Cocaine-associated biomedical and psychosocial problems are substantial twenty-first century global burdens of disease. This burden is largely driven by a cocaine dependence process that becomes engaged with increasing occasions of cocaine product use. For this reason, the development of a risk-prediction model for cocaine dependence may be of special value. Ultimately, success in building such a risk-prediction model may help promote personalized cocaine dependence prediction, prevention, and treatment approaches not presently available. As an initial step toward this goal, we conducted a genome-environmental risk-prediction study for cocaine dependence, simultaneously considering 948,658 single nucleotide polymorphisms (SNPs), six potentially cocaine-related facets of environment, and three personal characteristics. In this study, a novel statistical approach was applied to 1045 case-control samples from the Family Study of Cocaine Dependence. The results identify 330 low- to medium-effect size SNPs (i.e., those with a single-locus p-value of less than 10−4) that made a substantial contribution to cocaine dependence risk prediction (AUC = 0.718). Inclusion of six facets of environment and three personal characteristics yielded greater accuracy (AUC = 0.809). Of special importance was the joint effect of childhood abuse (CA) among trauma experiences and the GBE1 gene in cocaine dependence risk prediction. Genome-environmental risk-prediction models may become more promising in future risk-prediction research, once a more substantial array of environmental facets are taken into account, sometimes with model improvement when gene-by-environment product terms are included as part of these risk predication models.
cocaine dependence; genome-environmental risk prediction; childhood abuse; GBE1 gene; tree-assembling ROC
Children prenatally exposed to cocaine may be at elevated risk for adjustment problems in early development because of greater reactivity and reduced regulation during challenging tasks. Few studies have examined whether cocaine-exposed children show such difficulties during the preschool years, a period marked by increased social and cognitive demands and by rapid changes in reactivity and regulation. The authors addressed this question by examining frustration reactivity and regulation of behavior during a problem-solving task in cocaine-exposed and -unexposed preschoolers. Participants were 174 4.5-year-olds (M age = 4.55 years, SD = 0.09). Frustration reactivity was measured as latency to show frustration and number of disruptive behaviors, whereas regulation was measured as latency to approach and attempt the problem-solving task and number of problem-solving behaviors. Results indicated that cocaine-exposed children took longer to attempt the problem-solving task but that cocaine-exposed boys showed the most difficulties: They were quicker to express frustration and were more disruptive. Effect sizes were relatively small, suggesting both resilience and vulnerabilities.
reactivity; regulation; prenatal cocaine exposure
Compromised ability to exert control over drug urges and drug-seeking behaviour is a characteristic of addiction. One specific cognitive control function, impulse control, has been shown to be a risk factor for the development of substance problems and has been linked in animal models to increased drug administration and relapse. We present evidence of a direct effect of cocaine on the neurobiology underlying impulse control. In a laboratory test of motor response inhibition, an intravenous cocaine administration improved task performance in 13 cocaine users. This improvement was accompanied by increased activation in right dorsolateral and inferior frontal cortex, regions considered critical for this cognitive function. Similarly, for both inhibitory control and action monitoring processes, cocaine normalized activation levels in lateral and medial prefrontal regions previously reported to be hypoactive in users relative to drug-naive controls. The acute amelioration of neurocognitive dysfunction may reflect a chronic dysregulation of those brain regions and the cognitive processes they subserve. Furthermore, the effects of cocaine on midline function suggest a dopaminergically mediated intersection between cocaine's acute reinforcing effects and its effects on cognitive control.
cocaine; impulsivity; functional magnetic resonance imaging; addiction
Children prenatally exposed to cocaine may be at increased risk for behavioral problems due to disruptions of monaminergically regulated arousal systems and/or environmental conditions.
To assess behavioral outcomes of cocaine (CE) and non-cocaine exposed (NCE) children, 4 through 10 years old, controlling for other prenatal drug exposures and environmental factors.
Low socioeconomic status (SES), primarily African-American children (n = 381 (193 (CE), 188 (NCE)) were recruited from birth. Generalized Estimating Equation (GEE) analyses were used to assess the predictive relationship of prenatal cocaine exposure to odds of caregiver reported clinically elevated behavioral problems at 4, 6, 9 and 10 years of age, controlling for confounders.
Prenatal cocaine exposure was associated with increased rates of caregiver reported delinquency (OR=1.93, CI: 1.09-3.42, p<.02). A significant prenatal cocaine exposure by sex interaction was found for delinquency indicating that only females were affected (OR=3.57, CI: 1.67-7.60, p<.001). There was no effect of cocaine on increased odds of other CBCL subscales. Higher prenatal tobacco exposure was associated with increased odds of externalizing symptoms at 4, 9 and 10 years of age. For CE children, those in foster or adoptive care were rated as having more behavior problems than those in biologic mother or relative care. Greater caregiver psychological distress was associated with increased behavioral problems. There were no independent effects of elevated blood lead level on increased behavior problems after control for prenatal drug exposure and other environmental conditions.
Prenatal cocaine and tobacco exposure were associated with greater externalizing behavior after control for multiple prenatal drug exposures, other environmental and caregiving factors and lead exposure from 4 through 10 years of age. Greater caregiver psychological distress negatively affected caregiver ratings of all CBCL domains. Since cocaine and tobacco use during pregnancy and maternal psychological distress have the potential to be altered through prenatal educational, drug treatment and and mental health interventions, they warrant attention in efforts to reduce rates of problem behaviors in children.
behavior; delinquency; prenatal cocaine-exposure; lead exposure; longitudinal
Researchers have identified the association between the use of cocaine and sexual behavior as an important risk factor for HIV infection and have attempted to elucidate the nature of this association. Several lines of research have suggested that facilitation of sexual behavior during intoxication with cocaine may be due to the direct pharmacological effects of the drug (e.g., increase in sexual desire), whereas others have pointed to the importance of factors related to the context of drug use (e.g., opportunities for sexual behavior, expectations about the effects of the drug, social norms). The present study explored the perceived effects of cocaine and heroin on sexual behavior, as well as the social context of drug use as a function of drug type (cocaine versus heroin), among 46 inner-city drug users who reported a history of regular use of both crack cocaine and heroin. Results indicated that compared to heroin, cocaine had deleterious effects on participants’ perceived sexual desire and performance. Despite such deleterious effects on sexual behavior, cocaine was more frequently used with an intimate partner than heroin. Furthermore, participants did not differ in the extent to which they used the two drugs in other social contexts (e.g. with friends, family or neighbors). These preliminary results suggest that the relationship between cocaine and sexual behavior, especially among long-term cocaine users, may be facilitated by opportunities for sex that exist in the context of cocaine use, rather than by the pharmacological effects of the drug.
sexual behavior; cocaine; social context
Little is known about the possible role that smoking crack cocaine has on the incidence of HIV infection. Given the increasing use of crack cocaine, we sought to examine whether use of this illicit drug has become a risk factor for HIV infection.
We included data from people participating in the Vancouver Injection Drug Users Study who reported injecting illicit drugs at least once in the month before enrolment, lived in the greater Vancouver area, were HIV-negative at enrolment and completed at least 1 follow-up study visit. To determine whether the risk of HIV seroconversion among daily smokers of crack cocaine changed over time, we used Cox proportional hazards regression and divided the study into 3 periods: May 1, 1996–Nov. 30, 1999 (period 1), Dec. 1, 1999–Nov. 30, 2002 (period 2), and Dec. 1, 2002–Dec. 30, 2005 (period 3).
Overall, 1048 eligible injection drug users were included in our study. Of these, 137 acquired HIV infection during follow-up. The mean proportion of participants who reported daily smoking of crack cocaine increased from 11.6% in period 1 to 39.7% in period 3. After adjusting for potential confounders, we found that the risk of HIV seroconversion among participants who were daily smokers of crack cocaine increased over time (period 1: hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.57–1.85; period 2: HR 1.68, 95% CI 1.01–2.80; and period 3: HR 2.74, 95% CI 1.06–7.11).
Smoking of crack cocaine was found to be an independent risk factor for HIV seroconversion among people who were injection drug users. This finding points to the urgent need for evidence-based public health initiatives targeted at people who smoke crack cocaine.
Drug addiction is a serious public health problem. There is increasing evidence on the involvement of augmented glutamatergic transmission in cocaine-induced addiction and neurotoxicity. We investigated effects of acute or chronic cocaine administration and cocaine challenge following chronic cocaine exposure on the release of excitotoxic glutamate and neuroprotective taurine in the rat striatum by microdialysis. Cocaine challenge, following withdrawal after repeated cocaine exposure markedly increased the release of glutamate, which may cause neurotoxicity. Simultaneously, cocaine challenge after withdrawal also significantly increased the release of taurine, which counteracts glutamate-mediated excitotoxicity and possibly cell death. Thus, the mammalian brain has an endogenous self-protective mechanism against cocaine-mediated neurotoxicity and potentially addiction.
Cocaine; glutamate; taurine; neuroprotection
Methamphetamine use has become a major problem among communities of men having sex with men (MSM), where it has been associated with high-risk behaviors. Methamphetamine is often combined with other drugs that may increase its risks and adverse health consequences. To examine differences in background characteristics, HIV-risk behaviors, and psychosocial variables among polydrug-using HIV-positive MSM, the researchers classified a sample of 261 HIV-positive, methamphetamine-using MSM into three user groups: (1) methamphetamine only; (2) methamphetamine, marijuana, and poppers (light polydrug users); and (3) methamphetamine and other drugs (e.g., cocaine, heroin, hallucinogens, and ketamine; heavy polydrug users). Only 5% reported using only methamphetamine during the past 2 months; 31% were classified as light polydrug users, and 64% were classified as heavy polydrug users. Heavy polydrug users were significantly younger than light polydrug users (35.6 vs. 38.4, P<.01) and reported using methamphetamine for significantly fewer years (10.3 vs. 14.2 years, P<.001), but did not differ in the amount and frequency of methamphetamine or alcohol consumed. Heavy polydrug users reported significantly more sex partners of HIV-negative and unknown serostatus and had more unprotected sex with these partners. Heavy polydrug users had significantly higher scores on impulsivity and negative self-perceptions, as compared with those of light polydrug users. In this sample of HIV-positive MSM, most of those who used methamphetamine had a pattern of polydrug use. Heavy polydrug users reported significantly more high-risk sexual behaviors and tended toward higher levels of impulsivity than light polydrug users. The implications of these findings are two-fold: (1) Longitudinal research is needed to establish causal relationships among methamphetamine use, impulsivity, negative self-perceptions, and sexual risk behavior in this target population; (2) behavioral interventions should evaluate whether methamphetamine use and sexual risk behavior can be reduced by modifying impulsivity and negative self-perceptions.
HIV; Methamphetamine; MSM; Polydrug abuse; Sexual risk
Injection drug users engage in behaviors that increase the spread of human immunodeficiency virus (HIV) and other infectious diseases. Although methadone maintenance (MM) is highly effective in decreasing heroin use and the spread of HIV, polydrug use, especially the combined use of cocaine and alcohol, is common in MM patients. Alcohol use is independently associated with HIV risk behaviors, and the effects of alcohol use on risk behaviors may vary by gender. This study evaluated the effects of recent heavy alcohol use and gender with respect to HIV risk behaviors in 118 cocaine-abusing methadone patients. Both lifetime and past month injection and sexual risk behaviors were examined. Recent heavy drinkers (n = 46) were more likely to be male than nonheavy drinkers (n = 72). Recent heavy drinkers reported more risky sexual behaviors over their lifetimes than nonheavy drinkers. Gender effects were also present for lifetime risk behaviors, with females demonstrating more sexual and injection risk behaviors than men. In terms of recent injection risk behaviors, there was a significant alcohol use by gender effect. Heavy drinking females reported significantly more drug-sharing behaviors and less frequent needle cleaning than nonheavy drinking females. Recent sexual behaviors did not differ based on alcohol use status or gender. These findings may inform HIV prevention strategies in cocaine-abusing MM patients, and they suggest that cocaine-abusing women who drink heavily are a particularly high risk group who should be counseled about risky injection drug use practices.
HIV risk behaviors scale; gender; alcohol use; methadone maintenance; opioid dependence; cocaine use
Few interventions have been designed to improve behavioral outcomes and reduce risk of HIV transmission of individuals living with HIV, most focusing on preventative efforts directed at individuals who are HIV-negative. However, people living with HIV present individual and public health risks (infection with a different strain of HIV, health complications from contracting STD’s, continued sexual activity with individuals with unknown HIV status) that have become the focus of intervention efforts. The current paper explores a promising new intervention, The Positive Choices Mapping intervention (PCM), designed to increase condom self-efficacy and use among African American crack cocaine smokers who are living with HIV. The intervention was grounded in Social Cognitive Theory and incorporated an empirically backed visual representation strategy (node-link mapping). The focus of the current paper is on the main components of the intervention.
This study examined the role of maternal psychopathology and maternal warmth as mediators of the association between prenatal cocaine and other substance exposure and toddler behavior problems. It was also hypothesized that infant cortisol reactivity and environmental risk may moderate these associations. Participants were 220 caregiver–infant dyads (119 cocaine exposed, 101 not cocaine exposed; 49% boys). Mother–infant dyads were recruited at delivery with assessments at 4–8 weeks and 7, 13, and 18 months of child ages. Results yielded no direct associations between prenatal cocaine/other substance exposure and toddler behavior problems, but significant indirect associations between prenatal cigarette/alcohol exposure and toddler behavior problems at 18 months. With regard to moderation, results indicated an indirect association between prenatal cocaine exposure and toddler behavior problems via lower maternal warmth for children with higher, but not lower, cortisol reactivity at 7 months. Results suggest potential pathways to toddler behavior problems among children at high biological risk.
Women who used cocaine during pregnancy may become at risk for increased physical and mental health problems.
Three hundred and twenty-one (158 cocaine use during pregnancy (PC), 163 no cocaine (NC)) women were assessed using the Health Survey Questionnaire (SF-36V2) 10 years after infant birth. Factors related to mental and physical health, and co-occurring with PC, were evaluated using multiple regression.
Controlling for age and education, PC women reported poorer total perceived mental health (PMH) (46.3 ± .9 vs. 50.7 ± .9, p < .001), more bodily pain (48.1 ± 1.0 vs. 51.5 ± 1.0, p < .02) and poorer health perceptions (46.8 ± .9 vs. 49.7 ± .9, p < .03) than NC women. PC women had lower BMI (29% vs. 32%, p < .006), higher current alcoholic drinks per/week (4.05 ± 15.5 vs. 1.29 ± 3.51, p < .005) and number of cigarettes per day (9 ± 10.6 vs. 4 ± 6.5, p < .0001) and greater total life strain (Family Inventory of Life Events and Changes (FILE)) (4.6 ± 4.9 vs. 3.2 ± 3.2, p < .004) than NC women. Regression analyses indicated that body mass index (BMI) mediated the effect of prior cocaine use on perceived physical health (PPH) and total life strain had additive effects. Current cigarette use and total life stress partially mediated the effects of cocaine use on PMH and also had additive independent effects.
PC use is a marker for poor health after 10 years. Mediators of these relationships (BMI, stressful life events and current tobacco use) should be considered when designing interventions to promote health.
Prenatal; Cocaine; Mental and physical health; Women
In this longitudinal study of prenatal cocaine exposure (PCE), school-age physical and cognitive development and behavioral characteristics were examined, while controlling for other factors that affect child development. At this follow-up phase, children were on average 7.2 years old, and their caregivers were 33.7 years old, had 12.5 years of education, and 48% were African American. During the first trimester, 20% of the women were frequent cocaine users (≥ 1 line/day). First trimester cocaine exposure predicted decreased weight and height at 7 years. There was no significant relationship between PCE and the cognitive and neuropsychological measures. Third trimester cocaine use predicted more total and externalizing behavior problems on the Child Behavior Checklist  and the Teacher Report Form , and increased activity, inattention, and impulsivity on the Routh Activity  and SNAP scales . Children who were exposed to cocaine throughout pregnancy had more mother- and teacher-rated behavior problems compared to children of women who stopped using early in pregnancy or who never used cocaine prenatally. These detrimental effects of PCE on behavior are consistent with other reports in the literature and with the hypothesis that PCE affects development through changes in neurotransmitter systems. These school-age behaviors may be precursors of later adolescent behavior problems.
prenatal cocaine exposure; school age; growth; cognitive development; behavior problems
Chronic cocaine use may lead to premature atherosclerosis, but the prevalence of and risk factors for coronary artery disease (CAD) in asymptomatic cocaine users have not been reported. The objective of this study was to examine whether vitamin D deficiency is associated with the development of CAD in human immunodeficiency virus (HIV)-infected African American cocaine users with low CAD risk.
In this prospective follow-up study, we investigated 169 HIV-infected African American cocaine users with low Framingham risk at baseline. The main outcome measures were incidence of subclinical CAD and development of subclinical CAD.
Fifty of the 169 African Americans had evidence of subclinical disease on the initial cardiac computed tomography. A second cardiac computed tomography was performed on the 119 African Americans without disease on the first scan. The total sum of person-years of follow-up was 289.6. Subclinical CAD was detected in 11 of these, yielding an overall incidence of 3.80/100 person-years (95% confidence interval 1.90–6.80). Among the factors investigated, only vitamin D deficiency was independently associated with development of subclinical CAD. The study did not find significant associations between CD4 count, HIV viral load, or antiretroviral treatment use and the incidence of subclinical CAD. This study appears to suggest that there is a threshold level of vitamin D (10 ng/mL) above which the effect of vitamin D on subclinical CAD is diminished.
The incidence of subclinical CAD in HIV-infected African American cocaine users with low CAD risk is high, especially in those with vitamin D deficiency. Well designed randomized clinical trials are warranted to confirm the role of vitamin D deficiency in the development of CAD in HIV-infected African American cocaine users with low CAD risk.
vitamin D deficiency; subclinical coronary artery disease; cocaine use; prospective follow-up study; African Americans
Neurocognitive studies of HIV typically target executive functions dependent on frontostriatal circuitry. The integrity of medial temporal systems has received considerably less attention despite high hippocampal viral load. Studies also predominately involve HIV+ men, though HIV+ women may be at increased risk for cognitive dysfunction due to the high prevalence of psychosocial/mental health problems and lower educational attainment. Our aim was to conduct a preliminary investigation of episodic memory and its neural correlates in HIV-infected and at-risk uninfected women.
Participants included 54 HIV+ and 12 HIV− women (mean age = 43 years; 86% African American) recruited from the Chicago site of the Women's Interagency HIV Study. Participants completed standardized tests of verbal and visual episodic memory, working memory, and executive function. A subset of 11 women also underwent functional MRI during a delayed verbal episodic memory task.
HIV serostatus predicted significantly lower immediate and delayed verbal episodic memory, working memory, and visual memory. Preliminary neuroimaging findings revealed group differences in bilateral hippocampal function, with HIV+ women showing decreased activation during encoding and increased activation during delayed recognition. These alterations correlated with worse episodic verbal memory.
Verbal episodic memory deficits are evident in HIV+ women and may be associated with hippocampal dysfunction at both encoding and retrieval.
= antiretroviral therapy;
= Center for Epidemiologic Studies–Depression Scale;
= functional MRI;
= highly active antiretroviral therapy;
= hepatitis C virus antibody;
= Hopkins Verbal Learning Task;
= region of interest;
= echo time;
= repetition time;
= Women's Interagency HIV Study;
= Wide Range Achievement Test–Revised.
Clinical and preclinical evidence suggests that cocaine exposure hastens progression of the HIV disease process. An established active, euphoric dose of cocaine (20 mg/kg) was administered to SCID mice according to a regimen consistent with exposure to the drug by cocaine-abusing HIV-infected patients to determine the effects of cocaine on four previously established pathological characteristics of HIV encephalitis: cognitive deficits, fatigue, astrogliosis, and microgliosis. Mice were intracranially inoculated with either HIV-infected, or uninfected macrophages and then injected with either cocaine or saline in a 2(Infection) × 2(Cocaine) factorial design. Cognition was assessed by acquisition and retention of a spatially cued learning task. Fatigue was assessed by monitoring motor activity following a 2 minute forced swim. Mice were then sacrificed to determine the extent of astrogliosis and microgliosis in the four groups. Results indicated that in comparison to uninfected controls, HIV positive mice had increased astrogliosis and microgliosis, cognitive deficits, and recovered more slowly from fatigue. However, despite evidence that the cocaine exposure regimen activated the central nervous system and had long-term CNS effects, the drug did not alter the behavioral or the neuropathological deficits noted in HIV-infected SCID mice.
AIDS; Dementia; HIV -associated Dementia; Animal models; Drug Abuse
Human immunodeficiency virus (HIV) infection and progression of acquired immunodeficiency syndrome (AIDS) can be modulated by a number of cofactors, including drugs of abuse. Opioids, cocaine, cannabinoids, methamphetamine (METH), alcohol, and other substances of abuse have been implicated as risk factors for HIV infection, as they all have the potential to compromise host immunity and facilitate viral replication. Although epidemiologic evidence regarding the impact of drugs of abuse on HIV disease progression is mixed, in vitro studies as well as studies using in vivo animal models have indicated that drugs of abuse have the ability to enhance HIV infection/replication. Drugs of abuse may also be a risk factor for perinatal transmission of HIV. Because high levels of viral load in maternal blood are associated with increased risk of HIV vertical transmission, it is likely that drugs of abuse play an important role in promoting mother-fetus transmission. Furthermore, because the neonatal immune system differs qualitatively from the adult system, it is possible that maternal exposure to drugs of abuse would exacerbate neonatal immunity defects, facilitating HIV infection of neonate immune cells and promoting HIV vertical transmission. The availability and use of antiretroviral therapy for women infected with HIV increase, there is an increasing interest in determining the impact of drug abuse on efficacy of AIDS Clinical Trials Group (ACTG) -standardized treatment regimens for woman infected with HIV in the context of HIV vertical transmission.
Opioids; Methamphetamine; Cocaine; Marjuana/Cannabinoid; Alcohol; HIV
Drug-associated cues and stress increase craving and lead to greater risk of relapse in abstinent drug addicts. This risk may be increased when these factors occur simultaneously. The current study examined whether the presentation of three different levels of intermittent footshock would trigger reinstatement or potentiate reinstatement of cocaine-seeking caused by conditioned cues. Male, Long Evans rats underwent daily i.v. cocaine self-administration, followed by extinction of lever responding in the absence of previously cocaine-paired cues. Reinstatement of cocaine-seeking was measured during presentation of cocaine-paired cues, following pretreatment with three levels of intermittent footshock (0.25, 0.5, and 0.75 mA), or after the combination of footshock and cues. Footshock at the 0.5 and 0.75 mA levels led to significant reinstatement when presented alone, and also potentiated the reinstatement triggered by the presentation of conditioned cues. These results demonstrate that while stress and drug-paired cues reinstate drug-seeking when presented in isolation, their interaction leads to potentiated reinstatement. Dual targeting of stress and cues is thus a critical consideration for treatment intervention in abstinent drug users.
cocaine; cues; footshock; reinstatement; relapse; stress
The authors examined 223 children at age 4 years for the effects of prenatal cocaine exposure, exposure to other substances, maternal and environmental risk factors, and neonatal medical problems on IQ, externalizing problems, and internalizing problems. Regression analyses showed that maternal verbal IQ and low environmental risk predicted child IQ. Cocaine exposure negatively predicted children’s overall IQ and verbal reasoning scores, but only for boys. Cocaine exposure also predicted poorer short-term memory. Maternal harsh discipline, maternal depressive symptoms, and increased environmental risk predicted externalizing problems. In contrast, only maternal depressive symptoms predicted internalizing problems. These findings indicate that early exposure to substances is largely unrelated to subsequent IQ or adjustment, particularly for girls.
Cocaine use is associated with poorer HIV clinical outcomes and may contribute to neurobiological impairments associated with impulsive decision making. This study examined the effect of cocaine dependence on brain activation during a delay discounting task involving choices between smaller immediate rewards and larger delayed ones. Participants were 39 HIV-positive adults on antiretroviral therapy who had current cocaine dependence (“active,” n=15), past cocaine dependence (“recovered,” n=13), or no lifetime substance dependence (“naïve,” n=11). Based on responses on a traditional delay discounting task, three types of choices were individualized for presentation during fMRI scanning: hard (similarly valued), easy (disparately valued), and no (single option). Active participants had significantly smaller increases in activation than naïve participants during hard versus easy choices bilaterally in the precentral gyrus and anterior cingulate cortex and in the right frontal pole (including dorsolateral, ventrolateral, and orbitofrontal cortex). During hard and easy choices relative to no choices, active participants had smaller increases in activation compared to naïve participants in frontoparietal cortical regions. These deficits in the executive network during delay discounting choices may contribute to impulsive decision making among HIV-positive cocaine users, with implications for risk behaviors associated with disease transmission and progression.
cocaine dependence; HIV/AIDS; functional magnetic resonance imaging; delay discounting; decision making
Chronic cocaine use is associated with neurobiological and cognitive deficits that persist into abstinence, hindering success of behavioral treatment strategies and perhaps increasing likelihood of relapse. The effects of current cocaine use and abstinence on neurobiology and cognition are not well characterized.
Adult male rhesus monkeys with an extensive cocaine self-administration history (~ 5 years) and age-matched controls (n=4/group) performed cognitive tasks in morning sessions and self-administered cocaine or food in afternoon sessions. Positron emission tomography (PET) and [18F]-fluorodeoxyglucose (FDG) was employed to assess cerebral metabolic rates of glucose utilization (MRglu) during cognitive testing.
Cocaine-experienced monkeys required significantly more trials and committed more errors on reversal learning and multi-dimensional discriminations, compared to controls. Cocaine-naive but not cocaine-experienced monkeys showed greater MRglu during a multi-dimensional discrimination task in the caudate nucleus, hippocampus, anterior and posterior cingulate, regions associated with attention, error-detection, memory, and reward. Using a delayed match-to-sample (DMS) task, there were no differences in baseline working memory performance between groups. High dose cocaine self-administration disrupted DMS performance, but tolerance developed. Acute abstinence from cocaine did not affect performance but by day 30 of abstinence, accuracy increased significantly while performance of cocaine-naive monkeys was unchanged.
These data document direct effects of cocaine self-administration on cognition and neurobiological sequelae underlying cognitive deficits. Improvements in working memory can occur in abstinence, albeit across an extended period critical for treatment-seekers, suggesting pharmacotherapies designed to enhance cognition may improve success of current behavioral modification strategies.
[18F]-fluorodeoxyglucose (FDG); CANTAB; delayed match-to-sample; PET imaging; set shifting; cerebral metabolic rates of glucose utilization
Cognitive enhancers that act by increasing glycine transmission might be useful adjuncts to cocaine-cue extinction training to deter relapse. The study investigated the effects of combining treatments of the glycine transporter-1 (GlyT-1) inhibitor, Org24598, with extinction training on the subsequent reacquisition of cocaine self-administration. Squirrel monkeys and rats were trained to self-administer cocaine under a second-order schedule of intravenous drug injection in which responding was maintained by cocaine injections and a cocaine-paired visual stimulus. During three weekly extinction sessions, saline was substituted for cocaine but responding still produced the cocaine-paired stimulus. Subjects were treated with Org24598 or vehicle, either before or after each extinction session. One week later, cocaine injections were restored, and reacquisition of cocaine self-administration was evaluated over 15 sessions. Compared with vehicle, administration of Org24598 (1.0 mg/kg in monkeys; 3.0 or 7.5 mg/kg in rats) before each extinction session significantly inhibited reacquisition of cocaine self-administration in each species. In contrast, administration of Org24598 (1.0 mg/kg in monkeys) following, rather than preceding, each extinction session did not affect reacquisition compared with vehicle. When extinction training was replaced by cocaine self-administration or abstinence control conditions, treatment with the same doses of Org24598 resulted in reacquisition that was significantly more rapid than the reacquisition observed when Org24598 was administered before extinction training sessions. The results support the potential clinical utility of GlyT-1 inhibitor pretreatments combined with cocaine-cue extinction training to inhibit relapse.
cocaine self-administration; glycine transporter-1 inhibitor; extinction training; relapse; addiction & substance abuse; psychopharmacology; animal models; learning & memory; glycine transporter inhibitors; relapse; extinction training; cocaine-seeking behavior
OBJECTIVE: To assess the neurodevelopment of adopted children who had been exposed in utero to cocaine. DESIGN: A case-control observational study. PARTICIPANTS: Twenty-three children aged 14 months to 6.5 years exposed in utero to cocaine and their adoptive mothers, and 23 age-matched control children not exposed to cocaine and their mothers, matched with the adoptive mothers for IQ and socioeconomic status. SETTING: The Motherisk Programme at The Hospital for Sick Children, Toronto, a consultation service for chemical exposure during pregnancy. MAIN OUTCOME MEASURES: Height, weight and head circumference at birth and at follow-up, and achievement on standard tests of cognitive and language development. RESULTS: Compared with the control group, children exposed in utero to cocaine had an 8-fold increased risk for microcephaly (95% confidence interval 1.5 to 42.3); they also had a lower mean birth weight (p = 0.005) and a lower gestational age (p = 0.002). In follow-up the cocaine-exposed children caught up with the control subjects in weight and stature but not in head circumference (mean 31st percentile v. 63rd percentile) (p = 0.001). Although there were no significant differences between the two groups in global IQ, the cocaine-exposed children had significantly lower scores than the control subjects on the Reynell language test for both verbal comprehension (p = 0.003) and expressive language (p = 0.001). CONCLUSIONS: This is the first study to document that intrauterine exposure to cocaine is associated with measurable and clinically significant toxic neurologic effects, independent of postnatal home and environmental confounders. Because women who use cocaine during pregnancy almost invariably smoke cigarettes and often use alcohol, it is impossible to attribute the measured toxic effects to cocaine alone.
Over the past 15 years, there has been a dramatic increase in the abuse of purified cocaine preparations throughout the industrialized world. The potential lethality of the drug is now recognized, and a growing series of case reports indicate that cardiotoxicity may be an important factor in the morbidity and mortality associated with the drug. Acute myocardial infarction is a demonstrated risk both in subjects with and without pre-existent coronary artery disease. The arrhythmogenic potential of cocaine is less clear and appears to have been overemphasized, although several documented cases of ventricular arrhythmia following cocaine use have been reported. Cardiomyopathy and myocarditis associated with cocaine have also been described, but an etiologic relationship is presently inferential. Based upon presumed pathophysiologic mechanisms, beta adrenergic blocking agents are recommended for arrhythmias, and calcium channel blocking agents and/or nitrates for ischemic syndromes related to cocaine. It is emphasized that these recommendations are based upon a paucity of relevant clinical studies, and controlled clinical trials to establish their efficacy have not been performed.
The impact of maternal substance abuse is reflected in the 2002–2003 National Survey on Drug Use and Health. Among pregnant women in the 15–44 age group, 4.3%, 18% and 9.8% used illicit drugs, tobacco and alcohol, respectively. Maternal pregnancy complications following substance use include increases in sexually transmitted disorders, placental abruption and HIV-positive status. Effects on the neonate include a decrease in growth parameters and increases in central nervous system and autonomic nervous system signs and in referrals to child protective agencies. In childhood, behavioral and cognitive effects are seen after prenatal cocaine exposure; tobacco and alcohol have separate and specific effects. The ongoing use of alcohol and tobacco by the caretaker affects childhood behavior. Therefore, efforts should be made to prevent and treat behavioral problems as well as to limit the onset of drug use by adolescent children born to women who use drugs during pregnancy.
Alcohol; Child medicine; Cocaine; Neonatal; Neurobehavioral outcome; Polydrug use; Tobacco