High Cocaine Research Articles

TREATING COCAINE-USING METHADONE PATIENTS: PREDICTORS OF OUTCOMES IN A PSYCHOSOCIAL CLINICAL TRIAL

Cocaine-using methadone patients in two clinics were assigned to 8 months of enhanced methadone treatment—primarily cognitive-behavioral therapy (CBT) for cocaine use—while similar patients in two “sibling” clinics were assigned to standard methadone treatment during 1995–1998. Cocaine use declined significantly from baseline to 4- and 12-month follow-ups. Patients receiving CBT rated the quality of their counseling relationship higher and obtained more supportive services than those receiving standard treatment. However, study treatment condition itself was not associated with outcome. Baseline measures associated with poorer outcomes across both treatment conditions were: currently enrolled in methadone treatment (in contrast to being newly enrolled), higher cocaine use frequency, greater cocaine use associated problem recognition, and an ambivalent attitude toward methadone. The results are consistent with some previous clinical trials showing that psychosocial treatments of different intensities result in similar declines in cocaine use. The findings indicate that methadone maintenance treatment can help dually-addicted patients reduce their cocaine use.

Role of the dopamine transporter and the sodium channel in the cocaine-like discriminative stimulus effects of local anesthetics in rats.

Local anesthetics bind to the dopamine transporter (DAT), inhibit dopamine (DA) uptake and have been reported to have cocaine-like discriminative stimulus effects. The hypothesis of the present study was that affinity at the DAT and potency as a DA uptake blocker determines potency as a cocaine-like discriminative stimulus among local anesthetics, and maximum DA uptake inhibition determines maximum cocaine-like discriminative stimulus effects. Cocaine-like discriminative potency was compared to DAT affinity and DA uptake inhibition potency, and maximum cocaine-like discriminative stimulus effects were compared to maximum DA uptake inhibition for procaine, chloroprocaine, dimethocaine, tetracaine and lidocaine. Discriminative stimulus effects were determined in two groups of rats using 10 mg/kg and 3.0 mg/kg cocaine training doses. DAT affinity and DA uptake inhibition effects were determined in vitro in rat caudate nucleus tissue. Additionally, sodium channel affinity was determined in rat frontal cortex tissue. In the 10 mg/kg group, none of the local anesthetics fully substituted for cocaine and all decreased response rate. Rate decreasing potencies were positively correlated with sodium channel affinities. In the low training dose group, all the local anesthetics except tetracaine substituted fully for cocaine. Discriminative potencies were positively correlated with sodium channel affinities. Maximum DA uptake inhibition did not adequately predict maximum discriminative stimulus effects. Cocaine-like discriminative stimulus effects of local anesthetics were more prominent at a low than at a high training dose of cocaine. Sodium channels seem to have a direct influence on discriminative effects at low cocaine doses, whereas they have an indirect influence on discriminative effects at high cocaine doses by decreasing response rates.

An Evaluation of a Brief HIV Risk Reduction Intervention Using Empirically Derived Drug Use and Sexual Risk Indices

This paper presents the results of an evaluation of a brief, educational HIV risk reduction intervention implemented in a community setting. Participants were 7,733 not-in-treatment drug users. Multi-item needle and sex risk measures were developed to assess the efficacy of the intervention. Behavior change was assessed within 6 empirically derived homogeneous risk groups. Drug users in all 6 groups reduced their needle use and sexual risks after participating in the brief educational intervention. Sexual risks were reduced to a greater extent than were risks associated with needle use, both in relative terms and when measured as a percentage of risk exhibited at intake. Brief educational interventions may be more effective in reducing sexual risk behaviors than it was previously believed. Needle risk, on the other hand, appears to be more robust, especially among high frequency cocaine injectors. Theses findings suggest that HIV prevention strategies may be more effective and more efficient if drug users are triaged into an intervention appropriate to their level of needle risk.

Dose-response effect of cocaine on newborn head circumference.

To evaluate the relationship between head circumference, birth weight, and cocaine dose in healthy term and near-term newborns exposed to cocaine in utero. We used radioimmune assay (RIAH) of cocaine metabolite in maternal hair to quantify third trimester cocaine exposure in 240 healthy newborn infants (gestational age: >36 weeks). Cocaine exposure was categorized into 3 levels: no exposure (n = 136), low cocaine exposure (n = 52; RIAH: 2-66 ng/10 mg hair), and high cocaine exposure (n = 52; RIAH: 81-4457 ng/10 mg hair). We collected information on maternal demographic characteristics, the pregnancy, and the use of substances through a structured interview and from the medical record. Means of birth weight, length, and head circumference of infants with high cocaine exposure differed significantly from those with low exposure and no exposure, but were similar between low exposure and no exposure. We used a multiple linear regression model to assess the association between newborn head circumference and cocaine level, adjusting for the effects of birth weight; gestational age; infant sex; and several maternal factors, including height, weight gain during pregnancy, syphilis during pregnancy, and the use of alcohol, cigarettes, marijuana, and opiates during pregnancy. Only birth weight, sex, and high cocaine exposure were significantly associated with newborn head circumference. The predicted head circumference deficit associated with high cocaine exposure (.44 cm) represents 34% of the unadjusted difference (1.28 cm) between mean head circumferences of infants in the high cocaine exposure and no exposure groups. Newborns exposed to a high level of cocaine in utero (RIAH: >81 ng/10 mg hair) exhibit asymmetric intrauterine growth retardation in which the head circumference is disproportionately smaller than would be predicted from the birth weight (head wasting). The deficit in head size associated with cocaine exposure may reflect the effects of a specific central nervous system insult that interferes with prenatal brain growth.

Treatment of cocaine dependence. Intoxication, withdrawal and prevention of relapse

The aim of this review article is to evaluate the treatment of cocaine-withdrawal, cocaine-intoxication and long-term relapse prevention of cocaine-addicts. Some 25% of police recognized first time drug users in Germany consume cocaine. However, there is an increasing number of cocaine-abusers and -addicts in the USA. The withdrawal of cocaine can be divided into three phases dominated mainly by psychiatric symptoms. Life-threatening condition can occur in cocaine-intoxication mainly in combination with other drug-use. A high risk of relapse is seen in follow-up trials of cocaine-addicts. Intensive craving, high cocaine- and substance-abuse is reported regularly in cocaine-addicts after detoxification therapy. Recommendations in the treatment of cocaine-intoxication, withdrawal and long-term relapse prevention are made. The use of antidepressives, anticonvulsants, dopaminergic and serotonergic medications as well as behavioural, psychoanalytical and combined therapies and their efficacy in clinical and trails is evaluated. A short review of new experimental therapies in the treatment of cocaine-dependence is shown.

Cocaine reward and MPTP toxicity: alteration by regional variant dopamine transporter overexpression

Polygenic factors play important roles in animal models of substance abuse and susceptibility to dopaminergic neurodegeneration. Genetic factors are also likely to contribute to the etiology of human drug abuse disorders, and may alter human vulnerabilities to Parkinsonian neurodegeneration. The dopamine transporter (DAT; SLC6A3) is densely expressed by the dopaminergic midbrain neurons that play central roles in drug reward and is believed to be a primary site of action for cocaine reward. This transporter is necessary for the action of selective dopaminergic neurotoxins, and is uniquely expressed on neurons that are the primary targets of Parkinsonian neurodegeneration. To study possible influences of variant DAT expression on these processes, we have constructed transgenic mice (THDAT) in which tyrosine hydroxylase (TH) promoter sequences drive expression of a rat DAT cDNA variant, increase striatal DAT expression by 20–30%, and provide modest alterations in striatal levels of dopamine and its metabolites. THDAT mice habituate more rapidly to a novel environment than wildtype littermates. These animals display enhanced reward conferred by cocaine, as measured by conditioned place preference. However, locomotor responses to cocaine administration are similar to those of wildtype mice, except at high cocaine doses. THDAT mice display more than 50% greater losses of dopaminergic neurons following a course of MPTP treatment than do wildtype control mice. These results document a model for allelic variation at a gene locus that can exert significant effects in murine models of human substance abuse vulnerability and dopaminergic neurodegeneration.

Brain β-Endorphin Immunoreactivity as an Index of Cocaine and Combined Cocaine–Ethanol Toxicities

The present study examines alterations in the cytoplasmic immunoreactivity of brain β-endorphin, an endogenous opioid peptide regarded as the mediator of both euphoria and antinociceptive systems, in relation to toxicities due to cocaine and combined cocaine–ethanol. β-endorphin–immunoreactive cells were visualized and counted in adjacent sections from male rat brains at the level of the arcuate nucleus. In this region, cytoplasmic β-endorphin immunoreactivity is prevalent. An intraperitoneal injection of cocaine (75 or 15 mg/kg) was given 15 min after an intraperitoneal injection of 3 g/kg ethanol or vehicle. With a fatally toxic dose (75 mg/kg) of cocaine, the number of neurons exhibiting cytoplasmic β-endorphin immunoreactivity (immunoreactive nerve cells) was significantly increased immediately after the drug administration. Ethanol further enhanced the effects of both 15 and 75 mg/kg of cocaine. When the immunoreactivity was visually estimated by computer imaging analysis, lightly stained, weakly immunoreactive cells with photographic light absorption values greater than 50% were enhanced in the cocaine–ethanol groups compared to the cocaine only groups. Fatal toxicities were only observed in the groups treated with the high cocaine doses (75 mg/kg), with or without ethanol. In these groups, the number of strongly immunoreactive cells had increased significantly compared to the other groups. In the group treated with the high cocaine dose (75 mg/kg) plus ethanol, an increased frequency of late deaths that occurred over 1 h after the drug administration was observed, together with a decreased severity of cocaine-induced seizures and an early enhancement of weakly immunoreactive cells. Unlike the strongly immunoreactive cells, the weakly immunoreactive cells appeared to be continuously enhanced, based on an experiment examining β-endorphin immunoreactivity at 24 h after an injection of 50 mg/kg cocaine.

Abnormal electroretinogram in cocaine-dependent patients. Relationship to craving.

The retina contains high concentrations of dopamine. We previously reported that recently withdrawn cocaine-dependent patients had significantly reduced blue cone b wave amplitude responses on the electroretinogram (ERG). In this study we wished to examine if there was a relationship between cocaine craving and reduced blue cone b wave ERG responses. A series of 14 recently withdrawn cocaine-dependent patients completed a 45-item cocaine craving questionnaire shortly before the ERG. Cocaine dependent patients who had a reduced ( < 0.5 microvolts) blue cone b wave ERG response had significantly higher cocaine craving scores than patients without a reduced blue cone ERG response. There was also a significant negative correlation between blue cone b wave amplitude responses and scores on the cocaine craving questionnaire. A reduced blue cone b wave ERG response may identify recently withdrawn cocaine-dependent patients with biological dysregulation and increased cocaine craving.

In vitro competitive inhibition of plasma cholinesterase by cocaine: normal and variant genotypes.

To determine the inhibitory constant, Ki, of cocaine for a number of the different genetic variants of human plasma cholinesterase. In vitro analysis of plasma cholinesterase activity in the presence of cocaine as a competitive inhibitor. Six normal (UU) control sera and seven sera with the following plasma cholinesterase genotypes were assayed: AA, UA, AS, UF, US, AF and SS. Plasma cholinesterase activity was determined in the samples by colorimetric measurement of propionylthiocholine metabolism over a range of concentrations. Competitive activities were then determined in the presence of varying concentrations of cocaine. Double reciprocal plots (1/v vs 1/S) were used to calculate Km and Vmax for propionylthiocholine, and Ki for cocaine for each genotype. The variant forms of the plasma cholinesterase had high cocaine Ki values--all were approximately ten times greater than the Ki for normal plasma cholinesterase. Since the inhibitory constant is an indirect measure of an enzyme's affinity for a competing substrate, a high Ki for cocaine at recreational or therapeutic concentrations would translate into a longer in vivo half-life. Our results support the growing evidence that low plasma cholinesterase activity predisposes to cocaine toxicity.

The failure of cocaine to serve as an orally self-administered reinforcer in Lewis rats

The aim of this study was to develop a procedure to establish orally delivered cocaine as a reinforcer for rats. Several procedures that have proven reliable in other studies were instituted. (1) Food-induced drinking: food was presented to engender high rates of drinking, then cocaine solutions replaced water, and finally the food was removed. Peak drug intakes ranged from 9.4 to 13.8mg/kg. (2) Ethanol-fade: ethanol was established as a reinforcer, cocaine was gradually added to the ethanol, and the ethanol was gradually removed. Peak cocaine intakes ranged from 3.6 to 5.2mg/kg. (3) Modified food-induced drinking: food was presented, but was followed by a timeout period, allowing digestion to progress prior to cocaine drinking. Peak drug intakes ranged from 12.9 to 18.6mg/kg. However, cocaine was not established as a reinforcer with any of these methods. High cocaine doses may be necessary, but are not sufficient, to establish oral cocaine self-administration in rats.

125]RTI-55, a high affinity cocaine analog, labels two binding sites in human caudate membranes possibly related to the 5-HT transporter

rocking, head rolling, hand flapping) that occur without eliciting stimuli and have no clear function. SIB typically includes head banging, eye poking, and other repetitive self-injurious acts. As these behavior disorders have important similarities to compulsions, we examined the prevalence and co-morbidity of SBD, SIB, and compulsive behavior disorder (CBD) in a state residential facility for the mentally retarded, in severely mentally retarded adults, CBD typically consists of compulsive activities (e.g., arranging, checking, hoarding) as well as intricate personal routines (e.g., eating, drinking, or dressing rituals). Our sample included all ambulatory and medically stable individuals at the facility (n-234). All subjects were severely or profoundly mentally retarded. The caseload psychologist for each subject completed a structured survey, which included a symptom checklist. SBD was reported in 59% of the subjects, SIB in 48.7%, and CBD in 38.5¢t. in comparing subjects with CBD (n-90) to those without (n-144), we found a significant association of compulsive behavior with SBD (!)<.05) and SIB (p<.05). in addition, after excluding potential subjects who were taking medication known to affect appetite and/or weight, we found that subjects with CBD and SBD were significantly shorter and weighed less than matched controls at the same institution. This observation is consistent with reports that in the general population, adolescents with CBD are smaller and have different growth patterns than healthy control subjects, in light of the above links between SBD and CBD in the mentally retarded, we designed a placebo-controlled doubleblind, cross-over trial of clomipramine (CMI) for the treatment of SBD. In the I I subjects studied to date, CMI is associated with a significant decrease in stereotyped movements, as well as a reduction in self-injurious behavior.

Time Course of Direct Cardiotoxic Effects of High Cocaine Concentration in Isolated Rabbit Heart

Time Course of Direct Cardiotoxic Effects of High Cocaine Concentration in Isolated Rabbit Heart

Time Course of Direct Cardiotoxic Effects of High Cocaine Concentration in Isolated Rabbit Heart

Studies of acute cocaine cardiotoxicity are often confounded by the effects of cocaine on peripheral hemodynamics and an intact sympathetic nervous system. To study the direct effects of an acute dose of cocaine on heart, we used Langendorff-perfused isolated rabbit hearts. The hearts were attached to a Langendorff perfusion system through the aorta and were perfused with Krebs-Henseleit buffer. In nonpaced hearts, cocaine in concentrations of 10, 25, and 50 microM (reported to be in the range of drug concentrations lethal for humans) caused dose-dependent deterioration in heart contractility (decrease in +dP/dt, -dP/dt, and developed pressure) and coronary flow, when measured at 10, 20, and 30 min of the protocol. Cocaine 25 and 50 microM also caused a decrease in heart rate (HR). In paced hearts treated with cocaine 50 microM, early events included a progressive decrease in +dP/dt (by 15% vs. baseline at 20 s of perfusion and by 26% vs. baseline and 19% vs. control group at 30 s of perfusion; p < 0.05) and in -dP/dt (by 20% vs. baseline at 30 s of perfusion and by 25% vs. baseline and 15% vs. control group at 40 s of perfusion, p < 0.05). Decrease in HR (failure to pace) was observed only at 60 s of perfusion and averaged 20% versus both baseline and control group (p < 0.05). No changes in coronary flow were observed during the first 60 s after onset of cocaine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of buprenorphine on the self-administration of cocaine by humans.

Seven male research volunteers reporting intravenous cocaine and morphine use participated in 12 cocaine self-administration sessions. A session consisted of sublingual buprenorphine pretreatment (0, 2, 4mg) 50min before seven self-administration trials. The first three trials were sampling trials, in which subjects were given each of the three reinforcers available for that session; the remaining four trials were choice trials in which subjects could choose between two doses of cocaine and tokens exchangeable for special privileges. Each buprenorphine dose was tested for four consecutive days under different cocaine dose/token combinations (e.g. 8mg vs 16mg vs two tokens). Following placebo, under all choice conditions, subjects reliably chose higher doses of cocaine over lower doses, and tokens about as often as high cocaine doses. Buprenorphine (4mg) significantly decreased high-dose cocaine choice and increased token choice, when the available cocaine doses were 16 and 32mg/70kg. Both buprenorphine doses significantly increased ratings of "sedated" and opiate symptoms and decreased ratings of "bad drug effect" following all cocaine doses. Both buprenorphine doses, in combination with cocaine doses greater than 8mg, significantly increased self-reported "high" and occasionally increased "stimulated" scores above values seen following cocaine alone. The results demonstrate that in the presence of non-drug alternative to cocaine (tokens), buprenorphine decreased high-dose cocaine choice. Despite the decrease, subjects were clearly intoxicated from a drug combination that mimicked a cocaine-heroin ("speedball") effect. Although buprenorphine may be useful in reducing cocaine use, the complex relationship between this reduction in use, behavioral alternatives, and the subjective effects of the drug combination remains unclear.

Water deprivation-induced oral self-administration of cocaine in the Lewis rat: Evidence for locomotor effects but not reinforcement

Oral cocaine self-administration was studied in water-deprived Lewis rats. Liquid was available to rats only during daily 90-min sessions, in chambers equipped with spouts that delivered precise volumes of liquid following completion of lever-press responses. Blocks of training and testing sessions were alternately carried out during which increasing cocaine concentrations were presented: 0.0, 0.0125, 0.025, 0.05, 0.1, 0.2, 0.282, and 0.4 mg/ml. Although high cocaine intakes (23.3–33.0 mg/kg) were obtained, neither avoidance nor preference for cocaine developed. Subsequently, fixed-ratio size was increased, and then distinctive stimulus lights were correlated with each liquid. One rat showed a preference for water following these changes, but two rats continued to show no preference. To determine if the amounts of cocaine self-administered had behavioral effects, locomotor activity tests were run immediately following self-administration sessions. Locomotor activity was substantially higher following cocaine self-administration than following water self-administration. These results demonstrate that the cocaine intakes reached under the present conditions did produce locomotor, but not reinforcing, effects.

Persistent Left Ventricular Dysfunction after Cocaine Treatment in Rabbits

The present study was undertaken to determine whether the diminished cardiac performance associated with cocaine administration persists after the drug has been eliminated from the body. Cocaine (5 or 10 mg/kg iv) was administered to conscious (n = 7) or pentobarbital-anesthetized (n = 7) rabbits, respectively. Seven conscious and seven anesthetized control rabbits received the saline vehicle. Two and one-half hours later, the hearts were removed from the animals and perfused under cocaine-free conditions. Left ventricular (LV) contractility was evaluated by plotting steady-state LV systolic and diastolic pressures as a function of LV end-diastolic volume (preload). LV systolic performance was diminished in a dose-related manner in hearts isolated from cocaine-treated rabbits, but was statistically different from control only at the higher cocaine dose (P < 0.05). In a second set of experiments, hearts (n = 6) were isolated, and their LV function was evaluated before, during, and after cocaine exposure. In these experiments, cocaine was added to the perfusate in increments to produce concentrations of 5, 10, and 15 mg/liter. After LV function was evaluated at the highest cocaine dose, cocaine-free perfusion conditions were restored, and LV function was reevaluated. In these experiments, cocaine produced a dose-dependent decrease in LV function that readily reversed when cocaine-free perfusion was reinstated. We conclude that cocaine diminishes LV contractility, and that the diminished cardiac performance may not readily reverse after in vivo exposure. Moreover, the rapid restoration of cardiac performance after exposure to cocaine in vitro suggests that the mechanism operating in vivo involves more than a simple direct action on the myocyte. Catecholamine cardiotoxicity does not appear to be a primary factor.

Behavioral effects of cocaine alone and in combination with ethanol or marijuana in humans

Intranasal cocaine (COC) and oral ethanol (ETOH) were administered to one group of seven research volunteers during daily experimental sessions. Following the determination of baseline subjective and performance measures, an ETOH cocktail (0, 19.4, 38.7 or 58.1 g of ETOH in lemonade) was consumed over a 10-min period. COC hydrochloride (4, 48, 96 mg) was inhaled 35-min after the start of ETOH drinking. In a separate experiment, seven research volunteers received intravenous cocaine and smoked marijuana (MJ), alone and in combination during daily experimental sessions. Following the determination of baseline measures, a 1-g MJ cigarette (0-2.7% delta 9-THC, w/w) was smoked and 13 min after the start of MJ smoking COC hydrochloride (0, 16, 32 mg) was given intravenously. ETOH increased simple-reaction time and decreased DSST trials. COC decreased DSST trials, increased incorrect responses on a list-learning task and attenuated the effect of ETOH on DSST performance. Only combinations of the high COC dose and the high MJ dose increased errors on a repeated acquisition task. Intranasal COC increased ratings of 'Stimulated,' and 'High' and LSD scores on the ARCI which were unaffected by ETOH. Increased ratings of 'Sedated' following ETOH alone were attenuated by intranasal (i.n.) COC. Intravenous COC and smoked MJ alone both increased ratings of 'Stimulated' and 'High.' There was a trend for combinations of i.v. COC and MJ to prolong these elevations. The results suggest that the interactive effects of COC in combination with ETOH or MJ, after acute administration, are subtle and in need of further analyses to better understand polydrug abuse.

Orally self-administered cocaine in rhesus monkeys: transition from negative or neutral behavioral effects to positive reinforcing effects

The establishment of orally delivered cocaine as a reinforcer was examined with nine rhesus monkeys. A 2% ethanol solution served as a reinforcer for all nine monkeys, for it maintained substantially higher response rates than did the concurrently available water vehicle. A test was initially conducted to determine whether cocaine would function as a reinforcer when substituted for 2% ethanol. When an intermediate cocaine concentration (0.2 mg/ml) was substituted for the ethanol solution, the drug maintained behavior at rates less than (seven monkeys), equal to (one monkey), or greater than (one monkey) those maintained by water. Thus, for eight of nine monkeys simple substitution of cocaine for ethanol was not sufficient to establish orally delivered cocaine as a reinforcer. In the next phase a stimulus-fading procedure was used. Blocks of training and testing sessions alternated. Across blocks of training sessions, increasing amounts of cocaine (0.0125, 0.025, 0.05, 0.1 mg/ml) were added to the 2% ethanol solution and subsequently the ethanol concentration was gradually decreased until only the 0.1 mg/ml cocaine solution remained; water was always concurrently available. Between each block of training sessions, a block of test sessions was inserted. Test sessions compared relative rates of responding maintained by two concurrently available drug solutions: (1) a solution containing the combination of ethanol and cocaine used in the prior training block and (2) a solution containing the same concentration of ethanol but with no cocaine. Thus, differences in rates of behavior maintained by the two solutions could be attributed to the presence of cocaine and the existence and degree of any such differences could be monitored at each step in the acquisition procedure. The outcome of the training procedure was that cocaine came to function as a reinforcer for six of the eight monkeys tested (the ninth monkey was not put through the fading procedure, having shown higher cocaine than vehicle rates during the initial substitution procedure). During the phase when ethanol was faded from the drug solution, differences between the combination cocaine-ethanol solution and the ethanol-only solution emerged: for the six monkeys that developed cocaine reinforced behavior, the combination solution maintained higher rates of responding than the ethanol solution alone. The opposite results were obtained with the remaining two monkeys. That cocaine had been established as a reinforcer was confirmed by persistent and orderly responding when dose and fixed-ratio size were subsequently varied.

Electrophysiological effects of high cocaine concentrations on intact canine heart. Evidence for modulation by both heart rate and autonomic nervous system.

Previous clinical reports have suggested that cocaine intoxication may produce severe ventricular arrhythmias due to a direct effect on the heart. However, the effects of high plasma levels of cocaine on the electrophysiology of the heart have not been well characterized and remain poorly understood. The purpose of this study was to characterize the electrophysiological effects of high doses of cocaine on the in situ dog heart. In dogs anesthetized with morphine and alpha-chloralose, cocaine (2-11 micrograms/mL) increased both atrial and ventricular refractory periods and produced rate-dependent increases in atrial, atrioventricular, His-Purkinje, and ventricular conduction intervals. The time constant for the onset of cocaine's conduction slowing effect following a reduction in pacing cycle length from 400 to 260 msec was approximately two beats, and the time constant for diastolic recovery from conduction slowing was approximately 200 msec, which are similar to values reported for several class Ib antiarrhythmic drugs. Cocaine produced a rate-dependent increase in QT interval that was greatest at high heart rates yet produced no change in the ST (QT-QRS) interval. This suggests that high plasma levels of cocaine delay repolarization primarily via slowing of conduction. Cocaine's effects on both atrioventricular and intraventricular conduction were significantly larger in autonomically blocked than in autonomically intact animals. We conclude that high plasma levels of cocaine, similar to those reported in autopsy reports following fatal cocaine overdose in humans, produce significant rate-dependent conduction slowing effects on atrial, atrioventricular, and ventricular conduction in the in situ heart. These rate-dependent effects are intensified following autonomic blockade.

The effect of cocaine on sperm motility characteristics and bovine cervical mucus penetration

To determine the in vitro effects of cocaine on sperm motility and bovine mucus penetration because cocaine abuse is associated with decreased sperm motility, and related compounds, such as procaine, are known to decrease sperm motility. Human semen samples were exposed to a range of cocaine concentrations and the effects quantified using computer-assisted sperm analysis and the bovine mucus penetration test. University research laboratory. Samples were obtained from 18 healthy volunteers. Normal semen samples were exposed to concentrations of cocaine ranging from 10 −11 to 10 −4 M. Motility characteristics were evaluated after 2 hours, and bovine mucus penetration was evaluated after 30 minutes, 1 hour, and 2 hours. Mucus penetration by washed sperm was also evaluated. Motility characteristics were evaluated using computer-assisted sperm analysis, and functional sperm motility was evaluated using the bovine mucus penetration test. Cocaine exposure decreased the percentage of motile sperm in a concentration-dependent manner with a maximum decrease of 23% at 10 −4 M but had no effect on other motility characteristics. Cocaine decreased bovine mucus penetration by 12% at high cocaine concentrations (10 −4 M), but increased penetration by 69% at low concentrations (10 −9 M). Washing sperm before cocaine exposure attenuated the increased sperm penetration. The ability of cocaine to decrease the percentage of motile sperm at high concentrations may explain the decreased sperm motility associated with cocaine use. Cocaine’s ability to augment sperm penetration at low concentrations suggests an interaction of cocaine with the sperm adrenergic system.