Cocaine Group Research Articles

メタンフェタミン,モルヒネ,コカイン急性中毒の病理組織学的検討

Methamphetamine, morphine or cocaine was injected intraperitoneally into Wistar rats (male, 6 weeks old) at a dose of 50 mg/kg, 125 mg/kg, or 50 mg/kg body weight, respectively. These doses of drugs were determined to ensure that the rats would show signs of drug intoxication and survive for a day. Over the period from 5 min to 18 hr after injection, concentrations of the drugs and metabolites in blood were analyzed by the GC/MS method, and the histopathological changes of the heart, lungs, liver and kidneys were examined by light microscopy. The time of maximum drug concentration in the blood after injection was 5 min in the methamphetamine-treated group, 1 hr (total morphine) in the morphine group and 5 min in the cocaine group. These blood concentrations decreased with time. In the liver at 2.5 hr after injection of methamphetamine, centrolobular vacuolation and diffuse eosinophilic changes of hepatocytes appeared. At 6 hr this damage spread to the midzone of the liver and partial necrosis of the centrolobe was found. At 18 hr the liver damage became worse and necrosis was also found in the midzone of the liver. In the heart, from 2.5 hr, eosinophilic changes of the myocardium were observed diffusely. Furthermore, at 18 hr, partial inflammatory cell infiltration and contraction bands were observed. The degree of histopathological damage did not coincide with the time of maximum drug concentration. In the morphine group, centrolobular and midzonal vacuolation, diffuse fatty degeneration and eosinophilic changes were observed in the liver from 2.5 hr to 18 hr after the administration. No necrosis was found, perhaps because the rats did not suffer the hyperthermia observed in the methamphetamine group. The degree of histopathological damage became more serious with time, as it did in the methamphetamine group. In the cocaine group, no histopathological changes were observed, probably because the doses of cocaine were too small to cause histopathological damage, and because cocaine is more rapidly metabolized than methamphetamine or morphine. These results suggest that in histopathological investigations necessitated by drug intoxication, measuring drug concentrations in the blood might be useful in determining the causes of histopathological changes more clearly.

Intravenous lidocaine decreases but cocaine does not alter the rate of cerebrospinal fluid formation in anesthetized rabbits.

Considering that adrenergic stimulation was reported to decrease the rate of cerebrospinal fluid (CSF) formation (Vf), it was hypothesized that cocaine might exert a similar effect. Accordingly, the present study was designed to examine the effects of low, moderate, and high doses of cocaine on Vf and resistance to reabsorption of CSF (Ra). Because cocaine possesses both adrenergic-stimulating and local anesthetic properties, the present study examined the effects of lidocaine, a local anesthetic without adrenergic-stimulating properties, as a comparison treatment to cocaine. New Zealand white rabbits (n = 17) weighing 3.5-4.3 kg were anesthetized with halothane. A needle was inserted into the left lateral cerebral ventricle and a catheter was inserted into the cisterna magna to permit ventriculocisternal perfusion with mock CSF labeled with blue dextran. A1 each of four experimental conditions, control and three doses of cocaine or lidocaine, fluid volumes and concentrations of blue dextran in timed samples of cisternal outflow were used to determine Vf and the rate of reabsorption of CSF (Va). In turn, Va at normal and elevated CSF pressures (+6 cmH2O) were used to determine Ra. For both the cocaine group (n = 9) and the lidocaine group (n = 8) the three drug doses were 0.5 mg.kg-1 followed by 1.0 microgram.kg-1.min-1, 1.5 mg.kg-1 followed by 3.0 micrograms.kg-1.min-1, and 4.5 mg.kg-1 followed by 9.0 micrograms.kg-1.min-1 i.v. Cocaine caused no significant change of Vf or Ra. In the lidocaine group there was a dose/time-related decrease of Vf (although the slope relating Vf to dose/time was not significantly different from that in the cocaine group), but no significant change of Ra. It is concluded that during halothane anesthesia cocaine does not decrease Vf, a finding not consistent with previous reports that adrenergic stimulation decreases Vf. Decrease of Vf with lidocaine is consistent with previous reports of similar dose-related effects of thiopental, etomidate, midazolam, and fentanyl on Vf.

Prenatal alcohol treatment attenuated postnatal cocaine-induced elevation of dopamine concentration in nucleus accumbens: A preliminary study

Prenatal alcohol exposure has been shown to damage the developing central nervous system (CNS) in a variety of ways, including neuroanatomical anomalies, neurochemical imbalance, and neuropharmacological dysfunction. The present study investigated one of the functional aspects of dopaminergic system in neonatal rats exposed prenatally to a binge-like alcohol paradigm by measuring dopamine concentrations following a single postnatal cocaine challenge. Pregnant Sprague-Dawley rats were given daily intragastric intubations of 5.1 g/kg alcohol solution from embryonic day (E) 1 to 20. Pair-fed and ad lib-fed animals served as controls. On E33 (usually postnatal day 10), offspring from all groups were given injections (IP) of either 0, 20, or 40 mg/kg cocaine. Animals were sacrificed and the substantia nigra/ventral tegmental area (SN/VTA) and nucleus accumbens (NAc) were dissected for the determination of dopamine concentrations using HPLC. Basal dopamine levels (0 mg/kg cocaine group) did not alter as a function of prenatal alcohol treatment in either region. However, acute cocaine injection increased the dopamine content in NAc, but not in SN/VTA, in ad lib-fed animals, and this elevation in dopamine level was significantly attenuated by prenatal alcohol treatment in both female and male animals, and by prenatal pair-fed treatment in male animals. Taken together, these results indicate that there appears to be a regional difference in acute cocaine-induced dopamine elevation, and prenatal binge-like alcohol exposure significantly alters the functional responsiveness of dopaminergic system in NAc. Furthermore, these data suggest that male offspring may be more sensitive to stress-associated or nutritional influences during gestation.

Effects of prenatal cocaine and genotype on intermale agonistic behavior in Mus musculus

We exposed the pups of three F1 genotypes of mice to a daily regime of cocaine by injecting their mothers (all C57BL/10J strain) on days 7–18 of gestation with 20 mg/kg subcutaneously. Pups of the cocaine and control groups did not differ on measures of maternal and pup health or size. Male pups were weaned and isolated at 21 days of age and their behaviors measured in an intermale aggression situation at about 80 days of age. Treated and untreated males of each F1 genotype were paired in dyads with either a C3H/HeJ (hawk-like) or AKR/J (retaliator-like) standard tester male. Standard tester males were not exposed to cocaine. Cocaine treatment alone reduced the overall level of aggression in dyads, and in interaction with genotype or the standard tester it altered the behavior of dyads in all phases of social interaction: the initiation, content, and outcome. Standard testers used as behavioral probes, differentiated cocaine and control males with respect to their stimulus and behavioral qualities. Aggr. Behav. 23:183–196, 1997.© 1997 Wiley-Liss, Inc.

Effects of prenatal cocaine and genotype on intermale agonistic behavior inMus musculus

We exposed the pups of three F1 genotypes of mice to a daily regime of cocaine by injecting their mothers (all C57BL/10J strain) on days 7–18 of gestation with 20 mg/kg subcutaneously. Pups of the cocaine and control groups did not differ on measures of maternal and pup health or size. Male pups were weaned and isolated at 21 days of age and their behaviors measured in an intermale aggression situation at about 80 days of age. Treated and untreated males of each F1 genotype were paired in dyads with either a C3H/HeJ (hawk-like) or AKR/J (retaliator-like) standard tester male. Standard tester males were not exposed to cocaine. Cocaine treatment alone reduced the overall level of aggression in dyads, and in interaction with genotype or the standard tester it altered the behavior of dyads in all phases of social interaction: the initiation, content, and outcome. Standard testers used as behavioral probes, differentiated cocaine and control males with respect to their stimulus and behavioral qualities. Aggr. Behav. 23:183–196, 1997.© 1997 Wiley-Liss, Inc.

Differential effects of prenatal cocaine and retinoic acid on activity level throughout day and night

Prenatal cocaine exposure is associated with disrupted state control and lowered activity levels. Prenatal retinoic acid excess also influences activity levels in laboratory rats. Activity level is usually monitored during a brief period in young offspring. The effects of these drugs on pup activity levels throughout the day is unknown. There is also little information on the long-lasting effects of these teratogens in adult animals. We compared the daily activity of rats which were prenatally exposed to cocaine or retinoic acid (RA). Appropriate control groups were also used. The offspring were evaluated for activity levels in a neophobic situation and for a 22-h period in same-sex groups of 3 littermates. As both pups and adults, the cocaine groups were hypoactive while the RA group was hyperactive when first placed into the testing cage (neophobic situation). Similarly, during the remainder of the 22-h testing period, the pup and adult cocaine animals exhibited reduced activity levels while the RA animals exhibited elevated activity levels. Thus, prenatal cocaine and retinoic acid exposures affected offspring activity levels differently, both drugs have long-lasting neurobehavioral effects that persist into adulthood, and effects are influenced by time-of-day. Strain-dependent differences and mechanisms of action are discussed.

Cocaine toxicity and isoflurane anesthesia: Hemodynamic, myocardial metabolic, and regional blood flow effects in swine

Increasing numbers of people use cocaine recreationally and may require anesthesia care, having recently abused the drug. However, no data currently exist concerning potential interactions between toxic levels of cocaine and volatile anesthetic agents. This study investigated the effects of cocaine infusion on systemic hemodynamics, myocardial metabolism, and regional organ blood flow in relation to depth of isoflurane anesthesia. Prospective, randomized, controlled trial. A laboratory at a university medical center. Twelve miniature pigs. An open-chest swine model was used. Isoflurane (ISO) was the sole anesthetic, administered at 0.75 and 1.5 minimum alveolar concentration (MAC), and cocaine was infused (n = 6) at a rate of 0.5 mg/kg/min. Control animals (n = 6) received an equivalent amount of normal saline. Systemic and pulmonary arterial pressures and thermodilution cardiac output data were collected at 0.75 MAC and 1.5 MAC ISC. Regional myocardial and blood flows to other organs were measured using radiolabeled microspheres. Arrhythmias and altered ventricular conduction were noted only in the cocaine group, along with significant elevations in diastolic arterial pressure, coronary perfusion pressure, and systemic vascular resistance. Increased subendocardial blood flow occurred during cocaine infusion (p = 0.03); subepicardial perfusion was unchanged. Cerebral (p < 0.01) and spinal cord (p < 0.05) blood flows were reduced in animals receiving cocaine. Other organ blood flows were unchanged with depth of anesthesia or cocaine administration, with the exception of splenic blood flow (p < 0.04). Moderately toxic cocaine levels occurring during isoflurane at 0.75 MAC and 1.5 MAC are associated with hemodynamic abnormalities, a marked increase in systemic vascular resistance, and a tendency to produce cardiac arrhythmias. A reversal of endo/epicardial myocardial perfusion ratio occurs associated with cocaine infusion during ISO anesthesia. This is probably not related to a primary redistribution of subendocardial blood flow and may be related to a combination of increased myocardial oxygen demand and epicardial coronary vasoconstriction. The reductions in cerebral and spinal cord perfusion observed may explain, in part, the neurologic sequelae of cocaine toxicity.

The Effects of Prenatal Exposure to Cocaine on the Dopaminergic Cells in the Rat Retina. An Immunocytochemical and Neurochemical Study

There is a growing consensus that the development of the eye is affected by prenatal exposure to cocaine. Considering that the retina is affected by prenatal cocaine exposure, that this drug affects the dopaminergic systems, that the dopaminergic cells in the retina show a well-defined pattern of development and that they can be specifically stained in wholemounts by the antibody anti-tyrosine hydroxylase (TH), this study was undertaken to evaluate the effects of in utero cocaine exposure on the dopaminergic cells of the rat retina. Pregnant Wistar rats were given 60mg (kg body weight) −day −1of cocaine hydrochloride, subcutaneously, from gestational days 8 to 22. Control groups of pregnant rats were pair-fed. At PND14, 30 and 90, male offspring from different litters were perfused with fixative and the retinas processed as wholemounts and immunostained with the antibody anti-TH. Rats from other groups were decapitated at the same post-natal ages, the retinas dissected and processed by neurochemical techniques to measure the concentrations of dopamine, its metabolites and the turnover of dopamine. There was a significant increase of the retina surface area between PND14–30 in the control group, which was not found in the cocaine group. The density of the immunostained small TH cells was lower in the cocaine groups. No drug-effects were detected in the density of the large TH cells. The densities of the total large and small cells in the superior, inferior and nasal hemiretinas were similar to those found in the whole retinas; however, in the temporal hemiretinas of the cocaine groups, the density of the large TH cells was higher and of the small TH cells was lower than in controls, resulting in an absence of effects on the total density of TH-cells in this hemiretina. A transient increase in the level of dopamine metabolite (DOPAC) and of the turnover of dopamine at PND14 was detected in the cocaine groups. All quantitative parameters reached normal values, in all groups, at PND90. These results show that, during the critical periods in which catecholamines can influence the development of neurons, cocaine transiently affects the pattern of dopaminergic neurons in the retina. This may have functional importance due to the role of this neurotransmitter as a regulatory and/or trophic factor in developing neuronal circuitries.

Importancia dopaminérgica en farmacodinamia de cocaína evaluada por alteraciones de GABA y glutamato en el núcleo accumbens de ratas

The aim of the present study was to investigate the role of dopamine in cocaine pharmacodynamics in rats. To test this hypothesis, we measured GABA and glutamate level changes in the accumbens nucleus. This approach is supported by the preponderance of evidence which has consistently shown alterations in dopaminergic activity after cocaine administration. Furthermore, GABA and glutamate have considerable irnportance in cocaine's acute and chronic effects. The relationship between GABA and glutamate with dopaminergic activity in the nucleus accumbens is well-known. A 16-day study was designed for the administration of cocaine chlorhydrate (IP) at 30 mglkglday increasing by 5 mglkglday each 4 days to animals which had been stereotaxically injured in the nucleus accumbens with 6-OH-dopamine (6-OHDA) neurotoxin dissolved in ascorbic acid. A base group was formed which received ascorbic acid diluted in 0.9% saline solution stereotaxically in the nucleus accumbens, and was treated with an equal volume of 0.9% saline solution (IP). The control group received 6- OHDA (diluted in ascorbic acid) stereotaxically in the nucleus accumbens and was given 0.9% saline solution as treatment. GABA and glutamate levels were determined by enzymatic assays. The results of this work show a significant decrease of GABA levels in the group that received chronic cocaine administration in comparison to the base and control group. Glutamate levels were significantly higher in the cocaine group than in the base group, but not significantly different from the control group. In conclusion, the results of the present work suppofi the idea of the great irnportance of dopaminergic activity in cocaine pharmacotherapy. This dopamine role could be either through GABA or glutamate level alterations or both. Direct action of increased cocaine level on the so-called reward system could be another explication.

Effect of chronic cocaine exposure on carotid artery reactivity in neonatal rabbits

Chronic cocaine abuse by pregnant women results in chronic neonatal drug exposure. In adults, chronic cocaine use alters neurotransmitter concentrations and receptor dose-response relationships. Similar changes may also occur in the neonatal cerebrovasculature after in utero cocaine exposure. This study examined the effect of chronic cocaine exposure on internal carotid artery reactivity to norepinephrine, serotonin, acetylcholine, sodium nitroprusside, adenosine, and cocaine in neonatal rabbits. Internal carotid artery rings were isolated from 16 to 20 day old rabbits that had received cocaine (20 mg/kg IP BID, mn = 8) or saline (n = 8) from 5 days of age and were studied in organ baths using standard in vitro techniques. Chronic treatment with cocaine decreased the half-maximal relaxant response (ED 50) to adenosine (control 6.9 ± 1.8 vs cocaine 3.5 ± 0.99 μM, p = 0.05). The half-maximal contractile responses (EC 50) to norepinephrine and serotonin and the half-maximal relaxant responses (ED 50) to acetylcholine and sodium nitroprusside were similar between groups. The threshhold concentration of cocaine that induced vessel contraction was altered by chronic cocaine exposure (control group 10 −6 M vs chronic cocaine group 10 −4 M). We conclude that chronic cocaine exposure sensitizes carotid arteries to the relaxant effects of adenosine. In addition, chronic cocaine exposure desensitizes carotid arteries to the contractile effects of acute cocaine. These vasoreactivity changes may underlie altered cerebrovascular responses to asphyxia and play a role in the pathogenesis of postnatally acquired brain injury in critically ill “crack” babies.

The effect of cocaine on Ventricular fibrillation threshold in the normal canine heart.

We determined the effect of cocaine on ventricular vulnerability to fibrillation, as measured by ventricular fibrillation threshold (VFT), and cardiac electrophysiology in 20 anesthetized dogs with normal hearts. Animals were randomized in blinded fashion to receive a continuous 3-hour infusion of cocaine 0.11 mg/kg/minute (total dose 20 mg/kg) or placebo (lactose dissolved in normal saline). The VFT, systolic and diastolic blood pressures, ventricular effective refractory period (ERP), and electrocardiographic intervals were measured at baseline and every 30 minutes during infusion. Baseline mean +/- SE VFT in cocaine and placebo groups was 57.0 +/- 7.8 and 51.8 +/- 7.6 mA, respectively (p = 0.64). Cocaine did not significantly decrease VFT, but actually increased it (i.e., reduced ventricular vulnerability to fibrillation) compared with placebo (84.6 +/- 10.4 vs 55.8 +/- 7.2 mA, respectively, at 150 minutes, p = 0.04). Cocaine prolonged ERP and PR, QRS, QT, QTc, JT, and JTc intervals. Cocaine does not increase ventricular vulnerability to fibrillation in anesthetized dogs with normal intact hearts. Its electrophysiologic effects are similar to those of class I antiarrhythmic agents in this model.

Effects of postnatal exposure to cocaine on the development of the rat corpus callosum

We investigated the effects of cocaine on the development of the corpus callosum in rats. From postnatal days 1 (P1) to 10 (birth = P0), cocaine (10 mg/kg) was subcutaneously injected in the pups, and saline, at the same volume, was administered to control pups. The animals were sacrificed at 110 days of age and a midsagittal section of the callosum was obtained. Morphometric measurement of the corpus callosum was performed in this section. In the control group, but not in the cocaine group, males had larger callosa than females. The cocaine treatment significantly decreased the total callosal area in male rats. These findings indicate that early postnatal cocaine abolishes the sexual differentiation of the corpus callosum.

DOSE AND INTERACTIVE EFFECTS OF PRENATAL COCAINE, ALCOHOL AND TOBACCO USE ON BIRTH OUTCOME. 1564

To determine the effects of prenatal cocaine use on the medical and neurodevelopmental outcomes of infants from a rural, public health population, we interviewed over 2,000 women prenatally, identified 154 cocaine users and matched 154 controls on location/level of prenatal care, race, parity, and SES. Drug screening was done at the first prenatal visit and at delivery; detailed psychosocial/drug histories were taken at each trimester and follow-up visit. The cocaine group had significantly less prenatal care (92% vs. 97%), begun later (15 vs. 12 weeks), and were more likely to drink (76% vs. 31%), smoke (79% vs. 24%) and use marijuana (43% vs. 7%). There was no other illicit drug use in either group and marijuana was not related to any birth outcomes. There were no differences in fetal/perinatal deaths between groups but more preterms among cocaine users (17% vs. 9%). Ponderal Index did not differ between cocaine users and controls, but after controlling for alcohol and tobacco use, there remained a significant decrease in birthweight due to prenatal cocaine use. Head and chest circumference and length were significantly lower in cocaine users who also smoked tobacco. The average cocaine use per day for trimesters 1, 3 and overall pregnancy was significantly negatively related to birth length; and amount used in trimesters 2 and 3 was negatively related to head circumference. There were no significant group differences on any Brazelton cluster scores (by blinded certified examiners), but amount of alcohol used in the 2nd trimester was significantly negatively related to Brazelton motor scores. There were also dose-response effects of prenatal alcohol and tobacco use on birthweight, length, head and chest circumference. Because of the complexity of effects of cocaine exposure on birth outcome, evaluation of growth and development of infants should also consider the interactive effects as well as the amount and timing of drug exposure.

COCAINE AND WITHDRAWAL. 447

There continues to be controversy about whether cocaine causes withdrawal symptoms in newborn infants. Some of the controversy arises because many of these mothers abuse multiple drugs. We prospectively studied 444 consecutive mother-infant pairs. Detailed histories, including drug use were obtained by structured interviews on the post-partum floor. Concurrently, maternal and infant urine and meconium samples were obtained, numerically coded and matched to interview data to insure anonymity. Symptoms of withdrawal were obtained by researchers blinded to the toxicology data. 148 of the 444 (32%) were proven to have abused drugs during the pregnancy by history or toxicology data. 82 were proven to abusing cocaine alone (18%). 131 of our newborns had symptoms of withdrawal (29.5%). 40 of the cocaine group (49%) had withdrawal symptoms which was statistically greater than the number in the drug-free group (26%, p=.000). The symptoms among the cocaine using group were consistent with withdrawal as they started within the first few days of life and resolved within a few days. Most of the withdrawal cases were mild, with the most common symptoms being decreased sleep, tremors, increased tone, high pitched cry, hyperactive Moro, and sneezing. 2 of the babies (5%) had withdrawal severe enough to require treatment. In conclusion, cocaine does produce withdrawal which is usually mild, but occasionally requires therapy.

Decreased ventilatory response to hypoxia in sedated newborn piglets prenatally exposed to cocaine

OBJECTIVE: Infants exposed to cocaine in utero have been reported to have a higher incidence of apnea and altered ventilatory response to carbon dioxide and hypoxia. We investigated whether in utero cocaine exposure results in greater ventilatory depression during hypoxia in piglets. METHODS: Cocaine hydrochloride, 1.0 or 2.0 mg/kg given intramuscularly, or saline solution was administered daily to pair-fed pregnant sows during the last month of gestation. Thirteen cocaine-exposed piglets (mean ± SD: age, 4.4 ± 1.3 days; weight, 2.10 ± 0.10 kg) and 15 saline solution-exposed piglets (age, 4.6 ± 1.1 days; weight, 2.32 ± 0.42 kg) were studied under chloral hydrate sedation. Minute ventilation (v̇ E), arterial blood pressure (BP), heart rate (HR), oxygen consumption (v̇ O 2), and arterial blood gases were measured in room air. During hypoxia (fraction of inspired oxygen = 0.10), the values for v̇ E, BP, and HR were obtained at 1, 5, and 10 minutes, v̇ O 2 was calculated during the last 5 minutes, and arterial blood gas samples taken after 10 minutes. RESULTS: Basal v̇ E did not differ between saline solution- and cocaine-exposed animals. The increase in v̇ E at 1 minute of hypoxia was also similar. However, at 5 and 10 minutes of hypoxia, v̇ E was significantly lower in the cocaine group than in the saline group (6% ± 9% and 4% ± 10% vs 15% ± 13% and 21% ± 14%; p <0.02). Mean baseline BP and the initial increase in BP during hypoxia were not different between groups. However, BP remained increased throughout hypoxia only in the saline solution-exposed animals ( p <0.05). Changes in HR, v̇ O 2, arterial oxygen tension, and base excess during hypoxia were similar between groups. CONCLUSIONS: These results show a decrease in the ventilatory response to hypoxia in newborn piglets prenatally exposed to cocaine. This change is most likely to be centrally mediated because the initial hypoxic hyperventilation was not modified by the intrauterine cocaine exposure. This decrease in ventilation cannot be explained by changes in metabolic rate or in cardiovascular or acid-base status. (J P EDIATR 1996;128:389-95)

Effects of Long-Term Cocaine Exposure on Spermatogenesis and Fertility in Peripubertal Male Rats

Purpose This study was conducted to investigate the effects of long-term administration of cocaine on spermatogenesis and fertility in adult male rats. Materials and Methods Thirty-day-old male Sprague-Dawley rats were given cocaine hydro-chloride (15 mg./kg. body weight, corresponding to an average single dose for a heavy cocaine user) either daily or twice weekly (weekend group, cocaine given on Saturday and Sunday) and mated with pregnancy-proven female rats after 100 and 150 days of exposure to the drug. Pregnancy rates and litter birth weights were evaluated. Serum testosterone, follicle stimulating hormone and luteinizing hormone levels were measured in all adult rats. Morphologic analysis of the testis entailed the evaluation of quantitative and qualitative histologic parameters to assess the effect of cocaine on various stages of spermatogenesis. Results After 100 days of treatment, the rats receiving daily cocaine had a pregnancy rate of only 33 percent versus 86 percent for the controls (p less than 0.05). In rats exposed to cocaine for 150 days the pregnancy rate was 50 percent compared with 100 percent for controls (p less than 0.05). The birth weights of offspring from the group receiving daily cocaine was 10 percent less than that of controls (p less than 0.05). The weight of the testis and epididymis was not affected by cocaine exposure. Morphometric analysis showed significant differences between the cocaine-treated groups (both the daily cocaine and twice weekly cocaine groups) and their respective controls. The mean diameter of seminiferous tubules in the daily and twice weekly cocaine groups was reduced when compared with their respective controls. These differences between treated groups and their controls were statistically significant (p less than 0.05). Similarly the thickness of the germinal epithelium was less in the cocaine-treated groups than in the controls (p less than 0.05). Degenerating cells were more numerous in both daily and twice weekly cocaine groups than the controls. Furthermore, the number of step VII spermatids was reduced in both daily and twice weekly cocaine groups, a difference that was statistically significant (p less than 0.05). Conclusion Our findings demonstrate that chronic administration of cocaine to peripubertal male rats has a profound effect on their testicular function. Even with twice weekly administration there was a significant adverse effect on spermatogenesis although this was not manifested by diminished fertility in this group. These findings confirm that chronic administration of cocaine to male rats can have a deleterious effect on spermatogenesis and fertility.

Cigarette smoking in alcohol and cocaine abusers.

This study compared the cigarette smoking of substance abusers whose primary substance of abuse was cocaine (cocaine group: n = 18) or alcohol (alcohol group: n = 23). Cigarette smoking and smoking topography was assessed daily (via self-report and single cigarette topography assessments) at baseline and following a switch to a cigarette brand with 30% lower nicotine. The alcohol and cocaine groups did not differ at baseline on cigarettes smoked per day, cigarette nicotine, smoking topography, or the Fagerstrom Tolerance Questionnaire. However, the cocaine group exhibited marked increases in compensatory smoking relative to the alcohol group following the 30% reduction in cigarette nicotine, as evidenced by decreases in the average time interval between each puff, p < .05, increases in the total amount of time spent puffing, p < .05, and increases in estimated total amount of time spent puffing per day, p < .05. These findings provide initial data that cocaine and alcohol abusers may titrate nicotine differently and suggest that cocaine abusers may require additional or modified smoking cessation treatments.

Neonatal cocaine exposure and activity rhythms in rats

This study looked at the effects of neonatal cocaine exposure on activity rhythms over a 48-h period in rats. Subjects were artificially-reared from postnatal days (PN) 4–10 via intragastric cannulas. The four treatment groups included two cocaine doses (20 and 40 mg/kg per day), an artificially-reared control and a normally reared suckled control. Subjects were tested at PN 38–40 in an automated running wheel. Neonatal cocaine exposure did not alter activity rhythms over the 48-h test period. However, there was a gender-specific effect of neonatal cocaine exposure on response to the novel test chamber and to the experimenter. The 20 mg/kg cocaine-exposed females showed increased running wheel activity relative to all other groups after placement in the running wheel. During the second 24-h period, cocaine-exposed females from both cocaine groups showed increased activity relative to controls following the entry of an experimenter to the test room. These findings suggest that female rats exposed to cocaine neonatally show an increased response to novel environments and stimuli.

Problem solving following neonatal exposure to cocaine, ethanol, or cocaine/ethanol in combination in rats

This study examined the effects of neonatal drug exposure on performance in a digging maze. Subjects were Sprague-Dawley rats, artificially reared (AR) and fed through a gastrostomy tube from postnatal days (PND) 4–10. The AR groups included a cocaine group (20 mg/kg/day cocaine hydrochloride), an ethanol group (4 g/kg/day ethanol), a cocaine/ethanol group (20 mg/kg/day cocaine and 4 g/kg/day ethanol), and an AR control group. A suckled control raised by its dam was also included. At approximately PND 55, subjects were tested in a digging maze paradigm. The digging maze required subjects to use a species typical behavior (digging) to solve a novel problem (gaining access to water). While neonatal treatment had no effect on acquisition of a simple runway task for water reward, neonatal exposure to cocaine and ethanol in combination resulted in impaired performance on the digging maze task. None of the other neonatal treatment groups showed impairments on this task. These findings suggest that exposure to these doses of cocaine and ethanol during neonatal development may have more serious effects on problem solving tasks in rats than exposure to either drug alone.

Thrombocytopenia in pregnant women who use cocaine

OBJECTIVE: Our purpose was to determine the prevalence of cocaine-associated thrombocytopenia. STUDY DESIGN: This cohort study was conducted in an inner-city prenatal center. A total of 1907 patients were screened by the Mother's Project, which is an intervention project for inner-city cocaine-abusing parturients. Platelet counts were grouped by ellicit drug usage. RESULTS: Platelet counts were available in 37% (709) of subjects; there were no differences between subjects with available paltelet counts and those without on ellicit drug use or other demographic measures. Five groups were define: drug-free group ( n = 331), cocaine group ( n = 104), cocaine and opiates group ( n = 11), opiates group ( n = 18), and other-drug group ( n = 236). Nineteen subjects had a low platelet count (<150 × 10 9/L). The medical records of all subjects with a low platelet count were reviewed for any medical condition known to be associated with thrombocytopenia, and two subjects were excluded. The rate of thrombocytopenia in the drug-free group was 1.5%, whereas the rate in the cocaine group was 6.7% (relative risk 4.4, p < 0.05). Because of the reported association of thrombocytopenia with seropositive human immunodeficiency virus status, seropositive women were excluded from the analysis. Even after human immunodeficiency virus status adjustments for the estimated rate, the cocaine-using group continued to have a significantly higher rate of thrombocytopenia (5.4% to 7.2% vs 1.23% to 1.26%, p < 0.05 to p < 0.005). CONCLUSIONS: These results indicate that cocaine use is an independent risk factor for thrombocytopenia in an inner-city parturient population.