Risk Factors for Substance Use, Abuse, and Dependence PDF

12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness Risk Factors for Substance Use, Abuse, and Dependence Editors: Pamela Korsmeyer and Henry R. Kranzler Date: 2009 From: Encyclopedia of Drugs, Alcohol & Addictive Behavior(Vol. 3. 3rd ed.) Publisher: Macmillan Reference USA Document Type: Topic overview; Brief article Length: 24,626 words Full Text: Risk Factors for Substance Use, Abuse, and Dependence This entry includes the following essays: AN OVERVIEW Risk factors for use, abuse, and dependence on alcohol and drugs are characteristics of individuals or environments that increase risk. Such factors are not absolute determinants of alcohol and drug use or problems but, rather, factors that affect the probability that individuals with these factors will use, abuse, or become dependent on a given substance. Much individual variation occurs within groups and societies in alcohol and drug use, abuse, and dependence. Some people never use substances although they are readily available in their environments. Others use drugs sporadically or regularly for a short time, or for years, and yet never become dependent. Others become dependent but remit, whereas still others become chronic heavy users who cannot stop despite great costs to themselves and those close to them. The various patterns of use result from a complex combination of environmental and genetic factors. Risk factors for substance use, abuse, and dependence have been reported at various levels ranging from macro or large-scale societal factors to the molecular level. Large-scale changes in the prevalence of use over time in society indicate shifting macro-level factors. For alcohol, good sources of information on long-term time trends in the U.S. are per capita alcohol consumption statistics (http://pubs.niaaa.nih.gov/ ). For drugs, a good source of information on time-term time trends is the information from yearly surveys of U.S. high school and college students known as Monitoring the Future (http://www.monitoringthefuture.org ). General articles about sociodemographic risk factors for alcohol abuse and dependence (Hasin et al., 2007a; Compton et al., 2007) in 2001 and 2002 in the United States show that among adult residents of households or group quarters (such as college dormitories), a current or lifetime history of alcohol or drug abuse or dependence was associated with being male, younger, unmarried, of lower socio-economic status, and being white or Native American compared to black, Hispanic, or Asian race/ethnicity. https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 1/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness Macro-level factors affecting use of alcohol and drugs include influences such as laws (local or nationwide) against any use or sales (e.g., drugs) or laws that target certain age groups (e.g., minimum drinking age laws) (Voas et al., 2003; Hingson et al., 1998). An example is the Eighteenth Amendment to the U.S. Constitution, which from 1920 to 1933 outlawed the manufacture, transport, and sale of alcohol. This law was effective in limiting alcohol consumption in the United States. Some scholars Page 381 believe its unpopularity led to its demise, while others maintain that the amendment was repealed because it was not enforceable and may have actually caused crime to escalate. The strength of law enforcement has also been shown to influence use. Pricing is another macro-level factor that affects alcohol and drug use, as higher prices tend to decrease use (Chaloupka et al., 2002). Availability influences use; for example, the density of alcohol outlets within given geographic areas can affect the proportion of substance users. (LaScala et al., 2001). Advertising and marketing strategies can also influence the use of legal substances, for example, alcohol and cigarettes. In terms of more local environmental influences, adolescent peer groups have long been shown to influence substance use (Walden et al., 2004; Agrawal et al., 2007). However, while peer groups may provide modeling of substance use and access to substances, recognition has increased that adolescents with certain partially heritable personality traits may seek peer groups that include substance abusers (Kendler et al., 2007). Consequently, the relationship between substance-using peer groups and adolescent substance use is not entirely causal. External traumatic or stressful experiences can increase the use of substances, as has been shown by both animal and human studies. Childhood abuse is a risk factor for use of substances and for becoming dependent on them (Nelson et al., 2006; Kendler et al., 2000). The role of adult stressors is more difficult to determine because some personality traits associated with substance use (e.g., sensation seeking) may also increase the risk for traumatic experiences such as serious accidents. In such cases, an apparent relationship between accidents and subsequent substance use could actually be due to the common underlying sensation seeking personality trait, and attributing the substance use to the accident would be incorrect. A study that overcomes this difficulty is one that examines adolescent or adult civilian exposure to terrorism, since such exposure to traumatic experiences is independent of any personality or other personal characteristics and thus serves as a type of so-called natural experiment for understanding the relationship of stress exposure and subsequent alcohol or substance use. A series of studies in the United States and Israel have shown that adolescents' exposure to terrorism increases the risk for use of alcohol and drugs (Schiff et al., 2007; Wu et al., 2006) and adults (Hasin et al., 2007b). While no single personality trait predicts alcoholism (Sher et al., 2005), traits associated with the development of substance use disorders include novelty seeking (Cloninger et al., 1995) and sensation seeking (Zuckerman & Kuhlman, 2000; Martin et al, 2004). These traits also have their own risk factors, which include environmental and genetic influences. Cognitive factors that affect the risk for substance use and substance use disorders include expectancies and motivations. Expectancies (positive or negative) are beliefs about the expected effects of alcohol or another substance, that is, that use will make the user more social, feel good, or lead to some sort of problem (Goldman & Rather, 1993). A twin study indicated that alcohol expectancies are due to environmental rather than genetic influences (Slutske et al., 2002). Motivations are the reasons that individuals actually use the substances, that is, to socialize, to fit in, because the effects are enjoyable (Cooper et al., 1995). Drinking to cope with negative feelings and emotions has been associated with problem drinking in a number of studies (Mann et al., 1987; Carpenter & Hasin, 1998; Beseler et al., 2008). While expectancies and motives are related, they are not necessarily entirely overlapping. https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 2/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness Neuroscientists investigate aspects of brain functioning and neurotransmission as risk factors or causes of alcohol and drug use, abuse, and dependence. In addition, genetic influences are known to affect the risk for alcohol and drug use and dependence. See also Abuse Liability of Therapeutic Drugs: Testing in Animals; Addiction: Concepts and Definitions; Complications: Mental Disorders; Conduct Disorder and Drug Use; Epidemiology of Drug Abuse; Models of Alcoholism and Drug Abuse. BIBLIOGRAPHY Agrawal, A., Lynskey, M. T., Bucholz, K. K., Madden, P. A., & Heath, A. C. (2007). Correlates of cannabis initiation in a longitudinal sample of young women: The importance of peer influences. American Journal of Preventative Medicine, 45(1), 31–34. Beseler, C., Aharonovich, E., Keyes, K., & Hasin, D. (2008). Adult transition from at-risk drinking to alcohol dependence: The relationship of family history and Page 382 drinking motives. Alcoholism Clinical and Experimental Research, 32(4), 607–616. Carpenter, K. M., & Hasin, D. (1998) A prospective evaluation of the relationship between reasons for drinking and DSM-IV alcohol use disorders. Psychology of Addictive Behavior, 23, 41–46. Chaloupka, F. J., Grossman, M., & Saffer, H. (2002). The effects of price on alcohol consumption and alcohol-related problems. Alcohol Research and Health, 26, 22–34. Cloninger, C. R., Sigvardsson, S., Przybeck, T. R., & Svrakic, D. M. (1995). Personality antecedents of alcoholism in a national area probability sample. European Archives of Psychiatry and Clinical Neuroscience, 245, 239–244. Compton, W. M., Thomas, Y. F., Stinson, F. S., & Grant, B. F. (2007). Prevalence, correlates, disability, and comorbidity of DSM-IV drug abuse and dependence in the United States: Results from the national epidemiologic survey on alcohol and related conditions. Archives of General Psychiatry, 64(5), 566–576. Cooper, M. L., Frone, M. R., Russell, M., & Mudar, P. (1995). Drinking to regulate positive and negative emotions: A motivational model of alcohol use. Journal of personality and social psychology, 69, 990– 1005. Goldman, M. S., & Rather, B. C. (1993). Substance use disorders: Cognitive models and architecture. In K. S. Dobson & P. C. Kendall (Eds.), Psychopathology and cognition (pp. 245–292). New York: Academic Press. Hasin, D. S., Stinson, F. S., Ogburn, E., & Grant, B. F. (2007a). Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: Results from the National Epidemio-logic Survey on Alcohol and Related Conditions. Archives of General Psychiatry, 64(7), 830– 842. Hasin, D. S., Keyes, K. M., Hatzenbuehler, M. L., Aharonovich, E. A., & Alderson, D. (2007b). Alcohol consumption and posttraumatic stress after exposure to terrorism: Effects of proximity, loss, and psychiatric history. American Journal of Public Health, 97(12), 2268–2275. https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 3/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness Hingson, R., Heeren, T., & Winter, M. (1998). Effects of Maine's 0.05% legal blood alcohol level for drivers with DWI convictions. Public Health Reports, 113, 440–446. Kendler, K. S., Bulik, C. M., Silberg, J., Hettema, J. M., Myers, J., & Prescott, C. A. (2000). Childhood sexual abuse and adult psychiatric and substance use disorders in women: An epidemiological and co- twin control analysis. Archives of General Psychiatry, 57(10), 953–959. Kendler, K. S., Jacobson, K. C., Gardner, C. O., Gillespie, N., Aggen, S. A., & Prescott, C. A. (2007). Creating a social world: A developmental twin study of peer-group deviance. Archives of General Psychiatry, 64(8), 958–965. Lascala, E. A., Johnson, F. W., & Gruenewald, P. J. (2001). Neighborhood characteristics of alcohol- related pedestrian injury collisions: A geostatistical analysis. Prevention Science, 2, 123–134. Mann, L. M., Chassin, L., & Sher, K. J. (1987). Alcohol expectancies and the risk for alcoholism. Journal of Consulting and Clinical Psychology, 55, 411–417. Martin, C. A., Kelly, T. H., Rayens, M. K., Artin, C. A., Brogli, B. R., Himelreich, K., et al. (2004). Sensation seeking and symptoms of disruptive disorder: Association with nicotine, alcohol, and marijuana use in early and mid-adolescence. Psychological Reports, 94, 1075–1082. Nelson, E. C., Heath, A. C., Lynskey, M. T., Bucholz, K. K., Madden, P. A., Statham, D. J., et al. (2006). Childhood sexual abuse and risks for licit and illicit drug-related outcomes: A twin study. Psychological Medicine, 36(10), 1473–1483. Schiff, M., Zweig, H. H., Benbenishty, R., & Hasin, D. S. (2007). Exposure to terrorism and Israeli youths' cigarette, alcohol, and cannabis use. American Journal of Public Health, 97(10), 1852–1858. Sher, K. J., Grekin, E. R., & Williams, N. A. (2005). The development of alcohol use disorders. Annual Review of Clinical Psychology, 1(22),1–31. Slutske, W. S., Cronk, N. J., Sher, K. J., Madden, P. A., Bucholz, K. K., & Heath, C. C. (2002). Genes, environment, and individual differences in alcohol expectancies among female adolescents and young adults. Psychology of Addictive Behavior, 16, 308–317. Voas, R. B., Tippetts, A. S., & Fell, J. C. (2003). Assessing the effectiveness of minimum legal drinking age and zero tolerance laws in the United States. Accident Analysis and Prevention, 35, 579–587. Walden, B., McGue, M., Lacono, W. G., Burt, S. A., & Elkins, I. (2004). Identifying shared environmental contributions to early substance use: The respective roles of peers and parents. Journal of Abnormal Psychology, 113(3), 440–450. Wu, P., Duarte, C. S., Mandell, D. J., Fan, B., Liu, X., Fuller, C. J., et al. (2006). Exposure to the World Trade Center attack and the use of cigarettes and alcohol among New York City public high-school students. American Journal of Public Health, 96(5), 804–807. Zuckerman, M., & Kuhlman, D. (2000). Personality and risk-taking: Common biosocial factors. Journal of Personality and Social Psychology, 68, 999–1029. DEBORAH HASIN https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 4/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness Page 383 DRUG EFFECTS AND BIOLOGICAL RESPONSES Although many indirect factors lead to an individual abusing drugs, a person's response to the effects of the drugs themselves contribute both to their use and abuse. These drug effects should be considered in relation to four phases of drug use: (1) initiation-consolidation, (2) maintenance, (3) repeated withdrawal and relapse, and (4) postwithdrawal. During the initiation-consolidation phase, behaviors that lead to the taking of a drug are gradually strengthened through operant and classical conditioning processes and by biochemical changes in the brain. The drug effects include a cascade of discriminative or internally appreciated drug cues (i.e., subjective effects). The presence of these cues often leads to associated autonomic responses and reports of urges in humans. These responses and urges may result in an unfolding of a sequence of behavioral and physiological events leading to continued drug consumption. After a pattern of chronic drug use is established, individuals may become tolerant to certain effects of a drug. In addition, they may experience withdrawal effects when they stop taking a drug. Withdrawal effects are often opposite to the drug-induced state and usually involve some form of dysphoria—a state of illness and distress. Over time, withdrawal effects become associated with stimuli in the environment, as was the case for the euphoric and other direct effects of the drug. Because of operant and classical conditioning processes, these associated stimuli can then produce conditioned effects that are often characterized as urges or cravings, and that may trigger relapse. The underlying neurotransmitter systems within the brain, subserving these behavioral features of drug effects, are just beginning to be understood. Early research on the neural substrates of reward in general used electrical brain stimulation as the reward. For example, Olds (1977) found that rats would press a lever to receive a brief electrical pulse to the hypothalamus; rats would press this lever to such an extent that they did not engage in consummatory reward activities such as eating and drinking. Subsequent research indicated that activation of certain systems in the brain, namely the mesolimbic and nigrostriatal dopaminergic systems, were most sensitive to brain stimulation reinforcement. Several theories have been suggested to explain the importance of the brain reward system for the survival of species (Conrad, 1950; Glickman & Schiff, 1967; O'Donahue & Hagmen, 1967; Roberts & Carey, 1965). Further research demonstrated that most drugs of abuse lower the threshold for this brain stimulation reward, thus suggesting that such drugs may activate the same, or similar, reward pathways (see Koob & Bloom, 1988). As will be seen, furthermore, the reinforcing effects of the drugs themselves—that is, effects that lead individuals to take the drugs—are directly mediated by these reward systems. The fact that many drugs induce activation of these systems may indicate a mechanism underlying the addiction- related effects of drugs of abuse. COCAINE AND OTHER STIMULANTS Cocaine is an indirect catecholamine agonist that acts by blocking the reuptake of monoamines, including dopamine (DA), norepinephrine (NE), and serotonin (5-HT). During the process of reup-take, the previously released neurotransmitter is actively transported back from the synaptic cleft into the presynaptic terminal of the neuron where the neurotransmitter was produced and released (Pitts & Marwah, 1987). In contrast to cocaine, amphetamine acts not only by inhibiting uptake, but also by releasing catecholamines from newly synthesized storage pools from the presynaptic terminal of the neuron (e.g., Carlsson & Waldeck, 1966). https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 5/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness Amphetamine and cocaine are both potent psychomotor stimulants. They produce increased alertness and energy and lower anxiety and social inhibitions. The acute reinforcing actions of the stimulants are primarily determined by their augmentation of DA systems. With prolonged consumption: (1) acute tolerance becomes substantial, and (2) the individual starts to regularly consume higher and many more doses if the resources are available. Over time, in high-dose regimens, the behavioral pattern of use becomes stereotyped and restricted. In settings of low availability, the individual focuses on the acquisition and consumption of the drug. These effects of stimulants occur within weeks or months of continued use. The individual may also start “bingeing” during this period. A binge is characterized by the re-administration of the drug approximately every ten Page 384 to twenty minutes, resulting in frequent mood swings (i.e., alternations of highs and lows). Cocaine binges typically last twelve hours, but may last as long as seven days. It has been proposed that cocaine abstinence consists of a three-phase pattern: crash, withdrawal, and extinction (Gawin & Kleber, 1986; Gawin & Ellinwood, 1988). The crash phase immediately follows the cessation of a binge and is characterized by initial depression, agitation, and anxiety. Over the first few hours, drug craving is replaced by an intense desire for sleep. During this time, the individual may use alcohol, benzodiazepines, or opiates to induce sleep. Following the crash, hypersomnolence (excessive sleep) and hyperphagia (excessive appetite) develop. Following the first few days of hypersomnolence and hyperphagia, other symptoms emerge that are the opposite of the effects of cocaine—withdrawal symptoms. During this withdrawal period, which lasts three to ten days, individuals experience decreased energy, limited interest in their environment, and anhedonia. They are also strongly susceptible to relapse and starting another binge cycle (Gawin & Ellinwood, 1988; Gawin & Kleber, 1986). This phase is followed in time by the extinction phase, in which relapse to cocaine use is prevented. During the extinction phase, brief periods of drug craving also occur. These episodes of craving are thought to be triggered by conditioned stimuli that were previously associated with the drug. If the individual experiences these cues without the associated drug effects—that is, resists relapse—then the ability of these cues to elicit drug cravings should diminish over time, which in turn should lessen the probability of relapse (Gawin & Ellinwood, 1988). As already noted, acute administration of cocaine produces profound inhibition of dopaminergic uptake (Fuxe, Hamberger, & Malmfors, 1967). The relation between cocaine dose and DA levels is linear; therefore, larger amounts of cocaine result in higher extracellular DA levels. These levels of DA are thought to underlie the reinforcing effects of cocaine (Gawin & Ellinwood, 1988). Because both cocaine and amphetamine result in enhanced dopaminergic neuro-transmission, thereby producing elevated extracellular levels of catecholamines, these elevated neurotransmitter levels would presumably have local time-dependent Table 1. Effects of chronic cocaine and amphetamine administration on dopaminergic functioning. Amphetamine Cocaine Day I Day 7 Day 1 Day 7 Autoreceptor sensitivity sub super sub super Receptors decreased decreased unclear unchanged Biosynthesis reduced reduced unchanged unchanged Uptake sites decreased decreased unchanged unchanged https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 6/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness Table 1. Effects of chronic cocaine and amphetamine administration on dopaminergic functioning. ILLUSTRATION BY GGS INFORMATION SERVICES.GALE, CENGAGE LEARNING inhibitory effects on the enzyme tyrosine hydroxylase, which is responsible for controlling their rate of synthesis. Therefore, this substrate-inhibitory mechanism might compensate for the increased catecholamine levels and activity by decreasing their synthesis. Galloway (1990) found that cocaine, in a way that was consistent with this proposition, decreased DA synthesis in a dose-dependent manner in various brain regions. Chronic, intermittent stimulant use (e.g., 1–2 injections per 24 hrs) produces other behavioral effects besides euphoria and increased energy: (1) stimulant psychosis, which is characterized by paranoia, anxiety, stereotyped compulsive behaviors, and hallucinations, and (2) sensitization or “reverse tolerance.” Sensitization refers to the fact that the effects of cocaine are progressively enhanced. Although sensitization has been demonstrated in animal studies, it is not clear whether it occurs in humans. There are nevertheless several possible explanations for sensitization. First, because cocaine blocks dopaminergic uptake, chronic cocaine use could somehow harm the functioning of the dopamine uptake mechanism; the evidence regarding this possibility is equivocal (Zahniser et al., 1988b). Second, sensitization could also be the result of enhanced dopaminergic release, similar to that found to be chronic after amphetamine administration (Castaneda, Becker, & Robinson, 1988). Akimoto, Hammamura, & Otsuki (1989) found enhanced DA release in the striatum one week following chronic cocaine administration. Similar data has been obtained by others (Kalivas et al., 1988; King et al., 1993a; Pettit et al., 1990). Cocaine levels in blood and cerebrospinal fluid have also been reported to be elevated in chronically treated subjects (Reith, Benuck, & Lajtha, 1987); however, these Page 385 increases cannot account for most of the change in DA release (Pettit et al., 1990). Furthermore, some researchers report no consistent effects in this regard. Third, there could be changes in autoreceptor sensitivity following chronic cocaine administration. Autoreceptors for particular neurotransmitters are those receptors that reside on the same neuron that releases the neurotransmitter. The autoreceptors on the somatodendritic area of neurons regulate impulse flow along the neuron, whereas autoreceptors on the terminal regions of the neuron regulate the amount of neurotransmitter released per impulse and neurotransmitter synthesis (Cooper, Bloom, & Roth, 1986). Sensitization could, therefore, be the result of decreased autoreceptor sensitivity. Such subsensitivity would result in either increased impulse flow, if somatodendritic autoreceptors were altered, or increased neurotransmission/synthesis, if terminal autoreceptors were altered. The net effect, in either case, would be an increase in dopaminergic neurotransmission. There is some evidence of decreased somatodendritic autoreceptor sensitivity 24 hours after the cessation of chronic cocaine administration (Henry, Greene, & White, 1989). However, seven days after termination of daily cocaine injections, when cocaine-induced sensitization is still fully present, somatodendritic autoreceptors are no longer reduced in sensitivity (Zhang, Lee, & Ellinwood, 1992). Evidence regarding changes in terminal autoreceptor sensitivity is mixed. Dwoskin and colleagues (1988) found that terminal autoreceptors were supersensitive, not subsensitive, to a DA agonist 24 hours following chronic cocaine use. Henry and associates (1989) also found that terminal autoreceptors were https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 7/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness supersensitive to DA following chronic daily cocaine injections. Although autoreceptor super-sensitivity cannot explain sensitization, it is a possible mechanism underlying the previously described anhedonia and anergy experienced by cocaine abusers during the withdrawal phase. Fourth and last, there could be an increase in the number or sensitivity of postsynaptic DA receptors. The evidence regarding this hypothesis is also mixed (Zahniser et al., 1988a). For example, Peris and colleagues (1990) found an increased number of postsynaptic D2 receptors in the nucleus accumbens one day following cessation of chronic cocaine administration; however, after one week the number of receptors had returned to normal levels. In contrast, there is some evidence that post-synaptic DA receptors are decreased following chronic cocaine use. Volkow et al. (1990) found lower uptake values for [18 F]n-methylspiroperidol in human cocaine users who had been abstinent for one week, as compared with normal subjects. Uptake values were similar, however, for normal subjects and cocaine users who had been abstinent for one month. In contrast with these results, Yi and Johnson (1990) have reported that chronic intermittent cocaine use impairs the regulation of synaptosomal 3[H]-DA release by DA autoreceptors, thus suggesting a subsensitivity or down-regulation of release-modulating DA autoreceptors seven days after chronic cocaine administration. The differences in the results of the Yi and Johnson (1990) and the Dwoskin et al. (1988) studies may be due to differences in the administration schedules or in the procedures used to measure autoreceptor sensitivity. In contrast with the changes induced by intermittent but chronic drug administration, a regimen that involves the chronic administration of steady-state levels of drug results in decreased DA overflow when striatal brain slices are perfused with cocaine. This result may be due to the development of super- sensitive autoreceptors. Autoreceptor supersensitivity would result in decreased dopaminergic activity. There is some support for this hypothesis from research involving the chronic administration of amphetamine. Lee and colleagues (Lee, Ellinwood, & Nishita, 1988; Lee & Ellinwood, 1989) found that 24 hours after withdrawal from a week of continuous administration of amphetamine, all indicators of autoreceptor activity demonstrated a pronounced subsensitivity. Similar results have been found following the continuous infusion of cocaine (Zhang et al., 1992). However, by the seventh day of withdrawal (a period associated with anergia, irritability, and “urges” in human stimulant abusers), nigrostriatal somatodendritic autoreceptors progress from an initial subsensitivity to a supersensitive state, whereas terminal autoreceptors are normosensitive. The changes in sensitivity of receptors clearly depend on the way the drug is administered and which receptors are evaluated. The evidence, moreover, is not always consistent. Page 386 There is also evidence that chronic cocaine administration produces neurotoxicity—i.e., actual destruction of neural tissue—although there are conflicting results and the relationship of this neurotoxicity to the addiction process is unclear. For example, Trulson and colleagues (1986) demonstrated decreased tyrosine hydroxylase activity sixty days after chronic cocaine treatment (see also Trulson & Ulissey, 1987), thereby indicating decreased DA synthesis. (Tyrosine hydroxylase is the rate-limiting step in the biosynthesis of DA; Cooper et al., 1986.) Similarly, Taylor and Ho (1978) found that chronic administration of cocaine decreased tyrosine hydroxylase activity in the caudate, but Seiden and Kleven (1988) were unable to replicate the findings of Trulson. As contrasted with the inconclusive results on cocaine, research involving amphetamine is much clearer. First, chronic meth-amphetamine administration reduces the number of DA uptake sites (Ricaurte, Schuster, & Seiden, 1980; Ricaurte, Seiden, & Schuster, 1984). Second, DA and tyrosine-betahydroxylase levels are reduced for extended periods following chronic amphetamine administration (Ricaurte et al., 1980, 1984). Third, there is evidence of neuronal https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 8/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness degeneration, chromatolysis, and decreased catecholamine histofluorescence (Duarte-Escalante & Ellinwood, 1970). As with cocaine's effects on DA reuptake, cocaine also blocks 5-HT reuptake. Since activation of 5-HT postsynaptic receptors affects neurotrans-mission in neurons that release DA, this blockade prolongs the inhibitory effects of 5-HT on dopaminergic neurotransmission (Taylor & Ho, 1978). However, cocaine also inhibits the firing rates of dorsal raphe 5-HT neurons (Cunningham & Lakoski, 1988, 1990). Thus, acutely the net effect of cocaine on 5-HT neurotransmission in the nucleus accumbens will depend on the relative contributions of uptake inhibition, which would increase synaptic 5-HT, and inhibition of neuronal firing, which would decrease synaptic 5-HT. Broderick (1991) reported that acute, subcutaneous injections of cocaine resulted in a dose-dependent increase in DA levels, as measured by dialysis of the nucleus accumbens. This suggests a decrease in 5-HT levels that may result from activation of somatodendritic 5- HT autoreceptors located in the dorsal raphe nucleus. Acute cocaine administration has indeed been reported to almost completely inhibit the basal firing rate of dorsal raphe serotonergic neurons. As with the effects of chronic amphetamine administration on the functioning of DA systems, chronic methamphetamine administration has been shown to induce pronounced long-term changes in tryptophan hydroxylase activity, as well as in 5-HT content and number of uptake sites (Ricaurte et al., 1980). The effects of chronic cocaine on serotonergic functioning are less well established. For example, Ho and colleagues (1977) found decreased levels of 5-HT following chronic cocaine administration. Seiden and Kleven (1988). however, failed to find any effects of chronic cocaine on the biosyn-thesis of serotonin. Some of these discrepancies can be reconciled by the fact that different chronic dosing regimens produce different changes in 5-HT systems. For example, Cunningham and colleagues found that daily injections of cocaine resulted in an increased sensitivity of dorsal raphe somadendritic 5-HT autoreceptors to cocaine's inhibitory effects as measured by electrophysiological techniques (Cunningham & Lakoski, 1988, 1990). These results are consistent with the behavioral data of King and colleagues (1993a), who found that daily cocaine injections produced an enhanced inhibitory effect of NAN-190 on cocaine-induced locomotion and an enhanced excitatory effect of 8-OHDPAT on locomotion. In contrast with these results, the continuous infusion of cocaine via an osmotic minipump results in a decreased sensitivity of dorsal raphe somadendritic 5HT autoreceptors and a decreased excitatory effect of 8-OHDPAT on locomotion (King, Joyner, & Ellinwood, 1993b; King et al., 1993a). Interestingly, the depletion of 5-HT or reduction of 5-HT neurotransmission is associated with impulsive behavior. For example, Linnoila et al. (1983) found that violent offenders with a diagnosis of personality disorder associated with impulsivity had lower levels of 5-hydroxyindoleacetic acid (5-HIAA, the metabolite of 5-HT) than other offenders. After extensively reviewing the literature, Brown and Linnoila (1990) concluded that low levels of CSF 5-HIAA are related to disinhibition of aggressive/impulsive behavior and not to antisocial acts in and of themselves. The transition to Page 387 high-dose cocaine use might be considered impulsive behavior because the individual is focusing on the immediate, short-term advantages of drug consumption while ignoring the long-term advantages of drug abstinence. Hence, the 5-HT receptor supersensitivity, and resulting inhibition of 5-HT neurotransmission, may be a contributing factor to the development of the high-dose, bingelike pattern of cocaine abuse. OPIATES The opiates are derived from the poppy plant and have been used for centuries. A number of types of endogenous opiate receptors have been identified and their locations mapped. There are high concentrations of opiate receptors in the caudate nucleus, nucleus accumbens, periventricular gray https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 9/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness region, and the nucleus arcuatus of medobasal hypothalamus (Pert, Kuhar, & Snyder, 1975, 1976). These areas may be differently involved in the reinforcing, aversive, and dependence-producing effects of the opiates. Furthermore, different receptor subtypes may mediate the different effects of the opiates. The opiates produce analgesia, changes in mood (e.g., euphoria and tranquility), drowsiness, respiratory depression, and nausea (Jaffe & Martin, 1990). These drugs also reduce motivated behavior; there is a decrease in appetite, sexual drive, and aggression. Intravenous administration of opioids results in initial effects of flushing of the skin and sensations in the abdominal regions that have been likened to a sexual orgasm (Jaffe, 1990). With continuous use of opioids, marked tolerance develops to some, but not all, of the effects of these drugs. Tolerance to opioids is generally characterized by a shorter duration of effect and attenuated analgesia, euphoria, and other CNS-depressant effects; however, there is less tolerance to the lethal effects of opiates. Therefore, if an individual administers ever larger doses to obtain the same effect (e.g., the rush or high), this may increase the probability of a lethal overdose (Jaffe, 1990). Although the course and severity of withdrawal symptoms following opiate abstinence depend on which opiate was used, the dose and pattern of consumption, the duration of use, and the inter-dose interval, the opiate withdrawal syndrome follows the same general progression. Approximately 8 to 12 hours after the last dose, individuals experience yawning, lacrimation, and rhinorrhea; 12 to 14 hours after the final dose, they may fall into a fitful, restless sleep and awaken feeling worse than when they went to sleep. With the continuation of opiate withdrawal, they experience increasing dysphoria, anorexia, gooseflesh, irritability, agitation, and tremors. At the peak intensity of the withdrawal symptoms, they may experience exacerbated irritability, insomnia, intense anorexia, weakness, and profound depression. Common symptoms include alternating coldness and intense skin flushing and sweating, vomiting and diarrhea (Jaffe, 1990). This pattern of symptoms indicates that during the initial withdrawal phase there is a generalized CNS hyperexcitability. Thus, the addicted opiate abuser continues to recycle opiate use to both avoid or terminate the wtihdrawal symptoms, and to reexperience the euphoric effects. This powerful combination of euphoria, tolerance, and withdrawal can lead to profound levels of addiction. Studies have found that rats and monkeys will self-administer opioids, thus indicating that these drugs serve as reinforcers (Koob & Bloom, 1988). Chronic opioid administration results in physical dependence, as demonstrated by the presence of a withdrawal syndrome following drug cessation. Most clinicians hold the classic position that physical dependence (i.e., avoidance of withdrawal symptoms) is a major motivating factor in opiate self-administration, but evidence indicates that reinforcement and withdrawal are separate processes. Bozarth and Wise (1984) demonstrated that rats will self-administer morphine into the ventral teg-mental area without the presence or development of any apparent withdrawal symptoms. Chronic administration of morphine into the periaqueductal gray area, however, produces signs of a strong withdrawal syndrome. Several lines of evidence indicate that dopaminergic neurotransmission may partially mediate the reinforcing effects of opiate administration. First, injection of met-enkephalin into the ventral tegmental area results in increases in DA release in the nucleus accumbens (Di Chiara & Imperato, 1988). Second, although opiates generally produce sedation, low doses of systemic morphine increase locomotor activity (Domino, Vasko, & Wilson, 1976). Third, injections of morphine into the ventral tegmental area Page 388 produce circling behavior (Holmes, Bozarth, & Wise, 1983); injections of opiates into the ventral tegmental area produce increased locomotion, as with systemic injections of opiates, thereby suggesting increased dopaminergic transmission (Blaesig & Herz, 1980). Fourth, selective lesions of the dopaminergic system decrease opiate self-administration, although not to the extent of affecting cocaine https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 10/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness self-administration (Bozarth & Wise, 1985). Fifth, rats learn to self-administer opiates directly into the ventral tegmental area (Bozarth & Wise, 1984), rats also inject opiates into the nucleus accumbens and the lateral hypothalamus (Goeders, Lane, & Smith, 1984). Sixth, administration of the D1 antagonist SCH 23390, but not the D2 antagonists sulpiride and spiperone, block the reinforcing effects of morphine. Ettenberg and associates (1982) found no effect of alpha flupenthixol, primarily a D2 antagonist, on heroin self-administration, although the same doses decreased cocaine self-administration. Similar results have been reported by others using other dopaminergic antagonists (DeWit & Wise, 1977). Thus, both place preference and self-administration procedures indicate that opiates are not reinforcing through D2 receptors, which are vital to stimulant reinforcement. These results indicate that opiate reinforcement is at least partially independent of the D2 stimulant type of reinforcement, yet they do act through a dopaminergic mechanism to induce a significant part of their effects. Chronic administration of opiates produces several behavioral and neurochemical effects that may be related to their reinforcing effects. First, chronic administration of morphine results in the augmentation of the behavioral effects of low doses of morphine. In other words, subjects undergoing chronic opiate administration become sensitized to the behavioral effects of morphine (Ahtee, 1973, 1974). Second, chronic morphine administration results in decreased DA turnover in the striatum and limbic system during withdrawal (Ahtee & Attila, 1980, 1987). Third, in mice withdrawn from morphine, the synthesis and release of DA are attenuated (Ahtee et al., 1987); similar results have been obtained with human heroin addicts in which CSF homovanillic acid concentrations were decreased (Bowers, Kleber, & Davis, 1971). These results indicate that during chronic morphine administration there is a down-regulation of the dopaminergic system and a neuroadaptation to this depletion. During withdrawal from opiate administration there is an augmentation of dopaminergic mechanisms. Indeed, during withdrawal rats are sensitized to the behavioral effects of apo-morphine (Ahtee & Atilla, 1987), and small doses of morphine increase striatal homovanillic acid levels more in withdrawn than in control rats, thereby indicating that the dopaminergic system is sensitized at this point (Ahtee, 1973, 1974). Thus, some of the withdrawal symptoms (e.g., irritability and dysphoria) may be mediated by changes in dopaminergic functioning. Acute administration of opiates increases the synthesis of 5-HT and the formation of 5-HIAA, and these effects are eliminated by the administration of opiate antagonists (Ahtee & Carlsson, 1979), thus suggesting that opiate administration results in increased serotonergic functioning. Indeed, acute administration of dynorphin-(1–13), while it decreases striatal dopamine, actually increases striatal serotonin (Broderick, 1987). This increased serotonergic functioning may contribute to the “post- consummatory calm” produced by opiate drugs: Increasing serotonergic functioning would tend to inhibit incentive-motivated behaviors and produce a calm, tranquil state. Indeed, the atypical anxiolytic drug buspirone exerts its anxiety-reducing effects via serotonergic activation. During withdrawal from chronic opioid administration, 5-HIAA levels are decreased (Ahtee, 1980; Ahtee et al., 1987). This pattern of serotonin results could well cause increased impulsivity and a higher probability of relapse, similar to that described earlier in relation to the psychomotor stimulants. In summary, like cocaine, the opiates are consumed because of their reinforcing properties. These reinforcing properties are the result of activation of endogenous opiate receptors; furthermore, activation of the dopaminergic system modulates the reinforcing effects of opiates. During chronic opiate administration, subjects become physically dependent. There is an increase in dynorphin levels that may mediate some of the aversive aspects of the withdrawal syndrome (e.g., decreased dopaminergic functioning). Furthermore, during chronic administration, there is functional down-regulation of both the dopaminergic and serotonergic systems. Upon withdrawal from opiates, there is a subsequent supersensitivity of the dopaminergic system. This https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 11/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness Page 389 dopaminergic supersensitivity may be involved in opiate craving and general irritability during withdrawal. 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Brain Research Bulletin, 19, 35–38. Trulson, M. E., et al. (1986). Chronic cocaine administration depletes tyrosine hydroxylase immunoreactivity in the rat brain nigral striatal system: Quantitative light microscopic studies. Experimental Neurology, 94,744–756. Volkow, N. D., et al. (1990). Effects of chronic cocaine abuse on postsynaptic dopamine receptors. American Journal of Psychiatry, 147, 719–724. Yi, S-J., & Johnson, K. M. (1990). Chronic cocaine treatment impairs the regulation of synaptosomal 3H- DA release by D2 autoreceptors. Pharmacology, Biochemistry and Behavior, 36, 457–461. Zahniser, N. R., et al. (1988a). Repeated cocaine administration results in supersensitive nigrostriatral D- 2 dopamine autoreceptors. In P. M. Beart, G. Woodruff, & D. M. Jackson (Eds.), Pharmacology and Functional Regulation of Dopaminergic Neurons. London: Macmillan. Zahniser, N. R., et al. (1988b). Sensitization to cocaine in the nigrostriatal dopamine system. In D. Clouet, K. Asghar, and R. Brown (Eds.), National Institute on Drug Abuse Research Monograph. Washington, DC: U.S. Government Printing Office. Zhang, H., Lee, T. H., & Ellinwood, E. H. Jr. (1992). The progressive changes of neuronal activities of the nigral dopaminergic neuron upon withdrawal from continuous infusion of cocaine. Brain Research, 594, 315–318. EVERETT H. ELLINWOOD G. R. KING GENDER A consistent finding throughout many epidemiologic investigations in the United States and worldwide is that men are more likely to initiate, use heavily, and become dependent on alcohol and most forms of illicit drugs. Because of the pervasive way in which gender roles affect most aspects of people's lives, it remains a complex task to understand gender differences in patterns of drug and alcohol abuse. This section reviews the evidence for the following factors: 1) a biological basis for sex differences; 2) a social and psychological basis for gender differences; and 3) the narrowing of gender differences over time. BIOLOGICAL BASIS FOR SEX DIFFERENCES With regard to alcohol consumption and related problems, epidemiologic data within and across time and culture indicate that women drink less alcohol than men and have a lower overall prevalence of alcohol abuse and dependence than men. Two theories regarding the biologic basis for sex differences are https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 16/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness genetic vulnerability and alcohol sensitivity. While early twin and adoption studies suggested greater genetic contribution to alcoholism among men, larger, population based twin samples show no sex difference in heritability. Thus it is commonly accepted that differences in genetic vulnerability do not explain the sex gap in alcohol use disorders. Other biological factors include male-female differences in alcohol metabolism and greater sensitivity to adverse health effects due to heavy drinking among women. Sex differences in the ratio of water to total body weight also cause differential metabolism of alcohol and drugs. This and other biological factors may cause women to have higher blood-alcohol concentrations (BACs) than men at equal dosages. This causes women to feel the ill effects of alcohol after a lower level of Page 392 consumption, possibly guarding against heavy alcohol consumption that can lead to symptoms of alcohol abuse and dependence. Similarly, epidemiologic data indicate that men are more likely to be current illicit drug users, and have higher rates of drug abuse and dependence across specific substance. Some data on adolescents show limited gender differences in the rate of drug initiation, with adolescent females more likely to report nonmedical use of prescription drugs such as amphetamines. This pattern could be indicative of decreasing gender differences in drug and alcohol use seen within younger age groups, and the use of amphetamines for weight control that may be desirable for more young women than men. Clinical studies have indicated that women differ from men in the biological response to drug administration. Animal studies show that female rats have a higher behavioral response to cocaine administration compared to male rats but that the difference diminished following ovariectomy (removal of the ovaries). Human studies indicate that women report more anxiety after cocaine administration but less euphoria and dysphoria. Drugs that are deposited in body fat, such as marijuana, may be slower to clear in women than in men because of the higher proportion of body weight that is fat in women. The path from first use to dependence also differs between men and women, although there is evidence that gender differences in these paths also decrease over time. Women who use alcohol and drugs often start using later than men, have a faster progression from first use to dependence, and enter treatment sooner than men given equal ages of dependence onset, although no such differences have been observed for crack-cocaine users. This phenomenon has been termed telescoping, although some evidence indicates that gender differences in the course of alcohol and drug abuse decrease over time. Further, despite drinking less alcohol than men and having a lower overall prevalence of alcohol abuse and dependence than men, women who drink have more alcohol-related problems compared to men who drink. SOCIAL AND PSYCHOLOGICAL BASIS FOR GENDER DIFFERENCES Social factors play an important role in the development of substance use disorders across gender, and thus the gender differences in social responses are implicated as the basis for the gender differences seen in substance use disorders. In the early part of the twentieth century, alcohol researchers theorized that women were less likely to use alcohol and drugs because female sex roles were characterized by “conventionality” and the “acceptance of the dominant ‘official’ standards of morality and propriety” (Clark, 1967). Women who abstained from drugs and did not drink heavily were hypothetically following the official standards of morality and propriety for women in the time period, and since men were not bound by the same standards with regard to alcohol use, they were more likely to develop chronic alcohol problems. Evidence supporting this theory shows that more women strongly disapprove of a women getting drunk alone or at a party and further https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 17/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness anticipate that they would be disapproved of for drinking heavily in public, compared to men. Further, both men and women are more likely to rate a woman who drinks while on a date as sexually aggressive compared to a man who drinks while on a date. Limited data on social stigma toward drug use exist, but existing literature shows similar if not stronger patterns of gender-related stigma. Stigma associated with drug and alcohol use across time and within subgroups of the population remains a rich area for future research. Other work using gender roles to explain differences in substance use posit that there are distinctive gender styles in expressing pathology. Specifically, the male style features acting-out or externalizing behaviors (including drug and alcohol use), whereas the female style involves the internalization of distress. These distinctions are sometimes labeled “distraction” versus “rumination” (respectively), and have been extensively studied as mechanisms for an abnormal psychological response to stress (Nolen- Hoeksema & Harrell, 2002; Nolen-Hoeksema Larson & Grayson, 1999). However, comorbidity between depression and alcohol use disorders is often greater in women than men, above that which would be expected due to differing base rates of the disorders; additionally, evidence suggests no difference in affective disorder comorbidity between male and female cocaine-dependent patients but females are twice as likely to express an anxiety disorder. Taken together, these data suggest that the presence Page 393 of psychopathology may obscure traditional gender differences in response styles. Sociological explanations for gender differences in alcohol and drug use include the hypothesis that stress among women due to the pursuit of both career and family leads to increased alcohol use and misuse. However, since other studies indicate that women with multiple roles are at lower risk for alcohol use disorders, this explanation seems unlikely. An association between the frequency of drinking among women and the number of men in their workplace was interpreted as showing an imitation effect. A study of medical students in the 1980s found that, at the start of medical school, female students had fewer alcohol-related problems than men, but by the start of clinical training, the gender difference had disappeared. Perhaps imitation as well as increased socialization to traditionally male medical roles decreased constraints against drinking shown by the women at the beginning of medical school. DECREASING GENDER GAP IN SUBSTANCE USE DISORDERS A wealth of epidemiologic data indicated that the gender gap in the initiation and use of alcohol and drugs was closing between 1998 and 2008 among adolescents and adults, providing support for the validity of sociological theories of the gender difference in alcohol and drug use disorders (as biological differences would not rapidly shift over such a short period). Studies of adolescent substance use have consistently shown a convergence between males and females in the rates of alcohol and drug use initiation in younger birth cohorts, especially those born after World War II, and many studies of adults across culture indicate convergence in the rates of alcohol consumption. Several genetically informative samples have been studied with respect to sex differences in DSM-IV alcohol and drug use disorders over time, unanimously finding support for such a convergence. Similarly, large, representative, cross-sectional studies in the United States support gender convergence in rates of DSM-IV alcohol abuse and dependence. Furthermore, evidence indicates that the traditional telescoping phenomenon whereby women exhibit later onset of drug use and disorders but earlier treatment and shorter course may be diminishing, as women are more closely approximating men in both the onset and course of these disorders. https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 18/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness Many explanations for the gender differences have been proposed, although these theories are difficult to test empirically because they mostly rely on historical analysis. The increases in the proportion of women working outside the home and decreases in the proportion of women having children has been hypothesized to be a cause of the diminishment of many gender-based social norms, possibly including stigma associated with female drinking and drug use. Furthermore, changes in gender-based drinking norms have been documented between 1979 and 1990, indicating that although there was no change in the proportion of respondents who felt that “a man drinking at a bar with friends” was acceptable, there was a significant increase in the proportion that felt “a woman drinking at a bar with friends” was acceptable (Greenfield & Room, 1997). This finding indicates a decrease in the negative perception associated with drinking in women, potentially leading to greater opportunities to experience alcohol problems. Finally, changes in the opportunity to drink and alcohol advertising may have an effect on changing gender differences. For instance, from 2001 to 2002, the proportion of young girls exposed to print advertising of low-alcohol beverages (e.g., wine coolers) increased by 216 percent (Jernigan et al., 2004). These and other time trends in young women's exposure to alcohol advertising may have increased the social acceptability of drinking by women in younger generations. In conclusion, despite a reduction in the gender gap regarding alcohol and drug use disorders, a robust difference remains. Some large scale epidemiologic data indicate that men are approximately three times more likely to have a current alcohol use disorder and a current drug use disorder (Hasin et al., 2007; Substance Abuse and Mental Health Services Administration, 2005). Regardless of a gender difference, however, alcohol and drug use disorders remain relatively common in both men and women compared to other psychiatric disorders, and drastically under-treated across gender as well. As gender norms continue to shift over time, people could see a further attenuation of the gender gap in the prevalence of disorders and/or new gender differences emerging in the onset, course, Page 394 and long-term effects of alcohol and drug use disorders. This area is important for continued monitoring and hypothesis testing to better understand the etiology of alcohol and drug dependence, as well as to develop effective treatment strategies for both men and women. See also Conduct Disorder and Drug Use; Epidemiology of Alcohol Use Disorders; Epidemiology of Drug Abuse; Gender and Complications of Substance Abuse. BIBLIOGRAPHY Alonso, J., Angermeyer, M. C., Bernert, S., Bruffaerts, R., Brugha, T. S., Bryson, H., et al. (2004). Prevalence of mental disorders in Europe: Results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatrica Scandinavica, 420 (Suppl.), 21–27. Blanco, C., Alderson, D., Ogburn, E., Grant, B. 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Archives of General Psychiatry, 52, 219– 229. Wilsnack, R.W., Kristjanson, A. F., Wilsnack, S. C., & Crosby, R. D. (2006). Are U.S. women drinking less (or more)? Historical and aging trends, 1981–2001. Journal of Substance Abuse, 67, 341–348. Wilsnack, R.W., Vogeltanz, N. D., Wilsnack, S. C., & Harris, T. R. (2000). Gender differences in alcohol consumption Page 397 and adverse drinking consequences: Cross-cultural patterns. Addiction, 95(2), 251–265. Wilsnack, S. C., & Wilsnack, R. W. (1991). Epidemiology of women's drinking. Journal of Substance Abuse, 3, 133–157. Wilsnack, R. W., Wilsnack, S. C., & Kalssen, A. D. (1996). Antecedents and consequences of drinking and drinking problems in women: Patterns from a U.S. National Survey. Nebraska Symposium on Motivation, 34, 85–158. KATHERINE KEYES DEBORAH HASIN GENETIC FACTORS https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 24/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness Substance dependence is strongly influenced by environmental factors, including the availability of the substance. However, substance dependence is also a familial and genetic disorder. Several lines of evidence demonstrate a substantial genetic component for the risk of substance dependence: 1. Alcohol dependence: Compared to the general population, siblings (brothers or sisters) of alcoholic parents have a 3- to 8-fold increased risk of developing alcohol dependence. 2. Drug dependence (including cocaine, opiates, nicotine, cannabis, hallucinogens, sedatives, and/or stimulants): Significant concordance rates between twin pairs shows a familial basis for different forms of drug dependence; the difference in pair wise concordance rates for monozygotic (MZ; i.e., identical) and dizygotic (DZ; i.e., fraternal) twins was significant for the abuse of marijuana, stimulants, cocaine, and all drugs combined. Because MZ twins share 100 percent of their genes and DZ twins share, on average, only 50 percent of their genes, a fully penetrant (expressed) genetic disorder should be twice as common in identical as in fraternal twins. For example, in one study, for stimulant (e.g., cocaine) abuse, the MZ twin correlation coefficient was 0.53 and for DZ twins it was 0.24. For opioid dependence specifically, the MZ twin correlation coefficient was 0.67 and the DZ correlation coefficient was 0.29 (Kendler & Prescott, 1998). 3. In genetics: Heritability is the proportion of phenotypic variation in a population that is attributable to genetic variation among individuals, reflecting the relative contributions of genetic factors to the total risk for a disorder (e.g., substance dependence). The heritability of substance dependence has been estimated from twin studies to be between 0.37 and 0.60, indicating that between 37 percent and 60 percent of the risk of substance dependence is due to genetic factors. For different types of substance dependence, the heritability has been found to be the following, in decreasing order: alcohol dependence (0.60), smoking persistence in males (0.59), smoking initiation in females (0.55), smoking persistence in females (0.46), smoking initiation in males (0.37), stimulant (including cocaine) abuse (0.44) and opioid dependence (0.43). Findings from family studies show the familial trends in substance dependence, but environmental effects are unaccounted for in these studies. Findings from twin studies have shown a greater weight for the genetic components in these familial trends. Further, findings from adoption studies have decreased estimates of the contribution of environmental components to these familial trends. Together, these three kinds of studies provide evidence that genetic factors constitute a significant cause of substance dependence; in other words, a substantial part of the risk for substance dependence can be attributed to genetic variation. GENE VARIATION AND DETECTION STUDIES Gene variation could alter the density or affinity of proteins. Alteration of the functions of proteins may affect risk for diseases including substance dependence. Substance dependence is a genetically complex disorder that is multigenic, meaning that many genes contribute to risk for this disorder, with the effects of each risk gene being minor. These genes may act independently or may interact with each other or with environmental factors to generate additive or multiplicative effects on risk for substance dependence. To detect risk genes for substance dependence, linkage studies, which detect the gene-disease relationship in families, and association studies, which detect the gene-disease relationship in unrelated cases and controls, are commonly performed. Usually, linkage studies using genome-wide scanning locate one or several chromosomal regions that are 10–20 million nucleotides wide and that may include dozens of genes. Association studies can https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 25/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness Page 398 be used to locate more finely the specific risk variants in those genes. Genome-wide linkage studies have detected multiple risk regions for substance dependence. Risk regions for alcoholism include chromosomes 1, 2, 4, 6, 7, 8, 10, 12, 14, 16, and 17 (in mixed European-American [EA] and African- American [AA] samples). Genome-wide scanning located risk regions for cocaine dependence or cocaine dependence-related traits at chromosomes 10 (in mixed European-American [EA] and African- American [AA] samples); 3 and 12 (in EAs), and 9 and 18 (in AAs); risk regions for opioid dependence at chromosomes 17 (in EAs and AAs) and 2 (in AAs); and eight risk regions for nicotine dependence at chromosomes 2, 4, 9–12, 17, and 18 in EAs, and 9–11 and 13 in AAs. Association studies, which mostly were based on hypothesized effects based on candidate genes (i.e., those involved in processes that have been shown to be important to the development of maintenance of substance dependence), have detected many risk genes for substance dependence (especially alcohol dependence), among which consistent and replicable findings mainly include a dopamine receptor D2 gene (DRD2); kinase-domain- containing gene (ANKK1); alcohol dehydrogenase genes (ADHs); aldehyde dehydrogenase genes (ALDHs); gamma-aminobutyric acid (GABA), type A receptor alpha 2 gene (GABRA2); mu-opioid receptor gene (OPRM1); a cannabinoid receptor gene (CNR1), and a cytochrome P450 gene (CYP2E1). Positive findings have also been obtained for catechol-O-methyltransferase gene (COMT), ð-opioid receptor gene (OPRD1), κ-opioid receptor gene (OPRK1), muscarinic acetylcholine receptor M2 gene (CHRM2) and neuropeptide Y gene (NPY). There are many other genes showing association signals, but these findings are still very preliminary. Researchers are performing genome-wide association studies to search the risk genes for substance dependence, increasing the likelihood that more risk genes will be identified in the near future. By combining the positive predictive values of all risk genes identified to date, the total contribution of genetic factors to risk for substance dependence can be calculated and the risk of substance dependence predicted. Overall, environmental influences account for 42 to 52 percent of the risk for substance dependence, and genetic factors are estimated to contribute 48 to 58 percent of the risk. GENETIC BASIS FOR THE CO-MORBIDITY IN SUBSTANCE DEPENDENCE Different types of substance dependence often co-occur. For example, patients with alcoholism are 35 times more likely to have comorbid cocaine dependence than non-alcoholics, and are 13 times more likely to have comorbid opioid dependence than non-alcoholics (Regier et al., 1990). One possible cause of this high rate of co-morbidity is the synergic actions of different substances, such as alcohol, which enhances the effects of many drugs. For example, cocaine and alcohol are metabolized to coca-ethylene, which has biological properties similar to cocaine but is longer acting. Many cocaine abusers therefore prefer to use cocaine together with alcohol, contributing to the high rate of co-morbidity of alcohol dependence and cocaine dependence. As another specific example, simultaneous systemic administration of both alcohol and nicotine results in an additive dopamine release in the nucleus accumbens (NAcc). This additive effect of alcohol and nicotine on the mesolimbic reward pathway may contribute to the high incidence of smoking in alcoholics. A second possible cause of the high rate of cooccurring substance dependence is a shared mechanism in the development of dependence on various substances. Several types of substance dependence share common features, including symptomatology, neuropsychological impairments, pathogenetic mechanisms, and response to specific treatments (e.g., the effects of disulfiram, an ALDH blocker, which was approved for the treatment of alcohol dependence, has also been shown to be efficacious in the treatment of cocaine dependence). Many studies have also demonstrated that different types of substance dependence may share susceptibility genes; for example, OPRM1 gene variation was found to moderate susceptibility to alcohol dependence and/or drug dependence; in some studies DRD4 gene variation was found to be related to alcohol dependence and/or drug dependence; multiple ADH genes, multiple OPR genes, the CHRM2 gene, and the CNR1 gene were associated with both alcohol dependence and drug dependence; and https://go.gale.com/ps/i.do?p=HWRC&u=j043912&id=GALE%7CCX2699700402&v=2.1&it=r&sid=bookmark-HWRC&asid=8413e809 26/73 12/9/24, 3:18 PM Risk Factors for Substance Use, Abuse, and Dependence - Document - Gale Health and Wellness finally OPRM1 and CHRNA4 have been reported to be associated with both nicotine dependence and alcohol dependence. These common features and shared susceptibility genes suggest that various types of substance dependence have common developmental Page 399 mechanisms. It is possible that the dopamine

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