Initial Cocaine Use Research Articles

Accumulation of NMDA receptors in accumbal neuronal ensembles mediates increased conditioned place preference for cocaine after prolonged withdrawal

Cue-induced cocaine craving gradually intensifies following abstinence, a phenomenon known as the incubation of drug craving. Neuronal ensembles activated by initial cocaine use, are critically involved in this process. However, the mechanisms by which neuronal changes occurring in the ensembles after withdrawal contribute to incubation remain largely unknown. Here we labeled neuronal ensembles in the shell of nucleus accumbens (NAcSh) activated by cocaine conditioned place preference (CPP) training. NAcSh ensembles showed an increasing activity induced by CPP test after 21-day withdrawal. Inhibiting synaptic transmission of NAcSh ensembles suppressed the preference for cocaine paired-side after 21-day withdrawal, demonstrating a critical role of NAcSh ensembles in increased preference for cocaine. The density of dendritic spines in dopamine D1 receptor expressing ensembles was increased after 21-day withdrawal. Moreover, the expression of Grin1, a subunit of the N-methyl-D-aspartate (NMDA) receptor, specifically increased in the NAcSh ensembles after cocaine withdrawal in both CPP and self-administration (SA) mouse models. Targeted knockdown or dysfunction of Grin1 in NAcSh ensembles significantly suppressed craving for cocaine. Our results suggest that the accumulation of NMDA receptors in NAcSh ensembles mediates increased craving for cocaine after prolonged withdrawal, thereby providing potential molecular targets for treatment of drug addiction.

Housing Instability Associated with Return to Stimulant Use among Previously Abstaining Women.

Stimulant use among unstably housed individuals is associated with increased risks of psychiatric co-morbidity, violence, HIV transmission, and overdose. Due to a lack of highly effective treatments, evidence-based policies targeting the prevention of stimulant use disorder are of critical importance. However, little empirical evidence exists on risks associated with initiating or returning to stimulant use among at-risk populations. In a longitudinal cohort of unstably housed women in San Francisco (2016-2019), self-reported data on stimulant use, housing status, and mental health were collected monthly for up to 6 months, and factors associated with initiating stimulants after a period of non-use were identified through logistic regression. Among 245 participants, 42 (17.1%) started using cocaine and 46 (18.8%) started using methamphetamine. In analyses adjusting for demographics and socio-structural exposures over the preceding month, experiencing street homelessness was associated with initiating cocaine use (AOR: 2.10; 95% CI: 1.04, 4.25) and sheltered homelessness with initiating methamphetamine use (AOR: 2.57; 95% CI: 1.37, 4.79). Other factors-including race, income, unmet subsistence needs, mental health, and treatment adherence-did not reach levels of significance, suggesting the paramount importance of policies directed toward improving access to permanent supportive housing to prevent stimulant use among unstably housed women.

Sex Chromosome Complement and Estradiol Modify Cocaine Self-Administration Behaviors in Male Mice

Introduction: Women are more vulnerable to cocaine’s reinforcing effects and have a more rapid course to addiction after initial cocaine use as compared to men. Studies in rodents similarly indicate an enhanced sensitivity to the reinforcing effects of cocaine in females versus males. Levels of estradiol (E2) are correlated with vulnerability to the rewarding actions of cocaine. Here, we asked if sex chromosome complement (SCC) influences vulnerability to cocaine use. Methods: We used the four-core genotype mouse that produces gonadal males and females with either XX or XY SCC. Mice were gonadectomized and implanted with either an estradiol (E2) or cholesterol-filled pellet. This allowed us to determine the effects of SCC in the absence (cholesterol-treated) and presence of tonic high physiological hormone levels (estradiol). Acquisition of cocaine self-administration was determined over a 12-day period using an escalated dose procedure (0.3 mg/kg/infusion, sessions 1–6; 0.6 mg/kg/infusion, sessions 6–12). Results: Without estradiol treatment, a greater percentage of castrated XY mice acquired cocaine self-administration and did so at a faster rate than XX castrates and ovariectomized XY females. These same XY males acquired sooner, infused more cocaine, and directed more nose pokes to the rewarded nose-poke hole than XX castrates and XY males receiving E2. Conclusion: Our results suggest that in gonadal male mice, SCC and estradiol can modulate the reinforcing effects of cocaine which may influence the likelihood of cocaine use.

Sex differences in the neuroadaptations associated with incubated cocaine-craving: A focus on the dorsomedial prefrontal cortex.

Women have a shorter course from initial cocaine use to meeting the criteria for cocaine use disorder as compared to men. Preclinical findings similarly indicate that females develop key features of an addiction-like phenotype faster than males, including an enhanced motivation for cocaine and compulsive use, indicating that this phenomenon is biologically based. The goals of this study were to determine whether cocaine-craving, another key feature of addiction, also develops sooner during withdrawal in females than males and to determine whether there are sex differences in the molecular mechanisms associated with its development focusing on markers known to mediate cocaine-craving in males (i.e., dorsomedial prefrontal cortex, dmPFC, expression of brain-derived neurotrophic factor exon-IV, Bdnf-IV, and NMDA receptor subunits, Grin2a, Grin2b, and Grin1). Cocaine-craving was assessed following extended-access cocaine self-administration and 2, 7, or 14 days of withdrawal using an extinction/cue-induced reinstatement procedure. Tissue was obtained from the dmPFC immediately after reinstatement testing and gene expression changes were analyzed using real-time qPCR. In males, cocaine-craving (total extinction and cue-induced reinstatement responding) progressively increased from early to later withdrawal time-points whereas in females, cocaine-craving was already elevated during early withdrawal (after 2 days) and did not further increase at later withdrawal time-points. Levels of cocaine-craving, however, were similar between the sexes. Gene expression changes differed markedly between the sexes such that males showed the expected relapse- and withdrawal-associated changes in Bdnf-IV, Grin2a, Grin2b, and Grin1 expression, but females only showed a modest increase Grin1 expression at the intermediate withdrawal timepoint. These findings indicate that cocaine-craving is similarly expressed in males and females although the time-course for its incubation appears to be accelerated in females; the molecular mechanisms also likely differ in females versus males.

Tamoxifen Blocks the Development of Motivational Features of an Addiction-Like Phenotype in Female Rats.

Women become addicted sooner after initiating cocaine use as compared to men. Preclinical studies reveal a similar vulnerability in females, with findings from ovariectomized rats suggesting that estradiol mediates the enhanced vulnerability. However, since ovariectomy depletes not only estradiol, but all ovarian hormones, its role in a physiological context is not clear. Thus, the goal of this study was to determine the role of estradiol in the development of an addiction-like phenotype in ovary-intact females treated chronically with the selective estrogen receptor (ER) modulator tamoxifen. We hypothesized that tamoxifen, by antagonizing ERs, would block the development of an addiction-like phenotype as defined by an enhanced motivation for cocaine (assessed under a progressive-ratio schedule), and a heightened vulnerability to relapse (assessed under an extinction/cue-induced reinstatement procedure). Effects were examined following extended access cocaine self-administration (24-h/day; 4-discrete trials/h; 1.5 mg/kg/infusion) and 14-days of abstinence, conditions optimized for inducing an addiction-like phenotype. As predicted, motivation for cocaine was increased following extended-access self-administration and protracted abstinence in the vehicle (sesame oil) and no-injection control groups, but not in the tamoxifen group indicating that ER signaling is critical for the development of this feature of an addiction-like phenotype. Surprisingly, the increase in motivation for cocaine following abstinence was also attenuated in the vehicle group as compared to no-injection controls suggesting that oil/injections also affected its development. Contrary to our hypothesis, tamoxifen did not decrease vulnerability to relapse as this group responded at similar levels during initial extinction sessions and cue-induced reinstatement testing as compared to controls. Tamoxifen did, however, impair extinction learning as this group took longer to extinguish as compared to controls. Taken together, these findings indicate that estradiol is critical for the extinction of drug-associated cues and the development of motivational features of addiction.

Cocaine effects on generation of reactive oxygen species and DNA damage: formation of 8-hydroxydeoxyguanosine in active abusers

Cocaine abuse continues to be a major public health problem in the world. An upper numbers of individuals are initiating cocaine use with a stable rate of growth each year with an increasing number of people with cocaine related problems. Following cocaine oxidative pathways a ROS formation are generated. Oxidative stress has been demonstrated to play an important role in cocaine addiction and toxicity due to its oxidized metabolites produced by cytochrome P450 during cocaine biotransformation. The ROS induced genotoxicities include DNA damage, gene mutation, chromosome aberrations and micronuclei formation. 8-Hydroxy-2’-deoxyguanosine (8-OHdG) an oxidative modified DNA product, is the most representative product that may reflect oxidative damage induced by ROS. The present study was designed to investigate whether a systemic cocaine administration and its metabolism increase 8-OHdG production. Our findings clearly showed that cocaine promoted the ROS formation with significant increased of urinary 8-OHdG and MDA with a decreased of total scavenging capacity (TSC).

Prevalence of traumatic brain injury in cocaine-dependent research volunteers.

There is a high prevalence of traumatic brain injury (TBI) among those with substance dependence. However, TBI often remains undiagnosed in these individuals, due to lack of routine screening in substance use treatment settings or due to overlap in some of the cognitive sequelae (eg impulsivity, disinhibition) of TBI and cocaine dependence. The prevalence of self-reported mild to moderate TBI in a group of cocaine-dependent (n = 95) and a group of healthy volunteers (n = 75) enrolled at the same facility was assessed. Additionally, the relationship between TBI and clinically relevant correlates, including impulsivity, cocaine use history, and treatment outcome in the cocaine-dependent group was also examined. A higher proportion of individuals with cocaine dependence (29.5%) reported having suffered a TBI in their lifetime compared to controls (8%) on a Closed Head Injury scale. Among cocaine users, the average age of sustaining TBI was significantly lower than the age of initiating cocaine use. Presence of TBI was not associated with higher impulsivity on the Barratt Impulsiveness Scale-11 or self-reported years of cocaine use. No differences were noted on treatment outcome for cocaine dependence as measured by treatment effectiveness scores (TES) between cocaine users with TBI and their non-TBI counterparts. These results are the first to highlight the high prevalence of TBI among individuals with cocaine dependence. This study underscores the possible role of TBI history as a risk factor for onset of cocaine use, however, more research is needed to determine the impact of co-morbid TBI as a complicating factor in the substance abuse treatment setting.

Substance abuse treatment patients with early onset cocaine use respond as well to contingency management interventions as those with later onset cocaine use

Early onset drug use is associated with increased risk of developing substance use disorders, but relatively little is known about the correlates of early drug use among adults receiving treatment. A retrospective analysis of a randomized study of contingency management treatment compared cocaine-dependent patients who reported initial cocaine use at age 14 or younger (n=41) to those who began using after age 14 (n=387). Patients with early onset cocaine use had more legal and psychiatric problems than those who initiated cocaine use later. Patients with early-onset cocaine use also dropped out of treatment sooner and achieved less sustained abstinence than those who began using at older ages, but the interaction between age of first use and treatment condition was not significant. Early-onset cocaine use is associated with persistent psychosocial problems and an overall poor response to treatment. However, contingency management is efficacious in improving outcomes in early onset cocaine users.

Low- and high-cocaine locomotor responding rats differ in reinstatement of cocaine seeking and striatal mGluR5 protein expression

Behavioral responsiveness to initial cocaine use varies among individuals and may contribute to differential vulnerability to cocaine addiction. Rats also exhibit individual differences in cocaine's effects and can be classified as low or high cocaine responders (LCRs or HCRs, respectively), based on their initial cocaine-induced locomotor activity (10 mg/kg, i.p.). Here, we used the extinction/reinstatement model to address whether or not LCRs and HCRs differ in (i) extinction/reinstatement of cocaine self-administration behavior and (ii) levels of metabotropic glutamate receptors (mGluRs) following these behaviors. During the earliest acquisition sessions, LCRs exhibited significantly greater cocaine intake (0.8 mg/kg/infusion) and cocaine-paired lever responding than HCRs, but intake and lever responding converged by the end of the cocaine self-administration portion of the study. LCRs and HCRs did not differ in cocaine seeking during the first extinction session and extinguished cocaine seeking similarly. HCRs exhibited greater reinstatement than LCRs to lower (2.5 and 5 mg/kg), but not higher (10 mg/kg), i.p. priming doses of cocaine. The effect of drug-paired cues on reinstatement following extinction was complex, with HCRs and LCRs showing the greater effect of cue depending on the order in which cue- and drug-primed tests were given. Western blot analysis revealed that mGluR5 heteromers were significantly higher in the dorsal striatum of HCRs than LCRs following reinstatement testing. Although our previous findings with the LCR/HCR model have uniformly supported the idea that lower initial cocaine-induced activation predicts more ready development of cocaine addiction-like behaviors, here, we show a more complex relationship with cocaine reinstatement.

Estradiol as a Mechanism for Sex Differences in the Development of an Addicted Phenotype following Extended Access Cocaine Self-Administration

Women progress more rapidly after initial cocaine use to addiction as compared with men. Similarly, female rats appear to require less cocaine exposure before developing an addicted phenotype with evidence implicating estradiol as a potential mechanism. The goals of this study were to determine whether there are sex differences in the magnitude of the addicted phenotype under optimized conditions that induce its development in both males and females and to determine the role of estradiol in this effect. Following acquisition, intact male and intact and ovariectomized (OVX) female rats with and without estradiol replacement were given access to cocaine (1.5 mg/kg per infusion) under either extended access (ExA; discrete trial procedure, 4 trials/h, 24 h/day, 10 days) or short access (ShA) conditions (20 infusions maximum/day, 3 days). Motivation to obtain cocaine (0.5 mg/kg/infusion), as assessed under a progressive-ratio schedule, was then examined following a 2-week abstinence period. Results showed that following ExA self-administration, both males and females developed an addicted phenotype, with 9 of 11 males and 8 of 10 females showing a greater than 15% increase in levels of motivation to obtain cocaine as compared with ShA controls. In contrast, within the OVX groups, responding was enhanced from control levels after ExA self-administration in estradiol-replaced rats only. These results suggest that while females may have an enhanced vulnerability to developing an addicted phenotype, they may be similar to males once addiction has developed. These results also suggest that estradiol is critically involved in the development of an addicted phenotype in females.

Subjective responses to initial experience with cocaine: an exploration of the incentive–sensitization theory of drug abuse

This study investigated the relationship between positive and negative subjective responses at the time of initial cocaine use with adult cocaine dependence and life-time use rates. Psychostimulant pre-exposure, regular smoking or stimulant treatment before initiation were examined to explore the incentive sensitization theory of addiction. A total of 202 adult participants who had tried cocaine on at least one occasion were studied prospectively from childhood into adulthood. The cocaine-initiated group included 89 who met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for attention deficit hyperactive disorder (ADHD) and 113 age-matched controls. Five childhood and three adulthood interviews provided data on ages of initiation into cocaine and life-time use of cocaine from ages 16-40 years. Correlations of each subjective response and analyses of variance (ANOVAs) of cocaine 'liking' and 'wanting' with DSM-III-R cocaine dependence and life-time use provided support for the validity of the measures. ANOVA provided evidence of the effect of psychostimulant pre-exposure on 'liking' and 'wanting'. Logistic regression modeled the prediction of dependence and life-time use with the independent variables of 'liking' and 'wanting', psychostimulant pre-exposure and participant characteristics. When cocaine was first tried, 'liking' and 'wanting' were significant predictors of cocaine dependence and life-time use. Mean 'liking' or 'wanting' responses did not differ by participant characteristics. Those who were pre-exposed by regular smoking or stimulant treatment had higher 'liking' and 'wanting' scores; but participants who were pre-exposed by both stimulant treatment and regular smoking reported the lowest liking and the highest wanting responses, consistent with the incentive sensitization theory. Logistic regression showed that the 'liking' and 'wanting' responses increased significantly the odds of DSM-III-R cocaine dependence and life-time use. In this sample, subjective 'liking' and 'wanting' measured risk for cocaine abuse.

From First Drug Use to Drug Dependence: Developmental Periods of Risk for Dependence upon Marijuana, Cocaine, and Alcohol

The focal point of this paper is the transition from drug use to drug dependence. We present new evidence on risk for starting to use marijuana, cocaine, and alcohol, as well as risks for progression from first drug use to the onset of drug dependence, separately for each of these drugs. Data from the National Comorbidity Survey (NCS) were analyzed. The NCS had a representative sample of the United States population ages 15–54 years (n = 8,098). Survival analysis techniques were used to provide age- and time-specific risk estimates of initiating use of marijuana, cocaine, and alcohol, as well as of becoming dependent on each drug. With respect to risk of initiating use, estimated peak values for alcohol and marijuana were found at age 18, about two years earlier than the later peak in risk of initiating cocaine use. With respect to risk of meeting criteria for the clinical dependence syndrome, estimated peak values for alcohol and marijuana were found at age 17–18. Peak values for cocaine dependence were found at age 23–25. Once use began, cocaine dependence emerged early and more explosively, with an estimated 5–6% of cocaine users becoming cocaine dependent in the first year of use. Most of the observed cases of cocaine dependence met criteria for dependence within three years after initial cocaine use. Whereas some 15–16% of cocaine users had developed cocaine dependence within 10 years of first cocaine use, the corresponding values were about 8% for marijuana users, and 12–13% for alcohol users. The most novel findings of this study document a noteworthy risk for quickly developing cocaine dependence after initial cocaine use, with about one in 16 to 20 cocaine users becoming dependent within the first year of cocaine use. For marijuana and alcohol, there is a more insidious onset of the drug dependence syndrome.

Weekly Marijuana Use as a Risk Factor for Initial Cocaine Use:

The gateway hypothesis argues that most adolescents begin experimenting with cigarettes or alcohol, progress to marijuana use and finally to other illicit substance use. Prior research has supported this hypothesis, although prior research has not examined the effects of weekly marijuana use on specific illicit substances such as cocaine and has not attempted to identify psychosocial mediators of predictive relationships among substances. The current study uses longitudinal national survey data with six assessment periods and a comprehensive set of psychosocial risk factors for substance use to examine relationships between cocaine and marijuana use using discrete-time survival analysis for multiwave longitudinal data. The results of the current study show that weekly marijuana use, as opposed to initial marijuana use, is an independent risk factor for initial cocaine use. Weekly marijuana users were over ten times more likely to initiate cocaine within the next year. The results also show that many psychosocial predictors are not predictive of initial cocaine use after controlling for prior weekly marijuana use. However, the association between weekly marijuana use and cocaine use is, in part, mediated by delinquent attitudes. We conclude that weekly marijuana use is a risk factor for cocaine use that is equal to or greater in magnitude than other risk factors for initial cocaine use such as deviant peer bonding and attitudes toward deviance. These findings argue for some revision of the gateway hypothesis and psychosocial theories of substance use. In addition, the current research shows support for clinical observations which suggest that regular use of any illicit substance is likely to spawn experimentation with other illicit substances.

Gender Differences in Patterns of Cocaine Use

Gender differences in characteristics of substance use disorders may have important implications. To explore this question, the authors compared 27 women and 60 men presenting for treatment of cocaine dependence with regard to demographic and cocaine use patterns. Women had earned less in the previous year (P < 0.01) and were more likely to have been unemployed (P < 0.05). Although women began using cocaine at a later age than men, they attained regular cocaine use at the same age as men and bad fewer years of total cocaine use at the time of presentation for treatment (P < 0.001). Women were more likely to initiate cocaine use with crack cocaine (P < 0.01) and reported shorter duration of abstinent periods since initiating cocaine use (P < 0.05). (American Journal on Addictions 1996; 5:259–261)

Predicting cocaine use among methadone patients: analysis of findings from a national study.

Findings from a large-scale national study of clients admitted to publicly funded drug treatment programs between 1979 and 1981 were used to determine whether cocaine use by current and former methadone patients could be predicted. The sample for this analysis comprised 526 daily or weekly heroin users admitted to 17 methadone maintenance programs. The study found that cocaine use by both current and former methadone patients showed an overall decline during the follow-up year; that patients who stopped using heroin after entering treatment were much more likely to quit using cocaine than were their heroin-using counterparts; and that the odds of initiating cocaine use after admission to a methadone program were much higher among patients who continued using heroin. These findings suggest that methadone programs may be able to reduce cocaine use among some patients by improving their effectiveness in reducing heroin use.

Adolescent cocaine use: epidemiology, risk factors, and prevention.

Epidemiological studies of adolescent cocaine use are critically reviewed, risk factors for use are identified, and implications for prevention are discussed. Cocaine use among adolescents is increasing due, in part, to lower prices and the availability of “crack,” a potent smokable form of freebase cocaine. Although most use ends after mild to moderate experimentation, some users develop severe adverse consequences in a short period of time. Risk factors for initial cocaine use have been identified as male gender, use of marijuana, lack of social connections to family and school, peer influences, and psychopathology. However, further studies are needed to identify risk factors for developing more extensive or problematic cocaine use or abuse, including possible underlying biological factors. Prevention efforts should be targeted at preadolescents who show high risk characteristics. Parents, educators, and health care providers should all be involved in prevention programs, to provide a consistent message in the home, the school, and the popular media. Effective techniques that address the identified risk factors are required to maximize the success of prevention efforts.