Cocaine-abusing Patients Research Articles

M91. ADDICTION-RELEVANT BEHAVIOURS FOR COCAINE IN A NEUREGULIN 1 MUTANT MOUSE MODEL OF SCHIZOPHRENIA

BackgroundSubstance abuse is highly prevalent in schizophrenia patients, worsening symptoms, increasing hospitalisation, and reducing antipsychotic medication efficacy. The reason for high substance abuse rates in schizophrenia are unclear, however, it has been hypothesised that genetic predisposition for schizophrenia may increase the patients’ susceptibility to addictive behaviour. Elevated addiction propensity can be examined using mouse models of genetic risk for schizophrenia. The heterozygous neuregulin 1 transmembrane domain mutant (Nrg1 TM HET) mouse shows face, construct and predictive validity for schizophrenia and displays altered behavioural and neural responses to the major psychoactive cannabis constituent. However, the rewarding properties of drugs of abuse have not been assessed in these mice.MethodsWe examined addiction-like behaviours for cocaine in adult male Nrg1 TM HET mice. Cocaine reward (5, 10, 20 mg/kg i.p.) was assessed in conditioned place preference (CPP), where the pairing of a drug with a neutral context produces a preference for the drug-paired context. Self-administration of cocaine including the motivation to do so was also examined using intravenous self-administration (IVSA; cocaine doses: 0.1, 0.5, 1mg/kg/infusion). We also tested cessation of cocaine self-administration and relapse-like behaviour using IVSA.ResultsIn CPP, Nrg1 TM HET mice did not develop a preference for lower doses of cocaine (e.g. 5–10 mg/kg cocaine) which was evident in WT mice. However, at the highest dose (20 mg/kg), Nrg1 TM HET mice showed such a preference, which was absent in WT mice. These findings suggest a Nrg1-mediated shift in the dose-response curve.In IVSA, Nrg1 TM HET mice failed to extinguish cocaine-seeking more often than WT mice. There was also a trend for Nrg1 TM HET mice to exhibit greater relapse-like behaviour. Both behaviours are reminiscent of the DSM-5 criteria for drug addiction, and these addiction-like behaviours occurred in the absence of changes to cocaine self-administration or motivation for cocaine in Nrg1 mutant mice.DiscussionThe data presented suggest the Nrg1 TM mutation produces an addiction-relevant phenotype for cocaine. These findings provide the first evidence for a potential genetic link between schizophrenia and cocaine abuse and may help explain elevated susceptibility to cocaine abuse in patients.

P1535Multicentric analysis of adverse cardiovascular events in cocaine abuse patients in india

P1535Multicentric analysis of adverse cardiovascular events in cocaine abuse patients in india

Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction.

Drug addiction is a disease that manifests as an inappropriate allocation of behavior towards the procurement and use of the abused substance and away from other behaviors that produce more adaptive reinforcers (e.g. exercise, work, family and social relationships). The goal of treating drug addiction is not only to decrease drug-maintained behaviors, but also to promote a reallocation of behavior towards alternative, nondrug reinforcers. Experimental procedures that offer concurrent access to both a drug reinforcer and an alternative, nondrug reinforcer provide a research tool for assessment of medication effects on drug choice and behavioral allocation. Choice procedures are currently the standard in human laboratory research on medications development. Preclinical choice procedures have been utilized in biomedical research since the early 1940's, and during the last 10-15 years, their use for evaluation of medications to treat drug addiction has increased. We propose here that parallel use of choice procedures in preclinical and clinical studies will facilitate translational research on development of medications to treat cocaine addiction. In support of this proposition, a review of the literature suggests strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d-amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat heroin abuse or nicotine formulations to treat tobacco dependence.

Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV-1 pathogenesis in drug-abusing patients.

Epidemiologic studies suggest that cocaine abuse worsens HIV-1 disease progression. Increased viral load has been suggested to play a key role for the accelerated HIV disease among cocaine-abusing patients. The goal of this study was to investigate whether cocaine enhances proviral DNA integration as a mechanism to increase viral load. We infected CD4(+) T cells that are the primary targets of HIV-1 in vivo and treated the cells with physiologically relevant concentrations of cocaine (1 µM-100 µM). Proviral DNA integration in the host genome was measured by nested qPCR. Our results illustrated that cocaine from 1 µM through 50 µM increased HIV-1 integration in CD4(+) T cells in a dose-dependent manner. As integration can be modulated by several early postentry steps of HIV-1 infection, we examined the direct effects of cocaine on viral integration by in vitro integration assays by use of HIV-1 PICs. Our data illustrated that cocaine directly increases viral DNA integration. Furthermore, our MS analysis showed that cocaine is able to enter CD4(+) T cells and localize to the nucleus-. In summary, our data provide strong evidence that cocaine can increase HIV-1 integration in CD4(+) T cells. Therefore, we hypothesize that increased HIV-1 integration is a novel mechanism by which cocaine enhances viral load and worsens disease progression in drug-abusing HIV-1 patients.

Preoperative Screening and Case Cancellation in Cocaine-Abusing Veterans Scheduled for Elective Surgery

Background. Perioperative management of cocaine-abusing patients scheduled for elective surgery varies widely based on individual anecdotes and personal experience. Methods. Chiefs of the anesthesia departments in the Veterans Affairs (VA) health system were surveyed to estimate how often they encounter surgical patients with cocaine use. Respondents were asked about their screening criteria, timing of screening, action resulting from positive screening, and if they have a formal policy for management of these patients. Interest in the development of VA guidelines for the perioperative management of patients with a history of cocaine use was also queried. Results. 172 VA anesthesia departments' chiefs were surveyed. Response rate was 62%. Over half of the facilities see cocaine-abusing patients at least once a week (52%). Two thirds of respondents canceled or delayed patients with a positive screen regardless of clinical symptoms. Only eleven facilities (10.6%) have a formal policy. The majority of facilities (80%) thought that having formal guidelines for perioperative management of cocaine-abusing patients would be helpful to some extent. Results. 172 VA anesthesia departments' chiefs were surveyed. Response rate was 62%. Over half of the facilities see cocaine-abusing patients at least once a week (52%). Two thirds of respondents canceled or delayed patients with a positive screen regardless of clinical symptoms. Only eleven facilities (10.6%) have a formal policy. The majority of facilities (80%) thought that having formal guidelines for perioperative management of cocaine-abusing patients would be helpful to some extent. Conclusions. There is a general consensus that formal guidelines would be helpful. Further studies are needed to help formulate evidence-based guidelines for managing patients screening positive for cocaine prior to elective surgery.

Cocaine-Induced Loss of White Matter Proteins in the Adult Mouse Nucleus Accumbens Is Attenuated by Administration of a β-Lactam Antibiotic during Cocaine Withdrawal

We report significantly decreased white matter protein levels in the nucleus accumbens in an adult mouse model of chronic cocaine abuse. Previous studies from human cocaine abuse patients show disruption of white matter and myelin loss, thus supporting our observations. Understanding the neuropathological mechanisms for white matter disruption in cocaine abuse patients is complicated by polydrug use and other comorbid factors, hindering the development of effective therapeutic strategies to ameliorate damage or compliment rehabilitation programs. In this context, our data further demonstrate that cocaine-induced loss of white matter proteins is absent in mice treated with the β-lactam antibiotic, ceftriaxone, during cocaine withdrawal. Other studies report that ceftriaxone, a glutamate transporter subtype-1 activator, is neuroprotective in murine models of multiple sclerosis, thereby demonstrating potential therapeutic properties for diseases with white matter loss. Cocaine-induced white matter abnormalities likely contribute to the cognitive, motor, and psychological deficits commonly afflicting cocaine abusers, yet the underlying mechanisms responsible for these changes remain unknown. Our observations describe an adult animal model for the study of cocaine-induced myelin loss for the first time, and highlight a potential pharmacological intervention to ameliorate cocaine-induced white matter loss.

Contingency management is efficacious and improves outcomes in cocaine patients with pretreatment marijuana use

Background Marijuana use is common in patients seeking treatment for cocaine use. Nevertheless, few studies have examined effects of marijuana use on treatment outcomes in general, and even fewer with respect to contingency management (CM) treatment, which has been criticized for potentially increasing non-reinforced drug use. Methods Data from three randomized clinical trials of CM versus standard treatment (ST) in cocaine-abusing patients were examined ( Petry et al., 2004, 2005a, 2006a; N = 393) to assess effects of pretreatment marijuana use on outcomes. Patients were divided into two groups: (1) no self-reported marijuana use (No Pre-M; n = 315) and (2) any self-reported marijuana use (Pre-M; n = 78) in the 30 days pretreatment. Results CM was especially efficacious in enhancing retention in Pre-M patients such that retention nearly doubled among Pre-M patients assigned to CM versus those assigned to ST. In contrast, CM exerted only modest benefits on retention in No Pre-M patients. Pretreatment marijuana use was not related to during-treatment abstinence from cocaine, opioids, and alcohol, or abstinence at a Month 9 follow-up. However, CM treatment and longest duration of abstinence achieved during treatment were significant predictors of Month 9 abstinence. Pre-M patients also evidenced more improvements in drug problems over time when randomized to CM. Conclusions CM was especially efficacious in facilitating retention and improving severity of drug-related problems in those who used marijuana in the month before initiating treatment.

The selective dopamine uptake inhibitor, D-84, suppresses cocaine self-administration, but does not occasion cocaine-like levels of generalization

A successful replacement pharmacotherapy for treating cocaine dependency would likely reduce cocaine's abuse, support a low abuse liability, overlap cocaine's subjective effects, and have a long duration of action. Inhibitors with varying selectivity at the dopamine transporter (DAT) have approximated these properties. The objective of the present study was to characterize the behavioural effects of an extremely selective DAT inhibitor, (+) trans-4-(2-Benzhydryloxyethyl)-1-(4-fluorobenzyl) piperadin-3-ol (D-84), a 3-hydroxy substituted piperidine derivative of GBR-12935, for its cocaine-like discriminative stimulus effects, its effects on cocaine self-administration, and for its own self-administration. During cocaine discrimination tests, cocaine occasioned the 10 mg/kg cocaine training stimulus with an ED 50 value of 3.13 (1.54–6.34) mg/kg, and reduced response rates with an ED 50 value of 20.39 (7.24–57.44) mg/kg. D-84 incompletely generalized to the cocaine stimulus occasioning a maximal 76% cocaine-lever responding, while reducing response rates with lower potency than cocaine (ED 50 = 30.94 (12.34–77.60) mg/kg). Pretreatment with D-84 (9.6–30.4 mg/kg) significantly ( P < 0.05) reduced cocaine intake at 17.1 mg/kg D-84 when cocaine was self-administered at 0.5 mg/kg/infusion, and at 30.4 mg/kg D-84 when cocaine was self-administered at 0.1, 0.5 .and 1.0 mg/kg/infusion. During self-administration tests with D-84 (0.1–1 mg/kg/infusion), numbers of infusions significantly exceeded vehicle levels at 0.3 mg/kg/infusion. These results show that D-84 pretreatment can decrease cocaine intake especially when high doses of cocaine are being self-administered. This observation, combined with its incomplete generalization to the cocaine discriminative stimulus and its reported long duration of action, provides a profile consistent with a potential replacement therapy for treating cocaine-abusing patients.

Prize-based contingency management is efficacious in cocaine-abusing patients with and without recent gambling participation

Prize-based contingency management (CM) is efficacious in treating cocaine abuse, and the chance-based procedures of prize CM may be appealing to those who gamble. Using data from three randomized trials, we evaluated whether cocaine-abusing patients who had wagered in the month before treatment ( n = 62) responded more favorably to prize CM than those who had not ( n = 278). Participants were randomized to standard care (SC) or SC plus prize CM. Although prize CM was related to better outcomes overall, recent gambling was not associated with outcomes across or within treatment conditions. Gambling participation before treatment entry was associated with reductions in gambling over time, and this effect was more pronounced among those assigned to CM. These data suggest that prize CM is equally efficacious for substance-abusing patients who do and do not gamble, and they extend prior studies indicating that prize CM does not increase gambling.

HIV-1 Antigens in Neurons of Cocaine-Abusing Patients

Cocaine opens the blood-brain barrier by deregulating transcription of target genes. Here we show that cocaine at blood concentrations in drug abusers disrupts endothelial cell junctions in parallel with signaling by phosphorylation of extracellular signal-regulated kinase, myristoylated alanine-rich C kinase and myosin light chain. Cocaine effects may be important in vivo since the neurons of drug abusing patients with HIV-1 associated dementia displayed gp120, p24 and Nef.

Comorbid HIV Encephalopathy and Cocaine Use as a Risk Factor for New-onset Seizure Disorders

Patients living with human immunodeficiency virus represent a growing population, and an increased number of central nervous system presentations can be expected over the next decade. Emerging data suggests that both HIV-seropositive patients and cocaine-abusing patients may be at special risk of seizure phenomena. This case report discusses the risks of new-onset seizure activity when these two risk factors converge, which is a common occurrence in this population. Data from the fields of neuroanatomy and neurovirology are presented to explain the heightened risk of this patient population and provide the practitioner with an improved understanding of the central nervous system complexities in HIV.

Self administration of cocaine in monkeys receiving LAAM acutely or chronically

GERAK, L. R., R. GALICI AND C. P. FRANCE. Self administration of cocaine in monkeys receiving LAAM acutely or chronically. PHYSIOL BEHAV 00(0) 000-000, 2007. Polydrug abuse remains a common problem among opioid abusers as well as patients in opioid maintenance programs. Although cocaine abuse has been reported in patients receiving methadone, the incidence of cocaine use in patients receiving l-alpha-acetylmethadol (LAAM) has not been well established. The goal of this study was to determine whether acute or chronic administration of LAAM modified the reinforcing effects of cocaine using a self-administration procedure in rhesus monkeys. Four monkeys responded under a fixed ratio (FR) 30 schedule to receive i.v. infusions of cocaine (0.0032–0.32 mg/kg/infusion) in the absence of other treatment, after acute LAAM administration (0.1–1.0 mg/kg, s.c.), and during daily administration of 1.0 mg/kg of LAAM. Cocaine maintained self-administration responding that exceeded responding maintained by saline; acutely administered LAAM had small and variable effects on self administration of cocaine. Daily LAAM administration increased the number of infusions received of at least one dose of cocaine. These studies indicated that LAAM administration did not attenuate the reinforcing effects of cocaine, suggesting that LAAM would not likely alter cocaine abuse in patients undergoing treatment for opioid abuse.

The Effect of Lovastatin and Thioridazine on the Degradation of Cocaine in Human Serum In Vitro

The effect of lovastatin and thioridazine on the degradation of cocaine in human serum was studied by incubating therapeutic and toxic concentrations of either drug with cocaine in human serum at 37 degrees C. Without these other drugs, cocaine concentrations decreased by an average of 88% in 120 minutes. Lovastatin at all concentrations studied showed a negligible effect on the degradation of cocaine in human serum and did not alter the pseudocholinesterase activity of the serum. In contrast, in the presence of a therapeutic concentration of thioridazine, cocaine concentrations decreased by only 71% during this period of time, and, with a toxic concentration of thioridazine, cocaine concentrations decreased by only 55%. Thioridazine suppressed the pseudocholinesterase activity of human serum by up to 19% during the 120-minute incubation period, and this effect was more pronounced at higher thioridazine concentrations. These findings suggest that thioridazine may prolong the serum half-life of cocaine by inhibiting the pseudocholinesterase-mediated catabolism of cocaine to ecgonine methyl ester. This may be important in cocaine users who are treated with phenothiazines and other structurally similar drugs. They also may be of interest in cocaine-abusing patients who are treated with phenothiazines for schizophrenic disorders.

Midline Necrotizing Nasal Lesions: Analysis of 18 Cases Emphasizing Radiological and Serological Findings with Algorithms for Diagnosis and Management

The aim of this study was to assess the principal signs and symptoms for severe necrotizing midline nasal lesions and give diagnostic and management algorithms. Literature review and retrospective chart review were performed. Three patients with Wegener's granulomatosis (WG), six patients with sarcoid, eight patients with cocaine abuse, and one lymphoma patient were analyzed with respect to symptom complexes, laboratory results, and radiographic findings. Based on computed tomography findings, a nasal destruction score was tabulated for each patient. All diseases essentially had similar signs and symptoms within the head and neck but several extranasal sites were suggestive of specific etiologies. Serological laboratory testing was diagnostic in only two of the six sarcoid patients and two of the three WG patients. There were no specific tests associated with lymphoma or cocaine abuse, although erythrocyte sedimentation rate was consistently and significantly elevated in the latter group. Biopsy confirmed disease was found in one of the three sarcoid patients, in one of the three WG patients, and in one out of one of the lymphoma patients. Nasal destruction scores were highest in WG and lymphoma patients, intermediate in cocaine abuse patients, and lowest in patients with sarcoidosis. Two of the three WG patients had extensive neoosteogenesis. One out of one lymphoma and five of the eight cocaine abuse patients had oronasal or oroantral fistulas. Laboratory tests and biopsies were consistently unreliable in all diseases. Repeat studies should be performed in all cases of negative results if clinical suspicion is high. Neo-osteogenesis and mastoid disease were associated with WG when compared with patients with similar levels of nasal destruction due to other etiologies. Laryngeal and dermatologic changes without significant nasal bony abnormalities raised suspicion for sarcoidosis. Hard and soft palate defects were associated with cocaine abuse and extranodal nasal lymphoma.

Counseling as an Intervention for the Cocaine-Abusing Methadone Maintenance Patient

Using archival data from Bay Area Addiction Research and Treatment (BAART), a methadone treatment provider, this study examined the efficacy of the clinical intervention of counseling on cocaine use by BAART patients. California State Assembly Bill 2071 mandated that patients at methadone clinics be required to undergo a minimum of 50 minutes of counseling per month. Records of 179 patients continuously active in treatment beginning 12 months prior to (i.e., the baseline) and two years after AB 2071's implementation were reviewed. These patients were also identified as cocaine abusers. A pretest-intervention-posttest design was employed, with the increased counseling mandated by AB 2071 as the intervention. Cocaine abusers' urinalysis results during the one-year baseline were compared to the time period following AB 2071's implementation. The independent variable was the amount of counseling received and the dependent variable was cocaine use. The prediction was that cocaine-abusing methadone maintenance patients would have fewer cocaine positive urine analyses following AB 2071's implementation than in the 12-month baseline period preceding AB 2071. Results supported the main hypothesis that cocaine-abusing patients would show better improvement following AB 2071. Additionally, the actual amount of time in counseling was shown to lead to greater improvement in treatment for cocaine abusers. An important secondary finding was that heroin use was also negatively correlated to time in counseling. There were no gender differences in the response to the counseling treatment.

Cocaine, HIV, and their cardiovascular effects: is there a role for ACE-inhibitor therapy?

Cocaine abuse and HIV disease each have potentially adverse effects upon the heart and cardiovascular system which may be exacerbated when these risk factors are combined. The development of a safe and effective agent to treat both cocaine addiction and its cardiovascular sequelae, that is well-tolerated by HIV patients, would thus be of considerable clinical utility. In this article we discuss the rationale for the investigation of angiotensin converting enzyme (ACE) inhibitors, commonly used to treat hypertension, for treatment in cocaine-abusing populations, based on their potential to reduce cocaine use by modulating levels of dopamine and corticotropin releasing factor in the brain, and on their ability to reverse cardiovascular and platelet abnormalities. We present preliminary findings from echocardiographic and platelet activation studies in 16 HIV-positive, cocaine abusing patients, as well as tolerability and efficacy studies of the ACE-inhibitor, fosinopril, for the treatment of cocaine abuse in both HIV-positive ( n=6) and HIV-negative ( n=5) methadone-maintained cocaine abusers. Findings suggest that HIV-positive cocaine-abusing patients possess abnormalities of diastolic heart function and platelet activation that are potentially reversible with ACE-inhibitor therapy. Findings also suggest that fosinopril is well-tolerated regardless of HIV serostatus, does not appear to cause hypotension, and may possess effectiveness for reducing cocaine use. We conclude that ACE-inhibitor therapy may offer a new pharmacologic approach to the treatment of cocaine abuse and its complications, and that controlled research of this class of agents may be promising.

Influence of individual differences in craving and obsessive cocaine thoughts on attentional processes in cocaine abuse patients

In the present pilot-study, the relation between craving, obsessive thoughts about cocaine, experienced control, and attentional bias for cocaine related words is investigated. Sixteen cocaine abuse patients participated in a reaction time (RT) experiment which was employed to measure the ability of subjects to shift their attention away from cocaine related words. Postexperiment craving was found to be positively correlated with reaction times on drug related cues, in contrast to RT on neutral cues. Furthermore, obsessive thoughts about cocaine use and the experienced cocaine use control, in the week before the experiment, were correlated in a higher degree with RTs on drug cues than postexperiment craving. Attentional bias for drug cues was evidenced in patients with higher scores on obsessive cocaine thoughts and higher craving scores. This study shows that individual differences on information processing, within a cocaine abuse patient population, are present.

Prior treatment experience related to process and outcomes in DATOS

Using data collected from cocaine-abusing patients who participated in the Drug Abuse Treatment Outcome Studies (DATOS), we contrasted patients in treatment for the first time and patients having extensive histories of prior treatment to identify factors associated with better outcomes in each group. Compared with first-timers, treatment-experienced patients had less favorable post-treatment outcomes. Indicators of early engagement in DATOS treatment predicted post-treatment abstinence for both groups. Importantly, the interaction of treatment history and several process measures affected post-treatment abstinence. For example, individual counseling and program compliance had greater impacts on abstinence among treatment repeaters in outpatient drug-free programs than for first-timers. Social support and environmental context were significantly related to abstinence. These findings confirm the importance of considering treatment process and aftercare in developing and implementing strategies to optimize treatment for patients with different treatment histories.

Random versus nonrandom assignment in the evaluation of treatment for cocaine abusers.

Cocaine-abusing patients randomly assigned to day-hospital or inpatient rehabilitation were compared with patients who self-selected these treatment settings to examine differences in substance use and psychosocial outcomes under experimental and nonexperimental designs. There was little evidence of setting or assignment effects or Setting x Assignment interactions over the 12-month follow-up period. However, Assignment x Time interactions were obtained with 2 measures of cocaine use and measures of family-social and psychiatric problem severity. These interactions indicated greater problem severity at intake among the randomized patients coupled with greater improvements by the 3-month follow-up relative to the nonrandomized patients. Findings suggest that randomized studies of treatment for cocaine abuse may produce somewhat larger estimates of improvement than what is observed in more typical treatment situations.

Depression among cocaine abusers in treatment: relation to cocaine and alcohol use and treatment outcome.

The authors investigated the theoretical and clinical role of depression among cocaine abusers in treatment. Eighty-nine cocaine-abusing patients underwent 2 weeks of substance abuse treatment. Posttreatment major depressive disorder, depressive symptoms before and after substance abuse treatment, and alcohol diagnoses were assessed and their relation to pretreatment substance use, cravings in high-risk situations, and 3-month follow-up status was examined. High rates of major depressive disorder were found but were unrelated to pretreatment substance use. The decrease in depressive symptoms during treatment was independent of major depressive disorder or alcohol diagnoses and predicted treatment attrition. Higher levels of depressive symptoms during treatment were associated with greater urge to use cocaine, alcohol, and other drugs in high-risk situations. Concurrent major depressive disorder and depressive symptoms did not predict cocaine use at follow-up. However, patients who had an alcohol relapse episode experienced more depressive symptoms during treatment than did those who abstained. The results highlight the relationship of depression to alcohol use among cocaine abusers and suggest a need for further studies of the association between depression and substance use disorders.