Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity.

Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses ('cue reactivity') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.

Interactions between bipolar disorder and antisocial personality disorder in trait impulsivity and severity of illness.

OBJECTIVE: We investigated trait impulsivity in bipolar disorder and antisocial personality disorder (ASPD) with respect to severity and course of illness. METHOD: Subjects included 78 controls, 34 ASPD, 61 bipolar disorder without Axis II disorder, and 24 bipolar disorder with ASPD, by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (SCID-I and -II). Data were analyzed using general linear model and probit analysis. RESULTS: Barratt Impulsiveness Scale (BIS-11) scores were higher in ASPD (effect sizes 0.5-0.8) or bipolar disorder (effect size 1.45) than in controls. Subjects with both had more suicide attempts and previous episodes than bipolar disorder alone, and more substance-use disorders and suicide attempts than ASPD alone. BIS-11 scores were not related to severity of crimes. CONCLUSION: Impulsivity was higher in bipolar disorder with or without ASPD than in ASPD alone, and higher in ASPD than in controls. Adverse effects of bipolar disorder in ASPD, but not of ASPD in bipolar disorder, were accounted for by increased impulsivity.

Evaluation of heterogeneity in pharmacotherapy trials for drug dependence: a Bayesian approach.

AIMS: Difficulty identifying effective pharmacotherapies for cocaine dependence has led to suggestions that subgroup differences may account for some of the heterogeneity in treatment response. Well-attested methodological difficulties associated with these analyses recommend the use of Bayesian statistical reasoning for evaluation of salient interaction effects. METHODS: A secondary data analysis of a previously published, double-blind, randomized controlled trial examines the interaction of decision-making, as measured by the Iowa Gambling Task, and citalopram in increasing longest sustained abstinence from cocaine use. RESULTS: Bayesian analysis indicated that there was a 99% chance that improved decision-making enhances response to citalopram. Given the strong positive nature of this finding, a formal, quantitative Bayesian approach to evaluate the result from the perspective of a skeptic was applied. CONCLUSIONS: Bayesian statistical reasoning provides a formal means of weighing evidence for the presence of an interaction in scenarios where conventional, Frequentist analyses may be less informative. [Supplementary materials are available for this article. Go to the publisher's online edition of The American Journal of Drug and Alcohol Abuse for the following free supplemental resource: Appendix 1].

Effects of delays on human performance on a temporal discrimination procedure: evidence of a choose-short effect.

Studies of temporal discrimination in non-human subjects have reliably shown a choose-short effect: higher matching accuracy on short-duration-sample trials than on long-duration-sample trials. This effect occurs as a function of increasing the delay between the onset of sample and comparison stimuli in a delayed matching-to-sample procedure. The present experiment investigated whether the choose-short effect could be demonstrated in human subjects under conditions which paralleled those used with non-human subjects. Subjects responded under a discrete-trial procedure in which they were required to push one of two buttons depending on the duration of a sample stimulus (a blue square on a computer monitor). Delays (0, 8, 16, and 32s) separated sample and comparison stimuli (two white boxes) and were tested both within and across several sessions. Intermediate durations (probe stimuli between 2 and 4s) were also presented. The addition of a delay between the sample and comparison stimuli produced a bias to judge intervals as short when the 8 and 32-s delays were tested across sessions and when the 0, 16, and 32-s delays were tested within the same session. Thus, the choose-short effect was produced in human subjects using the interval bisection procedure regardless of delay length.

Acute effects of lorazepam on laboratory measures of aggressive and escape responses of adult male parolees.

Acute benzodiazepine administrations typically decrease aggressive responding, but increases in aggression have been reported in some studies. The benzodiazepine lorazepam has been studied less frequently than other benzodiazepines in aggression research, although it is often used to suppress violent aggression in patients. The present study was designed to investigate the effects of acute administrations of lorazepam on aggressive responding in adult humans on a laboratory aggression task. Eight adult males participated in experimental sessions on the Point Subtraction Aggression Paradigm (PSAP), which provided subjects with aggressive, escape and monetary-reinforced response options. Acute oral doses (1, 2 and 4 mg) of lorazepam decreased both aggressive responding and monetary-reinforced responding in seven of eight subjects. In one subject, lorazepam produced dose-dependent increases in aggressive responding. The effects of lorazepam on escape responding were the same as the effects on aggressive responding. The results are consistent with prior research using the PSAP and clinical data showing that benzodiazepines generally decrease aggression, and contrast with other studies that have shown that benzodiazepines can increase aggression. Since lorazepam affected both aggressive and escape responding, it is suggested that while lorazepam often produces sedation, it also modifies human aggressive responding, in part, by suppressing reactions to aversive stimuli.

Acute marijuana effects on response-reinforcer relations under multiple variable-interval schedules.

Acute marijuana administration may alter response-reinforcer relationships via a change in reinforcer efficacy, but may also impair coordination and motor function. One approach to evaluating drug effects on both motor function and reinforcer efficacy involves fitting the matching law equation to data obtained under multiple variable interval (VI) schedules. The present report describes an experiment that examined the effects of acute marijuana on response properties using this approach. Six human subjects responded under a multiple VI schedule for monetary reinforcers after smoking placebo and two active doses of marijuana. The low marijuana dose produced unsystematic changes in responding. As measured by the matching law equation parameters (k and rB), at the high dose five subjects showed a decrease-motor-related properties of response rate and four subjects' responding indicated a decrease in reinforcer efficacy. These data raise the possibility that, at high doses, marijuana administration alters both motor function and reinforcer efficacy.

Acute effects of D-fenfluramine on simultaneous measures of aggressive escape and impulsive responses of adult males with and without a history of conduct disorder.

RATIONALE: The role of serotonin in human aggression was evaluated by administering D-fenfluramine and comparing the effects on laboratory measures of aggression, escape and impulsivity among subjects with and without a history of conduct disorder. METHODS: Ten male subjects with a history of criminal behavior participated in experimental sessions that measured aggressive and impulsive responses. Five subjects had a history of childhood conduct disorder (CD+) and five control subjects did not. Aggression was measured using the Point Subtraction Aggression Paradigm (PSAP), which provides subjects with an aggressive, escape and monetary reinforced response options. Impulsive responses were measured using a paradigm that gives subjects choices between small rewards after short delays versus larger rewards after long delays. RESULTS: Acute doses (0.1, 0.2 and 0.4 mg/kg) of D-fenfluramine produced significant decreases in aggressive responses in CD+ subjects and large decreases in escape responses for CD+ subjects and smaller decreases for control subjects. Impulsive responses were decreased slightly and monetary reinforced responses were not changed in either group. Decreases in aggressive responses were not selective, since escape responses were also decreased, but such effects could not be attributed to a non-specific sedative action because monetary reinforced responses were increased and reaction times were decreased, indicative of central nervous system stimulation. CONCLUSIONS: Release of serotonin by D-fenfluramine is the possible mechanism for reductions in aggressive responses. These results are consistent with a large body of data linking reduced serotonin function and aggressive behavior.

Risk taking by adolescents with maladaptive behavior histories.

"High-risk" adolescents with maladaptive behavior histories and control adolescents (15-17 years of age) participated in a laboratory experiment that measured aspects of risk-taking behavior. High-risk adolescents had behavioral profiles entailing combinations of past substance use disorder, early onset substance use, conduct disorder, criminal history, and dropping out of school. A risk-taking task presented participants with "risky" and nonrisky response options. The risky response option offered a low probability of a large monetary reward or a high probability of a smaller monetary loss and resulted in a net loss of monetary earnings. The nonrisky option protected current earnings. High-risk adolescents chose the risky option more often, had lower overall earnings, and were more likely to persist in making (losing) risky responses following a single gain on the risky option. The data replicate previous findings with high-risk adults.

Racial and ethnic disparities in infant mortality: risk in social context.

This article presents the multifaceted efforts of Syracuse Healthy Start, a federally funded initiative of the Onondaga County Health Department and over 20 partnering agencies to reduce racial and ethnic disparities in infant mortality. The analyses presented in this article demonstrate that many women--Caucasian, African American, and Hispanic--have serious risks for low birth weight and infant death. In many cases, multiple, simultaneous risks complicate a pregnant woman's situation and in other cases the longitudinal cumulative risks impact health across generations. Infant mortality decreased overall, and for both Caucasian and African American infants during the first 3 years of the project.

Fenfluramine effects on impulsivity in a sample of adults with and without history of conduct disorder.

RATIONALE: The role of serotonin in impulsivity was examined by administering the serotonin-releasing drug, d,l-fenfluramine, and measuring effects on impulsive responding of male subjects with and without a history of conduct disorder (CD) under controlled laboratory conditions. METHODS: Five adult male subjects with a history of CD and five matched controls were recruited into a study to determine the acute effects of d,l-fenfluramine on a laboratory measure of impulsive behavior. This laboratory measure, based upon delay of gratification, presented subjects with choices between a small reward after a short delay and a larger reward after a longer delay. Impulsive behavior was indicated by frequent choices for the smaller reward. RESULTS: Acute oral doses of d,l-fenfluramine (0.21, 0.42, and 0.85 mg/kg) produced decreases in the number of impulsive choices in all subjects with a history of CD, but had no effect on the control subjects. CONCLUSIONS: This data suggests that a deficit in serotonin and/or dopamine may play a role in impulsivity in CD subjects, and drugs which act to reduce this biological deficit can reduce impulsiveness.

Analysis of risk taking in adults with a history of high risk behavior.

Antisocial behavior often involves frequent risk-taking, e.g. excessive substance use and criminality, which may lead to destructive consequences. In the present study, adults with a history of high-risk behavior (primarily drug dependence and conduct disorder) and matched controls worked on a novel laboratory task designed to measure risk-taking. The contingencies of the task were such that choosing a 'risky' response option resulted in a net loss of monetary earnings compared to a safer, more conservative response alternative. The risky option offered a low probability of a large monetary reward or a high probability of a smaller monetary loss. The non-risky option protected current earnings. High-risk history subjects chose the risky option more often, had lower overall earnings, and were more likely to persist in making (losing) risky responses following a single gain on the risky option. The data support theories of maladaptive behavior focused on hypersensitivity to reward and insensitivity to aversive events.

Towards a public health approach to bioethics.

In this paper we examine the central commitments of bioethical enquiry and reasoning from a public health perspective. We argue that a core element of American national culture is individualism, which resonates in scholarly and popular debates. Our contention is that the habitus of bioethical debate is in large measure animated by an overriding concern with the individual, and the resulting social practice of the community has been to downplay the importance and legitimacy of group-level health care dilemmas. This paper calls for re-focusing of bioethics by employing a public health perspective, which would include a population focus, evidence-based research topics, and engagement of the ethical dilemmas that arise from decisions concerning prevention. Racial and ethnic health disparities throughout the life span of a population in central New York State are used to illustrate the need for a public health focus in bioethics.

Effects of d,l-fenfluramine on aggressive and impulsive responding in adult males with a history of conduct disorder.

RATIONALE: The role of serotonin in aggression and impulsivity was examined by administering the serotonin-releasing drug, d, l-fenfluramine and measuring effects on aggressive and impulsive responding under controlled laboratory conditions. METHODS: Ten male subjects with a history of conduct disorder and criminal behavior participated in experimental sessions, which measured aggressive and impulsive responses. Aggression was measured using the Point subtraction Aggression paradigm (PSAP), which provides subjects with an aggressive, escape and monetary reinforced response options. Impulsive responses were measured using a paradigm which provided subjects with choices between small rewards after short delays versus larger rewards have long delays. RESULTS: Acute challenge doses (0.2,0.4 and 0.8 mg/kg) of d,l-fenfluramine produced significant dose-dependent decreases in aggressive and impulsive responses. Escape and monetary reinforced responses were not significantly changed. Decreases in aggressive responses were therefore selective, because escape responses were not affected, and could not be attributed to a non-specific sedative action because monetary reinforced responses were slightly increased. CONCLUSIONS: Release of serotonin and/or reuptake blockade by d,l-fenfluramine is the possible mechanism for reductions in aggression and impulsivity. These results are consistent with a large body of data linking reduced serotonin function and aggressive behavior and impulsivity.

Laboratory and psychometric measurements of impulsivity among violent and nonviolent female parolees.

BACKGROUND: Female parolees participated in a study to determine the relationship between behavioral and psychometric measures of impulsivity and their previous criminal history. METHODS: Subjects were assigned to a violent (n = 10) or nonviolent group (n = 20) based upon their criminal history. Subjects were given two response options defined as: 1) an impulsive choice--small monetary reward (5 cents) after a short fixed delay of 5 sec, and 2) a self-control choice--a larger monetary reward (15 cents) after a variable longer delay initially set at 15 sec. The measure of impulsivity in this behavioral choice procedure was the number of trials on which the subject selected the impulsive option. This definition of impulsivity is based upon an extensive experimental literature in nonhumans and humans related to delay of gratification, that is, the ability to tolerate long delays imposed between the initiation of behavior and the presentation of a reinforcer. RESULTS: Our results indicated that the violent female subjects selected the impulsive option significantly more often than the nonviolent female parolees. CONCLUSIONS: The correlation between impulsive and aggressive responses among the female parolees was nonsignificant and negative, in contrast to a significant positive correlation previously reported among male parolees.

Prolactin response to buspirone was reduced in violent compared to nonviolent parolees.

A neuroendocrine challenge procedure was carried out in male and female parolees. The parolees were divided into violent and non-violent groups based upon their criminal history. Buspirone (0.4 mg/kg), a 5-HT1a agonist, was used as the challenge agent and plasma prolactin levels were determined. The violent parolees had a blunted prolactin response compared to the non-violent parolees. While reduced serotonergic activity may account for this difference, the pharmacology of buspirone and control of prolactin release suggest a role for dopamine. A reduced serotonergic response would be consistent with a large body of data linking reduced serotonin function and aggressive behavior. While the mechanism is not definite, these data clearly provide evidence for an altered and blunted biological response in parolees with a history of violence.

Integrating Buddhism and HIV prevention in U.S. southeast Asian communities.

Asian Pacific Islander communities in the United States have experienced an alarming increase in HIV infection over the past few years, possibly due to a lack of knowledge and the relative absence of appropriate educational interventions. The authors propose a new approach to the development of HIV prevention programs in U.S. southeast Asian communities. This article reviews the cultural and economic factors that may facilitate HIV transmission within these communities. Relying on the basic precepts of Buddhism, the dominant religion of many southeast Asian populations in the United States, the health belief model is utilized to demonstrate how recognizable, acceptable religious constructs can be integrated into the content of HIV prevention messages. This integration of religious concepts with HIV prevention messages may increase the likelihood that the message audience will accept the prevention messages as relevant. This nuanced approach to HIV prevention must be validated and refined through field research.

Laboratory measurement of aggression in high school age athletes: provocation in a nonsporting context.

This study investigated the relationship between aggression and type of sports involvement in high school age boys. Athletes (16 boys), ages 15 to 18 years, were separated into two groups, one of 8 athletes who participated in sports with high physical contact, e.g., football and basketball, and the other of 8 athletes who participated in low contact sports, e.g., track and baseball. Students participated in six 25-min. Point Subtraction Aggression Paradigm sessions. The paradigm is an established laboratory model of aggression with three response options: (1) a point-maintained response, (2) an aggressive response, and (3) an escape response. Analysis indicated that the only difference between the groups was that individuals who participated in high contact sports emitted significantly more aggressive responses than individuals who participated in low contact sports. Similarly, psychometric measures of aggression indicated that individuals in the former group self-reported more behavioral incidents of aggression than those in the latter group.

Generalization of cross-modal stimulus equivalence classes: operant processes as components in human category formation.

This study employed a stimulus-class rating procedure to explore whether stimulus equivalence and stimulus generalization can combine to promote the formation of open-ended categories incorporating cross-modal stimuli. A pretest of simple auditory discrimination indicated that subjects (college students) could discriminate among a range of tones used in the main study. Before beginning the main study, 10 subjects learned to use a rating procedure for categorizing sets of stimuli as class consistent or class inconsistent. After completing conditional discrimination training with new stimuli (shapes and tones), the subjects demonstrated the formation of cross-modal equivalence classes. Subsequently, the class-inclusion rating procedure was reinstituted, this time with cross-modal sets of stimuli drawn from the equivalence classes. On some occasions, the tones of the equivalence classes were replaced by novel tones. The probability that these novel sets would be rated as class consistent was generally a function of the auditory distance between the novel tone and the tone that was explicitly included in the equivalence class. These data extend prior work on generalization of equivalence classes, and support the role of operant processes in human category formation.

Formative research for interventions among adolescents at high risk for gonorrhea and other STDs.

The gonorrhea infection rate among 15-19 year olds during 1993-1994 in an urban Upstate New York community was nearly twice the national norm. More than 50% of all the gonorrhea cases were concentrated in eight census tracts. This study was conducted to provide data regarding sexually transmitted diseases among high risk adolescents to increase successful public health interventions. The methodology consisted of six focus groups and a self-administered survey. The results determined the extent of accurate knowledge, their risk behaviors and beliefs, the barriers to treatment, and suggested interventions for clinic services and health education.

Laboratory measurement of adaptive behavior change in humans with a history of substance dependence.

Individuals vary in their ability to adapt to changes in environmental conditions. In the present study, two laboratory experiments investigated components of adaptation in subjects with and without a history of substance dependence. In each of two experiments, the subjects were exposed to conditions that required changing response patterns between experimental days. On day 1, subjects earned monetary rewards under conditions that produced high rate responding, but on day 2 were required to wait 10 s between each response. Collectively, the two experiments demonstrated that the subjects meeting criteria for past substance dependence, and having extensive histories of substance use (> 10 years), adjusted poorly to the transition. In both studies, these subjects tended to persevere on the previously established high-rate response pattern. These data suggest a deficiency in adaptive behavior change, particularly when that change requires an abrupt slowing of response rates following a brief history of high-rate responding.