Central administration of cocaine produces age-dependent effects on behavior in the fetal rat.

Rat fetuses were exposed to cocaine, lidocaine, or saline on Gestational Day 20 or 21 to provide information about cocaine effects on behavior during prenatal development. Cocaine was administered into the cisterna magna of individual fetal subjects to restrict effects to the CNS. Behavioral effects of cocaine were compared with lidocaine to help distinguish the effects of cocaine on monoamine systems in the brain from its properties as a local anesthetic. Cocaine promoted 3–5 fold increases in fetal motor activity in the absence of explicit sensory stimulation, in contrast to the slight suppressive effects of lidocaine. Cocaine and lidocaine also reduced coordinated behavioral responses to an artificial nipple. The behavioral effects of cocaine administered into the CNS of fetal subjects suggest specific mechanisms of action on developing neural and behavioral systems in the late prenatal period. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative and reinforcing stimulus effects of nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys.

Concurrent cigarette smoking and cocaine use is well documented. However, the behavioral pharmacology of cocaine and nicotine combinations is poorly understood, and there is a need for animal models to examine this form of polydrug abuse. The purpose of this study was twofold: first to assess the effects of nicotine on the discriminative stimulus effects of cocaine, and second, to study self-administration of nicotine/cocaine combinations in a novel polydrug abuse model. In drug discrimination experiments, nicotine increased the discriminative stimulus effects of low cocaine doses in two of three monkeys, but nicotine did not substitute for cocaine in any monkey. Self-administration of cocaine and nicotine alone, and cocaine + nicotine combinations was studied under a second-order fixed ratio 2, variable ratio 16 (FR2[VR16:S]) schedule of reinforcement. Cocaine and nicotine alone were self-administered in a dose-dependent manner. The combination of marginally reinforcing doses of cocaine and nicotine increased drug self-administration behavior above levels observed with the same dose of either cocaine or nicotine alone. These findings indicate that nicotine may increase cocaine's discriminative stimulus and reinforcing effects in rhesus monkeys, and illustrate the feasibility of combining cocaine and nicotine in a preclinical model of polydrug abuse. Further studies of the behavioral effects of nicotine + cocaine combinations will contribute to our understanding the pharmacology of dual nicotine and cocaine dependence, and will be useful for evaluation of new treatment medications. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Effects of repeated-dose isradipine on the abuse liability of cocaine.

Despite preclinical studies suggesting that isradipine may antagonize the abuse liability of cocaine, pretreatment with sustained-release isradipine did not reduce euphoric mood in cocaine-using volunteers. This double-blind, within-subject, crossover laboratory study determined whether maximal dose-loading with isradipine could antagonize effects of cocaine in 12 cocaine-dependent research volunteers administered intravenous cocaine doses (0, 0.325, and 0.65 mg/kg) on different days after 5 days of treatment with isradipine or placebo. Isradipine dose was 30 mg sustained release nightly plus 15 mg immediate release 2 hr before cocaine infusion. Cocaine produced dose-related increases in cocaine's subjective effects and a behavioral measure of reinforcement. Isradipine enhanced, rather than antagonized, subjective effects, indicating that isradipine does not antagonize cocaine's abuse liability in dependent research volunteers. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Microinfusion of cocaine into the medial preoptic area or nucleus accumbens transiently impairs maternal behavior in the rat.

Cocaine was microinfused bilaterally (50 μg/0.5 μl/side) into the medial preoptic area (MPOA) or nucleus accumbens (NA), 2 regions within the rat brain neural circuit known to mediate maternal behavior (MB). Additionally, 2 sites not involved in this neural circuit, the dorsal striatum and dorsal medial hippocampus, were used as control sites. Microinfusion of cocaine into the MPOA or NA impaired MB, whereas infusion into the control sites did not. MB impairment was not temporally coincident with the increased locomotor activity, also documented after cocaine infusion into the MPOA or NA, arguing strongly that impaired MB is a direct, specific effect of cocaine in these areas, not a derivative of increased motor activity. This is the first demonstration that cocaine action on single central nervous system (CNS) sites can impair MB to the same extent as systemic injections. Thus, cocaine's simultaneous effect on multiple CNS sites is not required for MB impairment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Oxytocin and addiction: a review

Neuropeptides affect adaptive central nervous system processes related to opiate ethanol and cocaine addiction. Oxytocin (OXT), a neurohypophyseal neuropeptide synthesized in the brain and released at the posterior pituitary, also is released in the central nervous system (CNS). OXT acts within the CNS and has been shown to inhibit the development of tolerance to morphine, and to attenuate various symptoms of morphine withdrawal in mice. In rats, intravenous self-administration of heroin was potently decreased by OXT treatment. In relation to cocaine abuse, OXT dose-dependently decreased cocaine-induced hyperlocomotion and stereotyped grooming behavior. Following chronic cocaine treatment, the behavioral tolerance to the sniffing-inducing effect of cocaine was markedly inhibited by OXT. Behavioral sensitization to cocaine, on the other hand, was facilitated by OXT. OXT receptors in the CNS--mainly those located in limbic and basal forebrain structures--are responsible for mediating various effects of OXT in the opiate- and cocaine-addicted organism. Dopaminergic neurotransmission--primarily in basal forebrain structures--is another important biochemical mediator of the central nervous system effects of OXT. Tolerance to ethanol (e.g. hypothermia-inducing effect of ethanol) also was inhibited by OXT.     

Dexamethasone pretreatment reduces the psychomotor stimulant effects induced by cocaine and amphetamine in mice

1. The present study examined a comparison of the effect of DEX on psychomotor stimulant effects of cocaine and amphetamine in mice by using the locomotor activity test. 2. Cocaine (10 mg/kg/i.p.) and amphetamine (5 mg/kg/i.p.) increased markedly locomotor activity of mice whereas DEX per se (0.1-1.0-10 mg/kg/i.p.) did not modify the activity of control mice. 3. DEX pretreatment decreased the stimulating effects induced both by cocaine and amphetamine but no consistent dose-related effects were observed. 4. The results suggest that DEX may play an important role on the stimulating effects of cocaine and amphetamine and that it may be of some utility in the clinical management of psychostimulants abuse.     

Comparison of the frequency and enjoyability of pleasant events in cocaine abusers vs. non-abusers using a standardized behavioral inventory

AIMS: To examine whether cocaine abusers differ from non-abusers in their frequency and enjoyability of engaging in various "pleasant events", in order to approximate the density of positive reinforcement experienced in their natural environment. DESIGN: Comparisons of cocaine abusers to normative data and matched controls. SETTING: An outpatient substance abuse treatment center in Burlington, Vermont, USA. PARTICIPANTS: Subjects included 100 individuals enrolled in outpatient treatment for cocaine abuse or dependence and 50 community volunteers without histories of drug abuse or other major psychiatric illness and matched to cocaine-dependent patients on age, sex and SES. MEASUREMENTS: Diagnostic assessments were based upon clinical interviews using the DSM-III-R checklist. The primary focus of this study was the Pleasant Events Schedule (PES), a self-rated behavioral inventory of the frequency and enjoyability of engaging in "pleasant" activities. Cocaine use history, treatment outcome and other relevant variables were also assessed. FINDINGS: Cocaine abusers reliably reported lower frequency of non-social, introverted, passive outdoor and mood-related activities than controls. These differences remained after controlling for demographic and life-style differences between groups, with the exception of mood-related activities. Perceived enjoyability of the activities did not differ across groups. Intravenous cocaine use and prior treatment for cocaine abuse predicted particularly low frequency of pleasant activities. Greater frequency of non-social activities predicted better treatment outcome. CONCLUSIONS: Drug abuse is associated with low density of certain types of non-drug reinforcement. Systematic increases in these activities may improve treatment outcome.     

Concurrent use of cocaine and alcohol is more potent and potentially more toxic than use of either alone--a multiple-dose study

BACKGROUND: Simultaneous abuse of cocaine and alcohol is widespread and increasingly detected in patients seeking emergent care. This double-blind, randomized, within-subjects study used a paradigm more closely approximating practices of drug abusers to better understand the pathogenesis of cocaine-alcohol abuse. METHODS: Subjects meeting DSM-IV criteria for cocaine dependence and alcohol abuse participated in three drug administration sessions: four doses of intranasal cocaine (1 mg/kg every 30 min) with oral alcohol (1 g/kg) administered following the initial cocaine dose and a second dose (120 mg/kg) at 60 min calculated to maintain plasma alcohol concentration at approximately 100 mg/dL during cocaine administration; four doses of cocaine/placebo alcohol; four doses of cocaine placebo/alcohol. Pharmacokinetic, physiological, and behavioral effects were followed over 8 hours. RESULTS: Cocaine-alcohol produced greater euphoria and increased perception of well-being relative to cocaine. Heart rate significantly increased following cocaine-alcohol administration relative to either drug alone. Cocaine concentrations were greater following cocaine-alcohol administration. Cocaethylene had a longer halflife with increasing concentrations relative to cocaine at later time points. CONCLUSIONS: Enhanced psychological effects during cocaine-alcohol abuse may encourage ingestion of larger amounts of these substances over time placing users at heightened risk for greater toxicity than with either drug alone.     

Acute myocardial infarction related to cocaine use. Report of a case

Cocaine use has been associated with ischemic syndromes, especially angor pectoris, myocardial infarction, cardiac arrhythmias and sudden death. A significant number of persons suffering from myocardial infarction associated with cocaine abuse do not have significant coronary atherosclerosis, and the mechanism for infarction in these patients have remained obscure. This report describes a young man with angiographically normal coronary arteries in whom cocaine abuse probably produced coronary artery spasm leading to coronary thrombosis and infarction.     

Cocaine, dopamine and the endogenous opioid system

Cocaine addiction and opiate addiction are both major health problems in the United States today. Prospective studies from our Laboratory, which were able to detect the advent of the HIV-1 epidemic in parenteral drug abusers in New York City beginning around 1978, also showed that, from the beginning of the AIDS epidemic, cocaine abuse was a very important co-factor significantly increasing the risk for developing cocaine dependency. Fundamental studies from many laboratories including our own have shown that cocaine has profound effects on dopaminergic function, primarily from its well-established primary action of blocking the reuptake of dopamine from the synaptic cleft, an action of cocaine directed at the specific dopamine transporter. It has also been well-established by others that cocaine similarly blocks the reuptake of serotonin and norepinephrine. However, recent studies from our laboratory have shown that chronic cocaine administration profoundly disrupts the endogenous opioid system. Extensive studies have been conducted using an animal model which we have developed in our laboratory, the "binge" pattern cocaine administration model. Findings from these studies have led us to recognize the profound disruption of both dynorphin gene expression and kappa opioid receptor gene expression in a setting of chronic cocaine administration and, in turn, have led us to question a possible role of disruption of this system in the acquisition and persistence of cocaine addiction. These findings may have significance for the development of new pharmacotherapeutic agents which may be directed to specific components of the endogenous opioid system and, in particular, possibly the kappa opioid receptor system. Therefore, we have initiated studies to examine further the role of the dynorphin peptide-kappa opioid receptor system in normal physiologic function in humans.     

Diabetic ketoacidosis associated with cocaine use

BACKGROUND: Multiple risk factors for diabetic ketoacidosis (DKA) have been described, including omission of insulin therapy and clinical conditions known to increase counterregulatory hormones. Recently, substance abuse has been identified in patients with DKA. We observed many cases of DKA in cocaine users, although the association between cocaine use and DKA has not been well described in the medical literature. METHODS: We performed a retrospective case-control study of admissions for DKA in cocaine users and non-user controls in an urban teaching hospital from January 1, 1985, to December 31, 1994. RESULTS: We identified 720 adult admissions for DKA. Twenty-seven cocaine users accounted for 102 admissions (14% of all DKA admissions). The users were compared with 85 nonuser controls who had 154 DKA admissions. Cocaine users had more admissions for DKA (mean, 3.78 vs 1.81; P = .03). Cocaine users were less likely than controls to have an intercurrent illness identified as a precipitating factor for DKA (14.7% vs 33.1%; P<.001) and were more likely to have missed taking insulin prior to admission (45.1% vs 24.7%; P<.001). Although cocaine users had higher serum glucose levels on admission (32.9 mmol/L [593.4 mg/dL] vs 29.5 mmol/L [531.1 mg/dL]; P =.03), no differences in intensity of illness or treatment outcome were detected. CONCLUSIONS: In this preliminary study, cocaine use was found in a significant number of adults admitted with DKA and was associated with more frequent omission of insulin therapy and the absence of precipitating systemic illness. Either because of its association with insulin therapy omission or its effects on counterregulatory hormones, cocaine use should be considered a risk factor for DKA, particularly in patients with multiple admissions.     

Cocaine during embryogenesis alters social, defensive, and immunological responses in a precocial avian model.

Cocaine administered to incubating eggs of precocial domestic fowl in dosages that did not affect birth weight or produce gross morphological abnormalities decreased hatchling vocalizations and activity during social isolation, decreased defensive immobility induced by a simulated predatory encounter, and altered T- and B-cell proliferation to mitogen stimulation. These cocaine effects on adaptive social, defensive, and immunologic responses occurred in the absence of the pre- and postnatal maternal influences that occur in nonprimate altricial animal models. The precocial avian model permits an evaluation of drug effects on the developing organism independent of drug-induced alterations in maternal health, nutrition, and behavior. This dissociation of drug effects may provide useful information in the development of treatment strategies for individuals prenatally exposed to cocaine or other drugs of abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Longitudinal study of tissue- and subunit-specific obesity-induced regulation of the pyruvate dehydrogenase complex

Cocaine use has been shown to increase the risk of HIV infection in humans, and this increased risk cannot be explained by i.v. drug use alone. It is thought that this increased susceptibility may be a result of decreased immune responsiveness in cocaine addicts. Scientists are now using animal models to study the effects of cocaine on immune function in vivo under controlled conditions. Many facets of the immune system are being examined, which include immune cell number and distribution, cellular- and humoral-mediated immunity, cytokine production, and immunocompetence to challenges such as infection and tumor growth. The effects of cocaine on many of these functions are not yet clear. Often there are variations in the response of the immune system to cocaine. Potential confounding factors include variations in dose, duration of treatment, and route of administration of cocaine, as well as variations in assay protocols. In addition, there appear to be species differences in immune responses to cocaine. Although it is clear that more research is necessary to resolve the discrepancies, a sufficient number of trends are starting to emerge. This review will systematically evaluate the reported effects of cocaine on immune cell function in vivo. In addition, the possible mechanisms that may be contributing to the immune modulation observed with cocaine in vivo will be addressed. Further, data will be presented describing the effects of cocaine on the autonomic nervous system and the neuroendocrine system suggesting that inhibition of serotonin uptake may be an important component of the overall effects of cocaine on the immune system.     

Treatment of malignant gliomas: a new approach

The etiology of seizures associated with cocaine use is unclear. Because cocaine seizures are relatively uncommon, they should be diagnosed by exclusion and a neurological workup to rule out central nervous system (CNS) catastrophe should be made. This report describes the clinical findings, treatment, and blood cocaine and metabolite concentrations in a patient who, on two separate occasions, had seizures associated with crack cocaine ingestion. Approximately 1 hour after the ingestion incidents, the patient had multiple, generalized seizures that abated spontaneously. His workup for CNS bleeding, infection, and trauma was negative. Cocaine concentrations on the first incident peaked at 2.48 mg/L and on the second incident peaked at 3.9 mg/L. Other clinical findings included tachycardia, hypertension, diaphoresis, and disorientation. Blood cocaine and metabolite analysis revealed extremely high concentrations. Other than the incident of seizures and transient cardiovascular aberrations, these high concentrations were tolerated by the patient without further sequelae. A review of cocaine-induced seizures and treatment is included.     

Review of Cocaine: A clinician's handbook.

Reviews the book, Cocaine: A clinician's handbook edited by Arnold M. Washton and Mark S. Gold (see record 1987-98183-000). Washton and Gold point out that the goal of this text is to provide "clinicians with information that is directly relevant to the treatment of cocaine abusers." I feel they accomplished their goal, by concentrating on various aspects of theory, research, and treatment of cocaine abuse. The book is divided into three major sections: Basic and Biomedical Issues, Treatment Approaches, and Special Topics. Overall, this text examines a range of topics. This book can be extremely valuable to physicians, psychiatrists, psychologists, social workers, counselors in the drug and alcohol fields, and students. The book is comprehensive in what it covers and well organized. Even experienced professionals in this field will be hard pressed to find flaws with this resource. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cocaine abuse and HIV-1 infection: epidemiology and neuropathogenesis

The epidemiology of cocaine abuse and potential relationships of cocaine withdrawal to human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) are discussed. Neuroendocrinological changes in HIV-1 infection of the central nervous system (CNS) are discussed with the relevant impact of cocaine abuse. HIV-1 load in the brain tissue of infected substance users is described along with possible associations with neuropathology and HAD. Finally, the molecular epidemiology and sequence heterogeneity of HIV-1 and their implications for neuropathogenesis are summarized. The complex context of addressing cocaine abuse in the setting of HIV-1 infection appears more tractable when decomposed into its components.     

Apoptosis mediated by Fas and its related diseases]

This study discusses the effect of gammahydroxy butyric acid (GHB) on growth hormone (GH) secretion changes in cocaine addicts. Ten male cocaine users and 10 normal controls were tested with a single oral administration of GHB at a dose of 25 mg/kg body weight. Cocaine addicts were tested before and after 30 days of abstinence. All subjects underwent a control with a placebo. Basal GH levels were similar in normal controls and cocaine users and remained unmodified during the control test. In the normal control subjects, plasma GH levels rose significantly after the administration of GHB; in contrast, plasma GH concentrations failed to increase after GHB treatment in cocaine addicts. These data show that a chronic abuse of cocaine induces alterations of the GABAergic system which were unmasked by the absent GH response to GHB.     

Muscle metabolism of professional athletes using 31P-spectroscopy

PURPOSE: Cocaine abuse has reached epidemic proportions in the United States. Our recent study has shown that cocaine has adverse action on spermatogenesis and fertility in male rats. The indirect action of cocaine occurs by blocking the reuptake of neurotransmitter, which causes local vasoconstriction. In this study we evaluate blood flow to the testes after subcutaneous injection of cocaine to male rats. METHODS: Male Sprague-Dawley rats were divided into two main groups. The treatment group received subcutaneous cocaine (30 mg/kg body weight) and the control animals received normal saline. Xenon-133 wash out experiments were carried out on testes at 5, 10, 15, 20, 30, 45, 60, 90 min and 4.5 hours after injection of cocaine or normal saline. Statistical analysis was done by SPSS V. 7.S for windows. P < 0.05 was considered statistically significant. RESULTS: There was a reduction in testicular blood flow after cocaine administration to male rats. This vasoconstrictor effect was most pronounced at 15 min after injection of cocaine and persisted up to 60 min. At 90 min, the early restitution of blood flow to ischemic tissue occurred. There was a significant increase in testicular blood flow in cocaine-treated groups than in the control group during restitution phases at 90 min. At 4.5 hours, there was no difference in blood flow in both groups. CONCLUSION: This study demonstrates that cocaine, when given subcutaneously at a 30 mg/kg body weight dose, results in prolonged vasoconstriction of the blood vessels to the testes. Adverse effects of cocaine on the testes may be in part due to ischemic and postischemic reperfusion injury to the organ.     

Cocaine abusers do not show loss of dopamine transporters with age

Cocaine blocks dopamine transporters (DAT) and this effect is crucial to its reinforcing properties. To assess the effects of chronic cocaine on DAT we evaluated 20 current cocaine abusers and 20 age matched controls using PET and [C-11]cocaine as a DAT ligand. Though there were no differences in DAT availability between groups, current cocaine abusers (and 12 detoxified cocaine abusers studied previously) did not show the typical age-related decline in DAT seen in controls. Though further studies are required to rule out sampling effects and to control for confounding variables (i.e. smoking), one could speculate that chronic DAT blockade by cocaine has a protective effect on the loss of DAT with age.     

Modulation of drug-induced sensitization processes by endogenous opioid systems

Behavioural sensitization involves progressive increases in behavioural responses to repeated intermittent administration of drugs of abuse. Behavioural sensitization is observed to the locomotor stimulant, rewarding and discriminative effects of a drug. These are effects which seem to be essential in the initiation, expression and maintenance of a drug-seeking behaviour. Therefore the phenomenon of behavioural sensitization may have important implications for the understanding of addictive processes. Findings given in this review demonstrate the involvement of endogenous opioid systems in the initiation of sensitized responses on the neurochemical level, i.e., within the mesolimbic dopaminergic system, as well as on the behavioural level. Specifically, it is shown that behavioural sensitization to morphine and cocaine is modulated by endogenous kappa-opioid systems.