biological components of substance abuse and addiction (part 6 of 8)

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Genetics 4

w hy does one person become dependent on drugs whileanother, exposed to the same environment andexperiences, does not? As progress in understandingthe role of genetics in various conditions and diseases

increases, there has been a realization that there is likely to be agenetic component to substance abuse and addiction. That is,inherited differences among individuals affect their response todrugs. To date, much of the work done in this field is related toalcoholism, less is known about the genetics of other drugs ofabuse.

Studies in both humans and animals contribute to theunderstanding of genetic factors in substance abuse and depend-ence. Human studies shed light on the question of whether drugdependency is transmitted between generations. In addition, thestudy of individuals with substance abuse problems as well asanimal studies provide information about what is actuallyinherited. For example, are there genetic differences in sensitiv-ity and responsiveness to drugs? And, if yes, are the differencesdrug-specific, or are they related to general mechanisms associ-ated with the actions of all abused drugs? Finally, the tools ofmodern molecular biology can be used to identify the specificgenes that control various cellular and biochemical functionspossibly involved in an inherited component of substance abuseand addiction.

While the existence of inherited differences seems likely, agenetic component alone probably is insufficient to precipitatesubstance abuse and addiction. Unlike disorders such as Hunt-ington’s disease and cystic fibrosis, which result from thepresence of alterations in a single gene, substance abuse is likely

39

40 | Biological Components of Substance Abuse and Addiction

to involve multiple genes that control variousaspects of the biological response to drugs. Inaddition, the complex nature of drug dependency,involving many behavioral and environmentalfactors, indicates that any genetic component actsin consort with other nongenetic risk factors tocontribute to the development of substance abuseand addiction. Thus, neither the presence norabsence of a genetic factor ensures developmentof, or protection from, drug addiction.

DO INHERITED FACTORS EXIST?A number of confounding factors complicates

the study of genetic transmission of substanceabuse liability in humans. One is the highincidence of psychiatric conditions among sub-stance abusers (104), which raises questionsabout the role of psychiatric comorbidity inliability to illicit drug addiction. In particular,antisocial personality disorder (ASPD) is oftenassociated with substance abuse. One studyshows that 84 percent of individuals with ASPDalso have some form of substance abuse duringtheir lifetimes (104). Other psychiatric conditionsthat may be associated with substance abuse aredepression, anxiety disorders, manic-depression,and schizophrenia.

Another issue related to studies of the geneticsof liability to abuse of specific drugs is that manydrug abusers engage in multiple drug use, so exam-ining any familial trends in the use of a particulardrug becomes difficult. Finally, rates of illicitdrug use show strong secular trends. Even assum-ing a vulnerability to drug-specific addictions,there might be tremendous variations in expres-sion of addiction, simply because of differencesin drug availability over time: No matter how vul-nerable an individual might be, addiction requiresexposure. Such issues often hamper studies on thegenetic transmission of drug liability.

I Family Studies

ALCOHOLISMReferences to a familial tendency or hereditary

‘‘taint’ of alcoholism date back to classical times(44); an observation repeatedly confirmed byfamily studies. While not all cases axe familial,the risk of alcoholism consistently has been foundto be higher among frost-degree relatives (i.e.,parents, siblings, children) of alcoholics as com-pared to the general population (79). Moreover,while family studies can establish that a disorder(or liability to a disorder) is transmitted; ingeneral, they are unable to distinguish betweenbiological and cultural transmission (though thisissue can be evaluated in large family studies byanalyzing multiple classes of relatives with differ-ing degrees of genetic relatedness).

Results of numerous family studies indicatethat alcoholism segregates within families, withmale first-degree relatives of alcoholics having ahigher incidence (ranging from 27 to 54 percent)than female first-degree relatives (6 to 17 percent)as compared to first-degree relatives of nonalco-holics (20 percent of males, 4 percent of females)(49,103,133). In fitting models of inheritance tofamily data, researchers concluded that observedpatterns of inheritance were consistent with thehypothesis that familial factors predisposing toalcoholism were the same in men and women, butthat nonfamilial environmental factors exertedmore influence in the development of alcoholismin women (20). Familial alcoholics (those with atleast one relative with alcoholism) appear to haveearlier onset, more antisocial symptoms, moresocial complications of alcohol use, and worsetreatment outcome than nonfamilial alcoholics(38,93,111).

Familial is not identical to genetic, and in thecase of alcoholism, the familial patterns ofinheritance are not consistent with those of apurely genetic condition (58,109). In addition,evidence suggests that the transmissibility ofalcoholism has increased over time (102). Thus,any genetic factors promoting the development of

Chapter 4-Genetics | 41

alcoholism are significantlygenetic influences.

OTHER DRUGS

moderated by non-

Fewer family studies have been conducted onthe genetic transmission of liability to other drugsof abuse. Nonetheless, the evidence availablesuggests that, as in the case of alcohol, addictionto other psychoactive substances appears to run infamilies.

One study found evidence for familial aggrega-tion of drug use, based on family history obtainedfrom individuals admitted for substance abusetreatment (78). However, this study also com-bined use of all illicit drugs into one category andrelied on self-reports by the subject on his or herdrug use as well as that of family members. In alarge family interview study comparing 201opiate addicts and 82 normal controls, as well asinterviews of 1,398 first-degree relatives of these

‘subjects, the relatives of opiate users had elevatedrates of drug addiction as compared with thecontrols (105). In addition there was an associa-tion between opiate use and the presence ofASPD. Further analysis of these data revealedthat the incidence of both drug abuse and ASPDwas higher among the siblings of the opiatesubjects than among their parents (69,70).

Some studies note a familial association be-tween opiate addiction and alcoholism (65).However, another family history study (51),comparing families of 32 alcoholics, 72 opiateaddicts, and 42 individuals addicted to bothsubstances, found that while both opiate addictionand alcoholism clustered within families, co-occurrence of the disorders within families oc-curred no more frequently than expected bychance, thus supporting the hypothesis of inde-pendent transmission. However, a later study of201 opioid addicts and 877 of their first-degreerelatives also showed familial aggregation of bothalcoholism and depressive illness suggesting apossible co-occurence of the disorders (64).

Little research has been done to test hypothesesregarding familial transmission of liability toaddiction to specific substances other than opiatesor alcohol. One study involving 350 treated drugabusers and 1,478 relatives, found that alcoholismwas equally common among relatives of individ-uals who preferentially abused opiates, cocaine,or sedative-hypnotics (27 percent, 31 percent, and24 percent of male relatives, respectively), whereasrelatives of sedative-hypnotic users were subjectto diagnoses of other substance abuses (2 percentof male relatives, versus 11 percent of malerelatives of opiate abusers and 16 percent of malerelatives of cocaine abusers) (80).

I Twin and Adoption StudiesWhile family studies can establish that a

disorder (or liability to a disorder) runs in afamily, they generally are unable to distinguishbetween biological and cultural transmission.However, two other methods are used to helpdisentangle the effects of genetic and nongeneticfactors. Adoption studies compare the presence ofa trait among biological versus adoptive familymembers or other control groups. In this wayindividuals that share the same environment butdifferent genetic heritages, or vice versa, can becompared. Twin studies, by contrast, involvesiblings raised in the same environment, butcompare how often identical twins, who aregenetically identical, and fraternal twins,1 whoare not, are similar, or concordant, for a trait. Ahigh concordance rate for a trait among identicaltwins versus fraternal twins usually indicates agenetic component for the trait.

TWIN STUDIESEvidence fromn twin studies suggests genetic

influences on ‘ drinking patterns as well as alcohol-related problems. Results from twin studiesdemonstrate genetic influences on measures ofalcohol consumption such as abstention, average

1 Fraternal twins share the same in utero environment but are genetically no more similar than any two siblings,


alcohol intake, and heavy alcohol use (50,60,92).Twin studies also indicate an inherited risk forsmoking (24).

When evaluating how alcoholism develops,twin studies generally support the existence ofgenetic influences on the development of thedisorder. One study found a higher concordancerate for alcohol abuse between identical twins (54percent) versus fraternal twins (28 percent) (57),while two subsequent studies found no suchrelationship (48,92,). A 1991 study (94) examined50 male and 31 female identical twin pairs and 64male and 24 female fraternal twin pairs, with 1member of the pair meeting alcohol abuse ordependence criteria. The study found that identi-cal male twins differed fromn fraternal male twinsin the frequencies of both alcohol abuse anddependence as well as other substance abuseand/or dependence. On the other hand, femaleidentical and fraternal twins were equally likely toabuse alcohol and/or become dependent on othersubstances, but identical female twins were morelikely to become alcohol dependent. Anotherstudy of 356 twin pairs also found higher identicalthan fraternal rates of concordance for problemsrelated to alcohol and drug use as well as conductdisorder (77). The same study also noted thatamong men, heritability was greater for earlyrather than late onset of alcohol problems, whereasno such effect was seen for women. Finally, astudy of 1,030 female twin pairs found evidencefor substantial heritability of liability to alcohol-ism, ranging from 50 to 60 percent (61).

Thus, twin studies provide general agreementthat genetic factors influences certain aspects of

. .drinking. Most twin studies also show geneticinfluence over pathological “drinking, includingthe diagnosis of alcoholism, which appears (likemany psychiatric disorders) to be moderatelyheritable. Whether genetic factors operate compa-rably in men and women, and whether severity ofalcoholism influences twin concordance is lessclear. How psychiatric comorbidity may affectheritability of alcoholism also remains to bestudied.

ADOPTION STUDIESAdoption studies have supported the role of

heritable factors in risk for alcoholism (1 1,18,1 17).The results from a series of studies conducted inDenmark during the 1970s are typical. Of 5,483nonfamily adoption cases from the copenhagenarea between 1924 and 1947, the researchersstudied 55 male adoptees, and later compared 20adoptees with 30 nonadopted brothers. They alsostudied 49 female adoptees, comparing them with81 nonadopted daughters of alcoholics. Compari-sons also were made with matched controladoptees. The Copenhagen study revealed thatadopted-away sons of alcoholic parents were fourtimes as likely as adopted-away sons of nonalco-holics to have developed alcoholism; evidencealso suggested that the alcoholism in these caseswas more severe. The groups differed little onother variables, including prevalence of otherpsychiatric illness or “heavy drinking.” Beingraised by an alcoholic biological parent did notfurther increase the likelihood of developingalcoholism. That is, rates of alcoholism did notdiffer between the adopted-away children andtheir nonadopted brothers. In contrast, daughtersof alcoholics were not at elevated risk of alcohol-ism. Among adoptees, 2 percent had alcoholism(and another 2 percent serious drinking prob-lems), compared with 4 percent of alcoholismamong the adopted controls and 3 percent amongnonadopted daughters (44).

Another analysis examined factors promotingdrug abuse as well as alcoholism (17). In thisstudy, all classes of illicit drug use were collapsedinto a single category of ‘‘drug abuse. ” Most ofthe 40 adopted drug abusers examined hadcoexisting ASPD and alcoholism; the presence ofASPD correlated highly with drug abuse. Amongthose without ASPD, a biological background ofalcoholism (i.e., alcoholism in a biological par-ent) was associated with drug abuse. Also,turmoil in the adoptive family (divorce or psychi-atric disturbance) was also associated with in-creased odds for drug abuse in the adoptee.

Chapter 4-Genetics |43

Finally, results from other adoption studiessuggest two possible forms of alcohol abuse(12,19). The two forms have been classified as“milieu-limited” or type 1 alcohol abuse and“male-limited” or type 2 alcohol abuse (21).Type 1 alcohol abuse characterized by mildalcohol problems and minimal criminal behaviorin the parents, is generally mild, but occasionallysevere, depending on presence of a provocativeenvironment. Type 2 is associated with severealcohol abuse and criminality in the biologicalfathers. In the adoptees, it was associated withrecurrent problems and appeared to be unaffectedby postnatal environment.

I n summary, adoption studies of alcoholismclearly indicate the role of biological, presumablygenetic, factors in the genesis of alcoholism. Theydo not exclude, however, a possible role fornongenetic, environmental factors as well. More-over, evidence suggests more than one kind ofbiological background conducive to alcoholism.In particular, one pattern of inheritance suggestsa relationship between parental antisocial behav-ior and alcoholism in the next generation. Thus,

adoption studies, like othereven at the genetic level,homogeneous construct.

designs, suggest thatalcoholism is not a

WHAT IS INHERITED?Although studies indicate that genetics contrib-

utes to alcoholism and probably other drug abuse,they lack information about what exactly isinherited. For example, do individuals with afamily history of drug abuse have an increasedsusceptibility or sensitivity to the effects of drugswith reinforcing properties? If a susceptibilityexists, what are the biological mechanisms thatunderlie it? To understand what might be inher-ited, both individuals who have a substance abuseproblem and animals models of substance abuseare studied. Various types of information can bederived from these studies. As with family, twin,and adoption studies, much more information is

available about alcoholism as compared withother drugs of abuse.

First, specific inherited risk markers for alco-holism and other substance abuse can be identi-fied. A risk marker is a biological trait orcharacteristic that is associated with a givencondition. Thus, if an individual is found to havean identified marker for substance abuse, he orshe is at risk for developing a drug dependency.To date, no biological characteristic has beenclearly identified as being a risk marker for eitheralcoholism or substance abuse, although evidencesuggests some possible candidates. The identif-cation of a valid and reliable risk marker couldprovide important information about the funda-mental mechanisms underlying substance abuseand addiction and would be an invaluable aid indiagnosis and treatment.

Second, inherited differences in biochemical,physiological, and anatomical processes relatedto differences in drug responses might be identi-fied and studied. Thorough biological assays canbe performed using animal models of substanceabuse. Animal models of substance abuse consistof strains of animals (usually rodents) that havebeen selectively bred to either exhibit a prefer-ence for taking a drug, exhibit a preference for nottaking a drug, or differ in some way in theirbehavioral or physiological response to a drug.Thus, such differences represent inherited traitsrelated to drug-taking behavior, and these animalscan be studied to determine what biologicalmechanisms are involved in the expression ofsuch traits.

Finally, the genetic technique of linkage analy-sis can narrow the area on a chromosome wherea gene may be located. It can lead to theidentification of the gene itself, which, in turn,can improve the understanding of the molecularevents that underlie the expression of the gene.There have been few genetic linkage studiesrelated to substance abuse since few specificbiological traits associated with drug dependencyhave been identified. Some studies in humanshave been carried out related to alcoholism but the

44 I Biological Components of Substance Abuse and Addiction

findings of these studies are contradictory andinconclusive (see later discussion).

Specific Risk Markers

ELECTROPHYSIOLOGICAL ACTIVITYAttempts to correlate distinctive patterns of

spontaneous electrical activity of the brain withalcoholism and substance abuse have been equiv-ocal. A few studies have found distinctive electro-encephalograph (EEG) patterns in individuals atrisk for alcoholism (32,39), but others have not(31,59,101). Similarly, the use of alcohol chal-lenge (i.e., giving the subject alcohol and thenrecording EEG) on subjects at high risk foralcoholism has likewise yielded inconclusiveresults. The rationale for challenge studies restson the observation that alcohol has been shown toaffect resting EEG, and thus might have adifferential effect on those at low and high risk foralcoholism (100). Again, some studies have seendistinctive responses (100,101), while other havenot (39,59).

A logical extension of studying resting EEGactivity is examining event-related potentials(ERPs). ERPs are patterns of brain electricalactivity produced in response to a particularstimulus (e.g., auditory, visual); they can reflecta variety of sensory and cognitive processes.Since ERPs may reflect heritable differences incognitive function or capability that may in turncontribute to liability to alcoholism, some havesuggested that ERP changes may allow discrimin-ation between those at low and high genetic riskfor alcoholism. The results of these studies havealso been equivocal. Some have found character-istic responses among individuals at risk foralcoholism (3,4,33,52,53,89,90,125) while othershave not (95,96,97,98). In addition to beingequivocal, the specificity for alcoholism of suchfindings is unclear. In particular, it is not yetknown whether similar findings might be identi-fied in subjects with (or at risk for) illicit drugabuse.

Currently, both EEGbest viewed as possible

and ERP findings seemmarkers. Further studies

are needed to confirm or refute the positive resultsthat have been observed. In addition, while ERPfindings in particular might relate to aspects ofsensory, perceptual, or cognitive functioning thatmay differ among those at risk for alcoholism,how such differences contribute to risk foralcoholism and perhaps substance abuse is notwell understood.

BIOCHEMICAL ASSAYSSerotonin—Results over the last two decades

from both human and animal studies have sup-ported a relationship between low levels ofcentral nervous system (CNS) (i.e., brain andspinal cord) serotonin and impulsive and violentbehavior (130,131). Since problematic use ofalcohol (as well as other drugs) has long beenassociated with a wide range of violent behavior,scientists have examined the relationship be-tween alcoholism and serotonergic abnormalities.While a consistent relationship between alcohol-ism and low CNS levels of serotonin and itsmetabolizes is lacking, mounting evidence sup-ports the presence of such abnormalities in asubgroup of alcoholics with early-onset problemsand a history of violence (16,67,68,107,130).

Because measures of serotonin activity aredifficult to obtain, researchers have used pharma-cologic probes of serotonin function, such ashormonal response to drugs that affect serotonin.These indirect measures have also indicated arelationship between impulsivity, substance abuse,and abnormal serotonin function (37,42,71,83).

For alcoholism, given that early-onset alcohol-ism and ASPD overlap substantially (16), thespecificity of the serotonin findings is unclear,especially as similar results have been found insubstance abusers with ASPD (71). However, atleast one report has indicated that, even aftercontrolling for the presence or absence of ASPDand illicit drug abuse, other neurochernical fin-dings remained significantly associated with alco-holism (106). While further work might delineate

Chapter 4-Genetics| 45

the relationship between decreased CNS sero-tonin levels and Specific psychiatric syndromes,current evidence suggests relatively specific bio-logical differences may exist between early- andlate-onset alcoholics; raising the possibility ofdefining biologically homogeneous subgroups.

Aldehyde and alcohol dehydrogenase en-zymes-Many Asians rapidly develop a promi-nent facial flush following ingestion of a smallamount of alcohol. Continued drinking leads tonausea, dizziness, palpitations, and faintness.This reaction is due to inactivity in individuals’aldehyde dehydrogenase, an enzyme that helpsmetabolize (i.e., break down) alcohol in the body.Ineffective enzyme activity results in a buildup ofthe chemical acetaldehyde in the blood followingalcohol consumption. Clinicians have taken ad-vantage of the aversive properties of acetaldehydebuildup by using the drug Antabuse to inhibitaldehyde dehydrogenase, thus inducing a severeform of the adverse reaction in abstinent alcohol-ics who begin to drink (30,135).

Alcohol dehydrogenase is another enzymeinvolved in the metabolism of alcohol. A mutantform of alcohol dehydrogenase also produces atransient increase in the acetaldehyde concentra-tion after alcohol ingestion. This form of theenzyme also has been reported in Asian popula-tions.

The two enzymes, aldehyde and alcohol dehy -drogenase, probably interact in some individualsto amplify the adverse reaction to alcohol con-sumption (129). Since this reaction discouragesheavy “drinking, the observation that it commonlyoccurs in some populations where alcoholism isrelatively rare suggests that alcohol and aldehydedehydrogenase mutations might be a major deter-minant of alcohol consumption, abuse, and de-pendence. This would seem to hold true forTaiwan and Japan where the reaction occurs in 30to 50 percent of individuals.

The genetics of the aldehyde and alcoholdehydrogenases are well described. The produc-tion of the different forms of these enzymes iscaused by variations of their normal genes. The

presence of these gene variations in an individualaccounts for variations in the metabolism ofalcohol (54). Thus, the presence of these genescan also effect alcohol consumption. For exam-ple, the gene variations that code for the ineffec-tive form of aldehyde dehydrogenase is not onlyless common in alcoholics, but also is rare inJapanese patients with alcoholic liver disease(27, 121,135). Despite identification of such genes,the relationship between their inheritance and thefamilial transmission of alcoholism remains un-studied.

Alcohol challenge-A number of studies havebeen conducted investigating the effect of admin-istering alcohol to young adult sons of alcoholics(99). These studies indicate that, despite similar-ity of blood alcohol levels, sons of alcoholicsdemonstrate less intense subjective responses toalcohol, as well as less intense upper body sway(110,111,113,114). Thus, one mechanism bywhich alcoholism might develop is that sincethese individuals have less of a reaction toalcohol, they would find it more difilcult toself-regulate alcohol consumption, thus increas-ing the risk of developing dependence. In con-junction with these findings, other studies havefound that sons of alcoholics demonstrate slightlylower levels of certain hormones (i.e., prolactin,cortisol, adrenocorticotropin hormone (ACTH))after ingesting alcohol as compared to controls(82,1 14,115,116,1 18). The relationship, if any, ofthese decreased hormonal levels to alcohol con-sumption is unclear.

COGNITIVE DIFFERENCESStudy of high-risk populations (e.g., sons of

alcoholics) has revealed temperamental, as wellas biological, differences between high-risk andcontrol subjects, leading to the suggestion thatvulnerability to alcoholism can be conceptualizedfrom a behavior-genetic perspective (127). Heri-table, constitutional differences, in other words,might affect temperament and, hence, risk foralcoholism and addiction to other drugs. Inparticular, these differences might influence cog-


nitive styles, learning ability, and capability tocontrol one’s own behavior.

In general, it appears that sons of alcoholicsdemonstrate group differences from low-riskpopulations in that the former tend to haveimpairment on tests of cognitive development,academic achievement, and neuropsychologicalfunction (34,12,8). However, the magnitude ofthese differences may depend greatly on how thepopulation is ascertained. To date, little is knownof what specific psychological, temperamental, orcognitive factors might distinguish between high-risk subjects who actually go on to developalcoholism from those who do not (128).

I Biological Mechanisms.Animals that have been bred for specific

characteristics are a valuable tool in drug use andabuse research. For example, certain strains ofrodents differ in their response to the analgesicand body temperature regulating effects of mor-phine, the motor activating effects of stimulantdrugs, and the convulsant producing properties ofbenzodiazepines (28,122). Since the essentialcharacteristic of human drug abuse and addictionis persistent drug-seeking behavior, the mostsalient models are those of genetic differences indrug self-administration and the factors associ-ated with it (e.g., tolerance). While there are somegenetic models of self-administration or prefer-ence for different drugs (i.e., alcohol, opiates,cocaine) (28,41), more information is availableabout the hereditary biological mechanisms thatunderlie the self-administration of alcohol thanother drugs.

ALCOHOLA general working hypothesis is that alcoholics

are sensitive to the low-dose rewarding propertiesof alcohol, are less sensitive to the high-doseactions of ethanol (i.e., have a higher aversivethreshold) and develop tolerance to the aversiveeffects of alcohol. The fact that rats can beselectively bred to have such alcohol drinking

characteristics supports a genetic link to thesetraits.

Dopamine and alcohol intake-Studies ofdopamine content in the brains of two differentstrains of rats bred for either preference ornonpreference for alcohol have found 25 to 30percent lower levels of dopamine in the nucleusaccumbens and the olfactory tubercle of thealcohol-preferring rats (45,74,86). No other dif-ferences in dopamine content have been observedin other brain areas. These data suggest anabnormality in the dopamine system projectingfrom the ventral tegmental area to limbic regions(nucleus accumbens and/or olfactory tubercle) ofthe alcohol-preferring rats. Since this system isthought to be involved in mediating the actions ofvarious drugs of abuse (see ch. 2) and alcohol isthought to increase dopamine levels in the system(see ch. 3), it may indicate that an abnormalfunctioning of the mesocorticolimbic dopaminesystem might be involved in promoting highalcohol “drinking behavior. That is, the alcoholpreference may be related to the ability of alcoholto compensate for the abnormality. The nature ofthis abnormality is unknown but may be due toone or more of the following factors: decreaseddopamine synthesis, a lower number of dopamineneurofibers, and/or reduced functional activity ofdopamine neurons.

Some evidence exists that the mesocortico-limbic dopamine system may respond to systemicethanol administration to a greater degree in thealcohol-preferring strains than in the nonprefer-ring strains. Studies have found that levels ofdopamine metabolizes were higher in areas of thissystem (i.e., caudate nucleus, medial prefrontalcortex, and olfactory tubercle) after ingestion ofalcohol in alcohol-preferring rats as compared tononpreferring rats (35,36). Also, one study hasreported that the oral self-administration of alco-hol, under experimental conditions where theanimal was allowed to receive alcohol as a rewardfor performing a task, increased the synapticlevels of dopamine significantly more in thenucleus accumbens of these alcohol-preferring

rats than in nonpreferring rats (132). It was alsoestablished that the alcohol-preferring strain ofrats will self-administer alcohol directly into theventral tegmental area (73,74). These studiessuggest that the mesocorticolimbic dopaminesystem is involved in regulating alcohol drinkingbehavior and that alcohol may be a strongerpositive reinforcer in alcohol-preferring rats thanin the nonpreferring rats.

Differences in dop amine receptor populationshave also been reported. Two genetically deter-mined high-alcohol seeking lines of rats havebeen reported to have fewer of one type ofdopamine receptor (i.e., the D2 receptor) in theirlimbic system compared with the nonalcoholicrats (74,124), Twenty percent fewer D2 receptors

were observed in the olfactory tubercle andnucleus accumbens of these rats. These studies,along with genetic linkage studies (see laterdiscussion), provide support for the involvementof the D2 receptor in alcohol-preference.

Serotonin and alcohol intake--Examinationof alcohol-preferring and nonpreferring rats hasindicated a relationship between high alcoholpreference and a deficiency in the CNS serotoninsystem. A number of studies have reported 10 to30 percent lower levels of serotonin and itsmetabolizes in the brains of alcohol-preferringrats as compared with alcohol nonprefening rats(45,66,74,84,85,86). Only one study, using astrain of rats not used in any of the others, did notfind lower brain serotonin levels (63). Areas ofthe brain found to have low serotonin levelsinclude the cerebral cortex, frontal cortex, nu-cleus accumbens, anterior and corpus striatum,septal nuclei, hippocampus, olfactory tubercle,thalamus, and hypothalamus.

Since several of these CNS regions may beinvolved in mediating the rewarding properties ofdrugs of abuse, including alcohol, these findingssuggest a relationship between lower contents ofserotonin in the brain and high alcohol preference.Evidence suggests that the serotonin system isinvolved in regulating the activity of the dopa-mine mesocorticolimbic system ( 136). Also, some

. . . . . . . . -- — .


of the areas found to have low serotonin levels(i.e., hypothalamus, hippocampus) may be in-volved in mediating the aversive effects ofalcohol. Since the development of tolerance to theaversive actions of alcohol is one possible charac-teristic of alcoholic abuse, a deficiency in sero-tonin in these areas may be an innate factorpromoting tolerance to the aversive effects ofethanol in alcohol-preferring lines of rodents.

Further study of one of the rat strains used inthese studies showed that low serotonin in thealcohol-preferring line compared with the non-preferring line was due to fewer serotonin con-taining axons (137). This study found fewerserotonin presynaptic fibers forming synapses inthe nucleus accumbens, frontal cortex, cingulatecortex, and hippocampus of alcohol-preferringrats. These results suggest that the low serotoninis the result of structural differences in the CNSserotonin system rather than lower production ofserotonin. Examination of this same strain of ratsfound that there were increased numbers of onetype of post-synaptic serotonin receptor in areasof the frontal cortex and hippocampus (73,76,134).This increase in the number of serotonin postsyn-aptic receptors may represent a compensation forthe lower number of presynaptic serotonin fibers.No such increase in receptors was found in thestrain of rats with normal levels of brain serotoninactivity discussed earlier (62).

Overall, the animal data favors an inverserelationship between the functioning of the CNSserotonin system and alcohol drinking behavior.Thus, innate low functioning of the serotoninsystem may be associated with high alcoholpreference. In support of this concept, somestudies have found lower cerebrospinal fluidserotonin metabolize concentrations in alcoholicsthan in various control populations (2,14).

GABA and the actions of alcohol—Evidenceindicates that alcohol can exert some of itsantianxiety and intoxicating effects by potenti-ating the actions of the neurotransmitter gammaamino butyric acid (GABA) at the G A B AA

receptor (see ch. 3) and that this receptor might be


involved in mediating alcohol drinking behaviorof alcohol-preferring rats (75). However, little hasbeen published that indicates an innate abnormal-ity may exist in the GABA system that could beassociated with alcohol preference. A recentstudy examined the densities of GABA contain-ing fibers in the nucleus accumbens and otherbrain areas of two different strains of alcohol-preferring and nonprefering rats (55). The resultsof this study indicated a higher density of GABAfibers in the nucleus accumbens of the alcohol-preferring rats compared with the nonpreferringrats. There were no differences between therespective lines in the other regions. These resultssuggest alcohol preference may involve an innate,abnormal GABA system within the nucleusaccumbens.

The experimental drug RO 15-4513 binds tothe GABAA-BDZ-Chloride channel receptor com-plex (see ch. 3) and is known to block the actionsof alcohol at this receptor (126). The administra-tion of RO 15-4513 reduced alcohol but not waterintake in a study using one of the alcohol-preferring line of rats (75). The blocking effect ofRO 15-4513 on alcohol intake could itself beblocked by administration of a drug that blocksthe benzodiazepine receptor. These results indi-cate that the GABAA-BDZ-chloride channel re-ceptor complex may be involved in mediating thereinforcing actions of ethanol that promote alco-hol drinking behavior in these rats. The observa-tion that RO 15-4513 blocks oral self-adminis-tration of alcohol supports this idea (56,108).Furthermore, treatment with a drug that activatesthe GABAA receptor was shown to markedlyincrease the acquisition of voluntary ethanolconsumption in laboratory rats (123). Also,GABAA receptor function is enhanced by alcoholin animals selected for sensitivity to alcoholintoxication, but alcohol has little effect onGABAA receptors of animals selected for resis-tance to alcohol intoxication (28). Overall, theseresults are consistent with the involvement of theGABAA receptor in regulating alcohol consump-tion. (See also ch. 3).

Alcohol withdrawal severity—Animal mod-els have been developed for differential geneticsusceptibility to alcohol withdrawal. For exam-ple, withdrawal seizure-prone mice display ahigher incidence of convulsions than do seizure-resistant mice when exposed to identical alcoholconcentrations (29). Other studies suggest thatthis alcohol withdrawal reaction is mediated byan increased sensitivity of channels for calciumions, coupled to receptors for excitatory aminoacids (46,47). Several results have emerged instudies of these mouse lines that are potentiallyimportant for understanding drug abuse. Forexample, studies indicate that independent ge-netic factors control alcohol sensitivity, toler-ance, and dependence, suggesting that thesefeatures of drug abuse are maintained by differentneurobiological mechanisms (28). In addition, thealcohol withdrawal seizure-prone mice have moresevere withdrawal to other depressant drugs (i.e.,diazepam, phenobarbital, nitrous oxide) (6,7,8)suggesting that a group of genes acts to influencedrug withdrawal severity not only to alcohol, butalso to a number of other depressant drugs.

OTHER DRUGSA variety of strains of rats and mice has been

developed that exhibit genetic variations in theirsensitivity to the reinforcing effects of drugs ofabuse and in their drug-seeking behavior (28). Inaddition, genetic differences in various biologicaland neurochemical mechanisms have been ob-served in these animals.

For example, strains of rats and mice that differin their sensitivity to the reinforcing properties ofcocaine and in their cocaine-seeking behaviorhave also been observed to have differences in thenumber of dopamine containing neurons andreceptors in certain brain areas (120). While therole of these biological findings in the expressionof the behavioral traits is unclear, given thatdopamine is the key neurotransmitter in cocaine’saction, it is likely that a link may exist. Otherstudies have shown that the development ofnicotine tolerance is genetically related. Strains of


mice that differ in the rate at which they developtolerance to nicotine have also been found todiffer in nicotine receptor changes followingchronic administration of the drug (72). Thus,inherited differences in nicotine receptor mecha-nisms may underlie inherited differences in thedevelopment of nicotine tolerance.

A recent study indicates that inherited differ-ences in the intracellular mechanisms of theneurons in the mesocorticolimbic pathway couldcontribute to a genetic predilection to drugaddiction (87). In a comparison of rats with eitherhigh or low rates of self-administering drugs ofabuse, the higher self-administering strain exhib-ited differences in the intracellular mechanismsthat control activity in the neurons of the ventraltegmental area and nucleus accumbens (5).

The further examination of causative relation-ships between inherited neurochemical altera-tions and inherited behavioral traits would pro-duce valuable information about the biologicalmechanism that underlies genetic factors relatedto substance abuse and addiction. The recentdevelopment of new and more sensitive tech-niques to analyze brain activity and processes willfacilitate such studies.

I Linkage StudiesGenetic linkage studies establish an associa-

tion between an area of a specific chromosomeand the expression of a trait. Linkage analysisuses specific markers that identify the area on achromosome that might contain the gene ofinterest. If the marker consistently occurs inassociation with the expressed trait, then it islikely that the gene interest is in chromosomalregion.

In the area of substance abuse and addiction,genetic linkage studies have purported to show alinkage between the gene for the dopamine D2

receptor and alcoholism. The gene for the D2

receptor has two forms associated with twomarkers, the A 1 and A2 alleles. The Al alleleoccurs in about 20 percent of the population,

while the AZ allele is found in the remaining 80percent (l). Two separate studies (9,10) reportedthat the frequency of the Al allele for the D2

dopamin e receptor was significantly greater insevere alcoholics compared with nonalcoholics.Furthermore, another study (88) found that indi-viduals with the Al allele had fewer D2 receptorsthan those with the A2 allele. In agreement withthese findings, another study (91) observed asignificant association between the Al allele ofthe D2 receptor and alcoholism. An association ofthe Al allele with alcoholism and decreasednumbers of D2 dopamin e receptors implies a rolefor an inherited deficit in the dopamine system inalcoholism. However, in contrast to these results,other studies have not found an associationbetween the frequency of the Al allele of the D2

receptor and alcoholism (13,26,40,1 19). The dis-crepancies between these studies has called intoquestion the validity of the association of the Alallele with alcoholism.

Moreover, the report of a higher prevalence ofthe Al allele not only in alcoholics, but also inother disorders such as autism, attention deficithyperactivity disorder, and Tourette’s syndrome(25), suggests that the presence of the Al allele isnot specific for alcoholism, but that it has a morediffuse effect that can contribute to the occurrenceof other conditions. Also, recent findings indicatethat the frequency of the Al allele varies mark-edly among different populations (e.g., it is highin some Native Americans) but there does notappear to be an association with its increasedfrequency and the occurence of alcoholism (43).This complexity, coupled with the heterogeneousand complex nature of alcoholism, could accountfor the disagreements among these studies. Suchcomplexity makes construction of appropriatecontrol groups difficult, which in turn can affectstudy results. Additional research is needed tounravel the disagreement and establish the impor-tance of these findings. It might be that thepresence of the Al allele is not unique toalcoholism, but rather, causes a general alteration


in the brain dopamine system that then exacer-bates or contributes to alcohol abuse.

SUMMARYThe existence of heritable influences on normal

and pathological consumption of alcohol is sup-ported by results from family studies, twinstudies, and adoption studies as well as researchon animal models. Animal studies have estab-lished that alcohol preference and the reinforcingactions of alcohol are influenced by geneticfactors. While there have been fewer studiesexamining the genetic component of vulnerabil-ity to the addictive properties of other drugs ofabuse, evidence from animal studies supports agenetic influence on the use and abuse of drugsother than alcohol. The study of nonalcohol drugabuse in humans is more difficult because ofsubstantially smaller populations that use orabuse these drugs and marked changes in availa-bility and, hence, exposure to these agents.Investigation in this area is further hampered bythe complexity of subjects’ drug use: Most drugabusers have used multiple agents. This has ledresearchers either to concentrate on one class ofdrug or to treat all illicit drug use as equivalent.The tendency to lump all illicit drugs into onecategory makes results difficult to interpret orcompare.

In the case of alcohol, studies indicate that lowdoses of alcohol are stimulating and produce astrong positive reward in animals susceptible tothe addictive properties of alcohol. Anothercomponent of excessive alcohol consumptionmight be that alcoholics have a high threshold tothe aversive effects of ethanol. This could be aresult of an innate low sensitivity to medium andhigh doses of alcohol and/or acute tolerance to itsaversive effects. Results from animal studiessuggest an association between high alcoholpreference and acute tolerance to the medium-andhigh-dose effects of ethanol. These animal exper-iments need to be extended and considerationshould be given to related studies in humans.

Findings with animals selectively bred for alco-hol preference need to be extended to studies ofsensitivity, tolerance, and preference for otherdrugs of abuse.

Neurobiological evidence points to commonpathways mediating the positive reinforcing ac-tions of alcohol and other drugs of abuse. Mostevidence is consistent with the involvement of themesocorticolimbic dopamine system in drug rein-forcement mechanisms. Other neuronal pathwaysthat regulate the activity of the mesocorticolimbicdopamine system may also be involved in mediat-ing the rewarding properties of ethanol and otherdrugs of abuse. In the case of serotonin, innate,genetically determined factors appear to reduceCNS activity of serotonin, which is associatedwith heavy alcohol drinking. In addition, animaland human studies suggest an inherited differencein dopamine response to alcohol consumptionand possibly an anomaly in the D2 receptor forDopamine associated with alcohol abuse. Addi-tional studies with animals and humans areneeded to clarify these differences and to explorethe relationship of other neurobiological mecha-nisms related to the inherited components of otherdrugs of abuse.

Alcoholism and drug abuse are complex condi-tions that are the result of multiple causal factors.Alcoholism and other forms of addiction repre-sent entities that have a genetic component butrequire specific (but as yet poorly understood)environmental influences to manifest. Thus, con-sideration of the impact of genetic factors mustalso take into account general social conditionssuch as availability and cost of substances,acceptability of use, and specific environmentalinfluences on initiation of use, maintenance orcessation of use, and development of use-relatedproblems. A major goal of addiction research inclinical populations is to determine who isvulnerable under what conditions. Understandingthis interaction might lead to better prediction ofrelapse as well as improved matching of patientsand treatments.

Chapter 4-Genetics 151

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biological components of substance abuse and addiction (part 6 of 8)

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