Family history influence on drug abuse severity and treatment outcome.

Influence of parental alcohol/substance abuse on methadone maintenance therapy (MMT) outcome was examined in 164 DSM-III-R opioid dependent adults with no other current DSM Axis I disorder. Family history positive patients had more DSM-III-R opioid dependence symptoms and were more likely to be classified as severely dependent. However, when placed on identical daily doses of methadone (50 mg), they had lower rates of illicit opioid use but higher rates of cocaine use than family history negative patients. Both effects remained significant after adjusting for gender and race. These results suggest that common genetic factors may underlie both susceptibility to heroin dependence and response to therapeutic methadone treatment.

A twin study on sensation seeking, risk taking behavior and marijuana use.

The contribution of genetic and environmental factors to the covariation between risk-taking and marijuana use was assessed in adolescent twins. Genetic factors were found to significantly influence some traits (i.e. risk-taking attitude), while familial environmental factors were important for others (i.e. sexual promiscuity). For marijuana use, genetic and environmental factors were equally important; however, the association between risk taking and marijuana use may not be comparable for different behaviors. Results suggest that different etiological factors may underlie various risk taking traits which is relevant to both prevention efforts and attempts to identify genes involved in risk taking and shared genetic influences with substance use.

Intravenous cocaine decreases cardiac vagal tone, vagal index (derived in lorenz space), and heart period complexity (approximate entropy) in cocaine abusers.

We assessed the effects of i.v. cocaine on parasympathetic and sympathetic nervous system activity, and on the complexity vs. regularity of changes in heart rate over time. Fourteen otherwise healthy men with histories of i.v. cocaine abuse received bolus injections of cocaine (20 mg or 40 mg) and placebo (saline) on different days. Cardiovascular measures derived from the electrocardiogram, including heart rate, Porges' vagal tone (respiratory sinus arrhythmia), the 0.10 Hz rhythm, Toichi's vagal index, Toichi's sympathetic index, and approximate entropy (ApEn), were measured continuously. As predicted, cocaine produced tachycardia, accompanied by pronounced decreases in response to 40 mg cocaine in two different vagal tone indexes that precisely mirrored the increases in heart rate. The measure of sympathetic (and vagal) neural influences on the heart (0.10 Hz wave) also decreased in response to cocaine. Converging evidence from Toichi's vagal index supported the conclusion that the tachycardia from cocaine was due to withdrawal of cardiac vagal tone. These findings, and evidence that cocaine decreased cardiovascular complexity, contradict the prevailing assumption that the mechanism by which cocaine produces tachycardia is sympathetic (beta-adrenergic). We discuss implications for cardiac arrhythmias associated with cocaine abuse and death due to overdose.

Season of birth and substance abuse: findings from a large national sample.

BACKGROUND: Season of birth is a putative etiological factor for several psychiatric illnesses. An excess of late winter and early spring births has been demonstrated repeatedly for schizophrenia, which has usually been interpreted as the result of prenatal or infant exposure to seasonally mediated "harmful effects," such as infectious diseases. This study determined whether the seasonal birth rates of substance abusers differed from those of unaffected control groups. METHODS: The 1992 National Longitudinal Alcohol Epidemiologic Survey, an interview-based study of 42,862 men and women, provided data to assess the association between quarter year of birth and lifetime diagnoses of substance abuse. RESULTS: Logistic regression revealed decreases in winter births in men with histories of alcohol dependence. The significant interaction of sex with season of birth reflected an excess of fall births among male but not female alcoholics. In contrast, there was no evidence of seasonality of birth among alcohol abusers. Men and women with histories of illicit drug use had excesses of fall birth. DISCUSSION: Birth rates of men with past or present alcohol dependence, and of men and women with histories of illicit drug use, implicated seasonal factors in the pathogenesis of substance abuse. The similar birth patterns of illicit drug users and male alcoholics suggest that they may share some common etiological factor, such as seasonal effects on environmental temperature, hormonal function, or susceptibility to viral infection during pregnancy or early infancy.

Environmental transmission of DSM-IV substance use disdorders in adoptive and step families.

BACKGROUND: One factor contributing to the 3- to 5-fold increase in risk for substance use disorders (SUDs) among children of alcoholics may be the rearing environment. These influences may include availability of substances, modeling of SUDs, inadequate parenting, or other factors. The contribution of parental environmental influences on offspring with SUDs may be estimated independently of genetic influences through assessment of adoptees raised by nonbiological parents. METHODS: Relative risk of SUDs was assessed in adult adoptees (N = 442) of alcoholic and nonalcoholic adoptive parents as well as in stepchildren (N = 1859) with alcoholic or nonalcoholic stepfathers who participated in the community-based National Longitudinal Alcohol Epidemiologic Survey (NLAES). RESULTS: Rearing by an alcoholic adoptive mother was associated with increased DSM-IV alcohol abuse. Rearing by an alcoholic adoptive father was predictive of adoptees' illicit drug use, as well as DSM-IV drug dependence. Rearing by an alcoholic stepfather was predictive of stepchild DSM-IV alcohol abuse, illicit drug use, and drug dependence, whereas an alcoholic stepmother was associated with increased illicit drug use in the stepchild. Alcoholism in adoptive parents or step parents did not increase risk for offspring DSM-IV alcohol dependence. In both adoptive and biological families, there was a subadditive interaction of mother by father alcoholism such that the rate of substance abuse when both parents were alcoholic was less than that expected based on the additive effects of each alcoholic parent. CONCLUSIONS: Rearing by an alcoholic parent had a greater influence on alcohol abuse by offspring than on alcohol dependence. The increased risk of proband illicit drug use and drug dependence associated with paternal alcoholism suggested nonspecificity of environmental transmission. Both maternal and paternal cultural transmission effects influenced offspring SUDs.

Effect of alcohol on vagal regulation of cardiovascular function: contributions of the polyvagal theory to the psychophysiology of alcohol.

Research was conducted to evaluate the influence of acute alcohol consumption on vagal regulation of heart rate. Nine men with histories of polydrug use participated in this residential study. On 5 separate days, they drank liquids consisting of cold water (on 2 days), a moderate dose of alcohol (0.64 g/kg), a high dose of alcohol (1.12 g/kg), and a placebo. Continuous recordings of heart period were quantified to produce 3 measures of heart rate variability, reflecting the amplitude of 3 neurophysiologically mediated rhythms. Heart period, respiratory rhythm (i.e., respiratory sinus arrhythmia [RSA]), and the 0.064-0.10-Hz vasomotor rhythm were significantly lower during the high alcohol dose condition, relative to the placebo and water conditions. Because the neural regulation of the heart by the vagus contributes to these variables, these findings suggest that alcohol reduces cardiac vagal tone. In support of this explanation, alcohol also decreased the coupling between changes in heart period and changes in RSA. This study demonstrated that alcohol produces a dysregulated state in which heart rate is relatively uncoupled from vagal activity.

Chronic tolerance and sensitization to alcohol in sons of alcoholics: II. Replication and reanalysis.

Data from D. B. Newlin and J. B. Thomson (1991) were reanalyzed, and data from an independent replication study were analyzed, relative to tonic (baseline) and phasic (response to alcohol challenge) aspects of drinking alcohol administered at the same dose on several occasions. Among the high-risk men (sons of alcoholic fathers), linear trends across days for resting (predrinking) baselines were opposite to alcohol-evoked changes for finger pulse amplitude, finger temperature, and skin conductance in Study 1 and for pulse transit time and body sway (static ataxia) in Study 2. In contrast, the structure of the low-risk men's (sons of nonalcoholic parents) data was precisely the opposite. Results are discussed in terms of sensitization as a potential mechanism that relates vulnerability to final manifestation of addictive behavior.

Evolutionary game theory and multiple chemical sensitivity.

Newlin's [Newlin D.B. Evolutionary game theory of tolerance and sensitization in substance abuse. Paper presented to the Research Society on Alcoholism, Hilton Head, SC, 1998] evolutionary game theory of addictive behavior specifies how evolutionarily stable strategies for survival and reproduction may lead to addiction. The game theory of multiple chemical sensitivity (MCS) assumes that: (1) the MCS patient responds to low-level toxicants as stressors or as direct threats to their survival and reproductive fitness, (2) this activates the cortico-mesolimbic dopamine system, (3) this system is a survival motivation center--not a 'reward center', (4) the subject emits a counter-response that is in the same direction as the naive response to the chemicals, (5) previously neutral stimuli associated with chemicals also trigger conditioned responses that mimic those to the chemicals, (6) these counter-responses further activate the dopaminergic survival motivation system, and (7) this produces a positive feedback loop that leads to strong neural sensitization in these structures and in behavior controlled by this system, despite a small initial response. Psychologically, the MCS patient with a sensitized cortico-mesolimbic dopamine system is behaving as though his/her survival is directly threatened by these chemicals. Non-MCS subjects have counter-responses opposite in direction to those of the chemicals and show tolerance. An autoshaping/sign-tracking model of this game is discussed. This evolutionary game makes several specific, testable predictions about differences between MCS subjects, non-MCS controls, and substance abusers in laboratory experiments, and between sensitized and nonsensitized animals.

Motivation, sustained attention, and autonomic regulation in school-age boys exposed in utero to opiates and alcohol.

The effects of incentive on sustained attention and autonomic regulation among boys exposed in utero to opiates were studied. Respiratory sinus arrhythmia (RSA), an indicator of autonomic regulation, was quantified during sustained attention in 3 groups of 7- to 12-year-old boys. RSA is a component of heart rate variability controlled by cortical influences and affected by changes in demand for attention. The Gordon Diagnostic System-Distractibility Task was performed with and without monetary reward. A cartoon task and a video game were used as measures of interest. Although opiate-exposed boys did not differ in performance as a function of incentive or interest, they had a tendency to perform more poorly overall across tasks. Alcohol exposure rather than opiate exposure covaried with autonomic regulation, with greater RSA decreases being associated with more alcohol exposure. Post hoc analyses revealed that the alcohol- and opiate-exposed boys responded with these hyperreactive RSA changes along with poorer performance.

A behavior-genetic approach to multiple chemical sensitivity.

This report emphasizes the application of behavior-genetic designs to the study of sensitivity to toxic chemicals, and features of multiple chemical sensitivity and substance abuse that are polar opposites. The implications of these issues for future research are discussed in relation to twin, adoption, and sibling pair studies, as well as in relation to the degree to which genetically selected lines of rodents that have been developed in the alcoholism field are applicable to multiple chemical sensitivity.

Testing the neural sensitization and kindling hypothesis for illness from low levels of environmental chemicals.

Sensitization in the neuroscience and pharmacology literatures is defined as progressive increase in the size of a response over repeated presentations of a stimulus. Types of sensitization include stimulant drug-induced time-dependent sensitization (TDS), an animal model related to substance abuse, and limbic kindling, an animal model for temporal lobe epilepsy. Neural sensitization (primarily nonconvulsive or subconvulsive) to the adverse properties of substances has been hypothesized to underlie the initiation and subsequent elicitation of heightened sensitivity to low levels of environmental chemicals. A corollary of the sensitization model is that individuals with illness from low-level chemicals are among the more sensitizable members of the population. The Working Group on Sensitization and Kindling identified two primary goals for a research approach to this problem: to perform controlled experiments to determine whether or not sensitization to low-level chemical exposures occurs in multiple chemical sensitivity (MCS) patients; and to use animal preparations for kindling and TDS as nonhomologous models for the initiation and elicitation of MCS.

Activation of memory circuits during cue-elicited cocaine craving.

Evidence accumulated over more than 45 years has indicated that environmental stimuli can induce craving for drugs of abuse in individuals who have addictive disorders. However, the brain mechanisms that subserve such craving have not been elucidated. Here a positron emission tomographic study shows increased glucose metabolism in cortical and limbic regions implicated in several forms of memory when human volunteers who abuse cocaine are exposed to drug-related stimuli. Correlations of metabolic increases in the dorsolateral prefrontal cortex, medial temporal lobe (amygdala), and cerebellum with self-reports of craving suggest that a distributed neural network, which integrates emotional and cognitive aspects of memory, links environmental cues with cocaine craving.

Effect of cocaine on vagal tone: a common factors approach.

This paper discusses a distinct cardiovascular pattern that is common to a wide variety of abused substances. The pattern consists of tachycardia that appears mediated by withdrawal of vagal inhibition, as indicated by decreases in cardiac vagal tone. This decrease in vagal tone was particularly robust with i.v. cocaine given to experienced cocaine abusers in a residential research setting. Following 40 mg i.v. cocaine, heart rate increased by approximately 30 beats/min at the same time that vagal tone decreased by approximately 2 log units. The theoretical significance of these findings is based on evidence that the results reflect a common factor among many abused drugs, but not the few aversive drugs that have been studied in this paradigm.

Vagal tone regulation during sustained attention in boys exposed to opiates in utero.

Attention and learning problems among children exposed to opiates in utero have been previously reported but are difficult to interpret due to imprecise measurement and inadequate control of postnatal factors. In this study, we used a behavior-based measure of attention (continuous-performance tasks) and a physiological index of sustained attention (cardiac vagal tone) to measure more precisely the process of sustained attention. Boys, aged 7 to 12, exposed to opiates in utero, were compared to boys whose mothers began using illicit substances after the child's birth (environmental controls), and boys whose mothers were non-drug users. This three-group design was intended to isolate in utero effects from postnatal environmental influences. Vagal tone, a measure of heart-rate variability sensitive to vagal influences on the heart, was measured pre- and postbaseline and during the three tasks of the Gordon Diagnostic System (Delay, Vigilance, and Distractibility). Vagal tone has been found to be sensitive to changes in environmental demand for sustained attention in infants, school-age children, and adults. Results indicated that when distractors were added to the vigilance task (Distractibility task), opiate-exposed boys failed to suppress vagal tone compared to both control groups. However, both the opiate-exposed boys and the environmental controls made fewer correct responses than non-drug-exposed controls on this task. These results indicate that normal physiological responses to increased attentional demand may be impaired in boys exposed in utero to opiates in this age range. However, the poor Distractibility scores of both the opiate-exposed and environmental controls suggests an important role of environmental influences on attentional performance.

Drug sensitization, substance abuse, and chemical sensitivity.

Substance abuse, involving drugs such as cocaine, heroin, alcohol, marijuana, nicotine, barbiturates, etc., is by far by the most prevalent psychiatric disorder. Much has been learned about the abuse of these substances that may be useful to consider in designing and analyzing research concerning multiple chemical sensitivities (MCS). We review the central role of sensitization in this literature, including its definition, measurement, and expression in animals and human volunteers. Common factors among abused drugs, including sensitization, are discussed. Finally, empirical studies are delineated or proposed to test some of the notions presented in this paper.

Cardiovascular responses to naloxone challenge in opiate-dependent individuals.

Vagally mediated tachycardia appears to be a common response to abused drugs and, therefore, has implications for abuse liability. To test the specificity of this common factor, we determined whether the tachycardia to naloxone in opiate-dependent individuals has a significant vagal component. Naloxone challenge (0.4 mg, IM) in 19 opiate-dependent men and women was associated with highly reliable tachycardia, but no significant change in vagal tone index, a noninvasive measure of parasympathetic inhibitory control of the heart. We conclude that tachycardia during naloxone-precipitated withdrawal is not vagally mediated. Thus, there is some degree of specificity to the common factor of vagally mediated tachycardia to abused drugs because it was ruled out in at least one drug (naloxone) with aversive subjective effects.

Genetic vulnerability to drug abuse. The D2 dopamine receptor Taq I B1 restriction fragment length polymorphism appears more frequently in polysubstance abusers.

Alcoholics are more likely than nonalcoholics to display the Taq I A1 restriction fragment length polymorphism of the D2 dopamine receptor gene, according to four of six studies that examined alcoholics and controls. The current study examines whether the association observed in alcoholism might extend to other addictive substances by examining D2 dopamine receptor Taq I A and B restriction fragment length polymorphisms in polysubstance users and controls free of significant substance use. We hypothesized a stronger association for the B1 restriction fragment length polymorphism since it lies closer to dopamine receptor protein coding and 5' regulatory regions. Heavy polysubstance users and subjects with DSM-III-R psychoactive substance use diagnoses displayed significantly higher Taq I B1 frequencies than control subjects; Taq I A1 results for these comparisons were less robust. These results are consistent with a role for a D2 dopamine receptor gene variant marked by these restriction fragment length polymorphisms in enhanced substance abuse vulnerability.

A comparison of drug conditioning and craving for alcohol and cocaine.

Craving is a potentially important concept that is difficult to define and study in the laboratory. Although alcohol and cocaine are very different pharmacologically, this discussion emphasizes common factors in addiction to these drugs, such as the tendency of alcoholics and cocaine abusers to crave these substances. I review commonalities in drug conditioning and cue reactivity to alcohol and cocaine. Both drugs support Pavlovian conditioning when they are presented as unconditioned stimuli, whether studied in rodents or humans. In addition, both drugs are craved when abusers are presented with stimuli associated with these drugs. Finally, I propose a theoretical definition of craving based on autoshaping and sign-tracking phenomena that suggests a common mechanism of addiction to these drugs. This model defines craving as a reflection of sign tracking to internal and external stimuli that have in the past reliably predicted presentation of these drugs.