threaten or harm the patient despite the fact that no real danger exists [40]. These manifestations have clinical implications involving visits to emergency departments and sometimes violent psychobehavioural symptoms [42]. Fifty to Eighty percent of cocaine users experiment these symptoms [43,44]. The appearance of CIP is not linked to the plasma levels of cocaine [45], but dependent upon the dose taken [40]. The associated risk factors are an early age of onset of cocaine use [42], being a male and age [46]. Route of administration especially smoking cocaine is also a risk factor [40].
Polymorphisms of interest in CIP The existence of a genetic vulnerability in the development of CIPs has been documented [47,48]. Cubells et al. were the first to report, in a retrospective work, on American Caucasian patients who were cocaine abusers, a connection between haplotype Dela (polymorphisms DBH*5-ins/del and DBH*G444A), a reduced activity of DßH and the appearance of psychotic symptoms under cocaine [47]. The enzyme DßH (Dopamine beta Hydroxylase) transforms dopamine into noradrenalin [49]. It is stored in the synaptic vesicles and is released with the catecholamine. The involvement of the variation of plasma levels of DßH in the occurrence of mental illnesses has been the subject of several investigations in particular on mood disorders, with conflicting results [50–53]. A reduction in activity of the DßH has been demonstrated in certain antisocial, hostile and impulsive behaviors which are frequently associated with substance abuse [54,55]. Familial studies on twins have shown that the levels of DßH were under the marked influence of a hereditary factor [56]. Several polymorphisms located at the level of the gene (DBH) coding for DßH or indeed near to it have been identified and associated with differences in circulating levels of DßH [57]. So the polymorphisms DBH*5-ins/del [47], DBH*G444A [57], C-1021T [58,59] and +1603C > T [60] appear linked with variations in the plasma levels of DßH. Therefore, variations in the level of the enzyme DßH, linked with different genotypes of DBH, were clearly linked with the appearance of psychotic symptoms under cocaine (Cocaine-induced psychosis). This link between the reduction of activity of the DßH and the CIPs was particularly found in the presence of polymorphism C-1021T [48]. Thus, in a prospective study Kalayasiri and Coll. assessed pharmacogenetic interaction between cocaine and this polymorphism in 31 cocaine users during three cocaine self-administration sessions (8, 16 and 32 mg/70 kg) [48,61]. The patients who were homozygote for allele T showed greater sensitivity to the induction of psychotic disorders under cocaine compared with patients CT and CC. The polymorphism C-1021T (1021C > T) is a SNP (in 50 of the gene in the promoter region) located around 1 KB before the codon of initiation of the gene DBH [59]. This polymorphism is involved in the alteration of the transcription of DBH (reduction of the transcription) and functionally leads to modifications of the plasma levels of DßH [47,57–59,62]. The individuals who are homozygotes for allele T present a very low activity of DßH [58,62,63]. This reduction of activity associated with polymorphism C-1021T is found in different populations (North American Caucasians, Afro-Americans, Indians, Japanese) and had been associated to nearly 52% of the variability of the levels of DßH [37,58,62]. As regards the study of polymorphisms C-1021T, Hess et al. [64] demonstrated a link between this polymorphism and ‘‘impulsive” and ‘‘novelty-seeking” personality traits which are frequently found in cocaine abusers or dependent.
As regards the other genes of the dopaminergic system studied in the field of addictions, other studies have reported a link between the presence of psychotic symptoms during cocaine abuse and the presence of a polymorphism of the gene SLC6A3 coding for the DAT (G2319A VNTR 9/9 and 9/10 repeat) [28]. As regards the D2 dopamine receptor in a recent publication Ujike et al. showed that the genotype A1/A1 of the gene DRD2 could constitute a protection as regards the psychotic symptoms induced by psychostimulants [65]. As regards COMT, several studies have suggested that the allele Val 158 is involved in certain mental illnesses such as schizophrenia or psychotic disorders in Alzheimer’s disease [66,67]. To our knowledge no study has looked for an association between this polymorphism and the appearance of psychotic symptoms under cocaine. Combination of polymorphisms So it could be relevant to study the phenotype CIP by focusing on a combination of a restricted number of polymorphisms of interest regarding the genes involved in dopaminergic transmission such as DBH, SLC6A3 (DAT), DRD2, COMT, some of which have also been linked to the appearance of CIP. This approach by combination of polymorphism was used in the pharmacogenetic study of the response to atypical neuroleptic treatment in schizophrenia [68]. Genes coding for proteins involved in the dopaminergic route relies on the one hand on the involvement of this route both in the physiopathology of dependence [7] and in the physiopathology of psychotic symptoms in other mental disorders [69,70]. We still do not know if the vulnerability to trigger psychotic symptoms plays a role such as an aversive protective factor against cocaine dependence in cocaine users. We can suggest such a hypothesis by relying on the neurobiological data from animals studies [71] but also on clinical findings in man [39]. The absence of DßH activity in Knockout Mice animal models results in hypersensitivity to the reward of low dose cocaine and the appearance of aversive effects at higher doses [71]. In man, the occurrence of CIPs can have interesting therapeutic consequences. Several authors have reported that cocaine-induced psychotic symptoms promote more rapid access to the care system and additional motivation to stop taking cocaine [43,72]. This aversive property of the CIPs is used during treatment with disulfiram [73]. Treatments with disulfiram cause aversive effects in cocaine-addict patients. These effects which they describe as ‘‘paranoiac” are accompanied by a reduction in cocaine-taking [74,75]. The data from clinical studies indicate that disulfiram, whose mode of action relies in particular on inhibition of activity of the DßH, results in reduced cocaine consumption by increasing the phenomena of CIP [73]. Polymorphism 1021C > T is involved in the response to treatment of cocaine addiction with Disulfiram which would be more effective in carriers of the mutated form of polymorphism 1021C > T, linked with reduced activity of the DßH. Hypothesis It could be assumed that the appearance of an aversive psychotic effect during the first intakes of cocaine, limits the development of the addiction to this substance. Subjects bearing a combination of polymorphisms of genes involved in dopaminergic transmission may be more prone to this aversive effect. In other words we could speculate that the dependent patients are less often presenting with CIP during their first contact with cocaine. However the involvement of the aversive effect in the development of an addiction is still under discussion. First and foremost this would be more favorably the positive hedonic factors linked to the first experience which would determine the appearance of
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the addiction rather than the aversive symptoms as for cannabis [76]. In addition, one of the rare studies which looked to demonstrate a link between the first negative experience under cocaine and development of an addiction found a positive relationship between the fact of having experienced unpleasant sensations during first taking cocaine and later development of an addiction [77]! This study was conducted on Vietnam veterans and may be hard to generalize. So it seems that the appearance of CIPs are equally subject to environmental vulnerability strongly determining development of the addiction despite the product’s aversive effects [41,43], which could be the case in situations of major stress such as that of war veterans. Study proposal and anticipated results A work aiming to confirm this hypothesis should demonstrate a greater early vulnerability to CIPs in patients exposed to cocaine and not dependent compared with patients exposed who have become addicted. It should also demonstrate a relationship between the occurrence of CIPs and a greater frequency of a combination of polymorphisms in particular allele T of the polymorphism 1021C > T of the gene DBH but also polymorphisms Val158Met of the gene COMT, TaqI A of the gene DRD2 and VNTR 9 repeat of the DAT this in patients not dependent on cocaine compared with dependent subjects. In a group of patients exposed during their lives to cocaine we will search for the existence of the occurrence of CIP during periods of consumptions. The type of misuse of the product will be documented using MINI (at risk use, abuse, dependence) [78]. The other addictions will be assessed (MINI) and documented as well as psychiatric disorders of axis I (DSM IV) [79]. The validation of this hypothesis, in lifetime cocaine exposed subjects, could enable better understanding of the protective factors to cocaine addiction, and thus the definition of new preventive or therapeutic targets in vulnerable sub-groups. The challenge of such research is also to approach the genetics of addictions in accordance with the product/gene/environment interaction model i.e. from the group exposed to a specific product to initiation and further to dependence. Moreover this pharmacogenetic original approach responds to recent recommendations focusing on criteria which must be respected for genetic studies. First candidates genes should be selected on the basis of known neurobiology, secondly polymorphisms should be selected only if they have known functional consequences, thirdly the total number of genes and polymorphism and the total number of phenotypes investigated should be reported [36]. This heuristic approach considers the risk of development of the illness in an interactional perspective, by studying the body’s response (physical and psychological) to the product, which determines in part the development of the addiction, and no longer the genetic terrain alone. This approach requires the definition and/or demonstration, by way of therapeutic or animal models for example, of phenotypes of interest reflecting an interaction between the product and the person. These interactions could result in positive reinforcements (hedonic effects) and/or negative reinforcement (relief of tension) which, as we know, encourage the development of an addiction.
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Conflicts of Interest Statement
[29]
None declared. [30]
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