Acute abstinence effects following smoked cocaine administration in humans.

Acute abstinence symptomatology following multiple deliveries of smoked cocaine was examined. Twelve crack cocaine users (male and female) participated in an inpatient study. Participants smoked 7 deliveries of cocaine on each of 4 experimental days, with each participant being exposed twice to 2 dose sizes of cocaine (0.40 vs. 0.07 mg/kg "placebo"). Symptoms of cocaine abstinence were measured for 6 hr following cocaine administration and again the following morning. Participants reported feeling increased craving, anxiety, and uncertainty 30 min after the 7th delivery of 0.40 mg/kg cocaine, when cocaine plasma levels were still on the descending curve. It is not clear whether these were true abstinence effects or were due to residual effects of cocaine. No significant differences were found at subsequent abstinence-assessment points. These data indicate that acute abstinence effects from smoked cocaine in a laboratory setting may be minimal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of chronic haloperidol and intermittent cocaine administration on behavior elicited by apomorphine.

Relatively little is known about the behavioral or neurophysiological effects resulting from the concurrent administration of haloperidol and cocaine. To investigate this drug interaction the effects of chronic, daily administration of haloperidol, intermittent cocaine injections, or the combination of both drug treatments on locomotion and stereotypy elicited by apomorphine in rats (Rattus norvegicus) were compared. The results indicated that, in comparison to treatment with either drug alone, the combination of daily haloperidol and intermittent injections of cocaine produced unique behavioral effects. Rats coadministered both drugs exhibited significant increases in apomorphine-induced locomotion that were maintained throughout the 64 days following suspension of drug treatment. These results are discussed in terms of the possible neurophysiological mechanisms underlying the observed behavioral changes and are related to the consequences of psychostimulant abuse in human neuroleptic treated populations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acute effects of cocaine on ornithine decarboxylase activity in fetal and neonatal rat heart: evidence for cardiotoxicity

Fetal exposure to cocaine is associated with increased perinatal cardiac risk. In the current study, we examined the effects of acute cocaine administration on ornithine decarboxylase (ODC) activity in fetal and neonatal rat heart. ODC is a key regulatory enzyme in the control of cell differentiation and growth, and rapid changes in ODC are associated with the response to cell injury. Administration of 30 mg/kg s.c. of cocaine to pregnant rats on the 20th day of gestation caused acute elevation of fetal cardiac ODC that persisted throughout the ensuing 24 h. In contrast, the same dose given directly to neonatal rats the day after birth evoked only a short-term (1-h) stimulation of ODC that was reversed by 4 h after treatment. By 4 days of age and subsequently, cocaine was unable to elicit acute stimulation of heart ODC and only evoked inhibition of enzyme activity. Elevated progesterone levels during pregnancy have been shown to sensitize the maternal myocardium to cocaine-induced catecholaminergic effects; the greater sensitivity of fetal heart ODC to cocaine, as compared to neonatal heart, supports the hypothesis that similar enhancement of fetal cardiac irritability can contribute to cocaine-induced cell damage.     

Interactive effects of prenatal cocaine and nicotine exposure on maternal toxicity, postnatal development and behavior in the rat

Two experiments were performed to investigate the interactive effects of prenatal coadministration of cocaine hydrochloride (C) and nicotine tartrate (N). Experiment I was designed to determine doses of C and N that could be coadministered without altering maternal gestational parameters and/or fetal viability. Exposure of Sprague-Dawley rats to combined high-dose C (20 mg/kg) and high-dose N (5.0 mg/kg) on gestation days 8-21 was not more toxic to dam or fetus that that of exposure to C alone. Experiment II investigated pregnancy outcome, postnatal development, and behavior of the offspring following drug exposure to either high-dose cocaine (20 mg/kg: CS), high-dose nicotine (5.0 mg/kg: NS), or both (NC) on gestation days 8-21. N was administered by osmotic minipump and C by sc injection. Saline-injected dams, fitted with saline-fitted pumps (SS), and untreated dams, pair-fed (PF) to NC females, served as controls. Alterations in maternal variables were limited to a 10-15% decrease in food consumption in NC and CS groups. Pregnancy outcome and birth statistics were unaffected by prenatal treatment, as was offspring body weight during the first four postnatal weeks. However, the development of surface righting was delayed inC CS pups, and only CS offspring were underresponsive to the stimulatory effects of dopamine agonists on activity and stereotypy. Behavioral responses to N challenge were similar in all groups. In addition, only CS offspring showed altered behavioral responses in a spontaneous alternation task. Treatment effects on dopamine D1 and D2 binding in the caudate nucleus were not observed. The combination of N and C did not exacerbate any of the behavioral changes seen in CS offspring. These results support the hypothesis that C is a behavioral teratogen in rodents, and suggest that in the present model, nicotine can mitigate some of the consequences of in utero exposure to cocaine.     

Cardiovascular and subjective effects of intravenous cocaine administration in humans

Nine volunteer subjects were tested with intravenously administered cocaine hydrochloride in doses ranging from 4 to 32 mg, as well as 10 mg of dextroamphetamine sulfate. Measures of cardiovascular and subjective effects were made. Generally parallel dose-effect functions were obtained for heart rate, blood pressure, Addiction Research Center Inventory scores, Profile of Mood Scales, and subject ratings. A substantial effect on each of these variables was recorded after 8 mg of cocaine. The increase continued and peaked at approximately 16 mg after which it usually leveled off. Ten milligrams of dextroamphetamine generally had an effect comparable to 8 to 16 mg of cocaine.     

Chronic disulfiram treatment effects on intranasal cocaine administration: initial results

BACKGROUND: Simultaneous abuse of cocaine and alcohol is common. Alcohol decreases negative stimulant effects and potentiates "high." Disulfiram (Antabuse) is being studied in outpatient trials as a cocaine pharmacotherapy with the rationale that inability to modulate cocaine effects with alcohol may decrease cocaine use. METHODS: We examined the interaction of disulfiram and cocaine in a randomized, double-blind, placebo-controlled study where subjects were chronically treated with disulfiram and then participated in intranasal cocaine administration studies. RESULTS: Disulfiram 250 mg/day treatment significantly increased plasma cocaine concentrations (p = .013), heart rate (cocaine 1 mg/kg, p = .046), and systolic (cocaine 2 mg/kg p = .003) and diastolic (cocaine 2 mg/kg, p = .022) blood pressure. "High" and "nervous" ratings were nonsignificantly increased. CONCLUSIONS: The combination of "high" with increased anxiety in the context of inability to lessen negative effects with alcohol may be an effective treatment in selected patients. The significant pharmacokinetic interaction must be considered in the decision regarding use of disulfiram.     

Changes of behavior and monoamine metabolites in the rat brain after repeated methamphetamine administration: effects of duration of repeated administration

1. The authors studied the mechanism of the reverse-tolerance phenomenon caused by long-term administration of central stimulant drugs. Methamphetamine(MAP) was chronically administered to rats, and the reverse-tolerance phenomenon was studied in terms of behavioral changes and changes in monoamine metabolites, the latter being examined by in vivo microdialysis of the extracellular compartment of the corpus-striatum. The authors also studied [3H]SCH23390 and [3H]spiperone binding to striatal membranes after chronic MAP administration. 2. MAP(4 mg/kg) or saline was administered intraperitoneally once daily to male rats. In Groups 1 and 2, 10 and 30 injections of MAP were given, respectively. In Groups 3 and 4, animals received 10 and 30 injections of saline as controls. One week after the final injection, all rats were challenged with 4 mg/kg MAP. 3. Groups 1 and 2 displayed more intense stereotypy than Groups 3 and 4, indicating that behavioral sensitization had been achieved in the former. Dopamine(DA) levels increased rapidly in response to MAP challenge in all groups, with the increases in Groups 1 and 2 being more marked than that in Groups 3 and 4. Group 1 showed greater persistence and a higher rate of DA increase than Group 2. 4. The number of D1 and D2 dopamine receptors did not change after the repeated MAP administration. 5. The rate of increase in DA release induced by MAP was dependent on the duration of repeated administration, and there was no correlation between the intensity of stereotypy and the rate of increase in DA release induced by MAP. These findings suggest that enhancement in DA release is unlikely to be the sole cause of behavioral sensitization.     

Vagotomy produces learned food aversions in the rat.

Two experiments, each with 28 female Long-Evans rats, examined whether some of the depression in food intake observed in rats with vagotomy could be due to the development of aversions to the foods eaten after surgery. In Exp I, significant aversions developed to the specific novel diet consumed after vagotomy, results indicating that the symptoms associated with vagotomy (hypophagia, weight loss, discomfort) can serve as effective UCSs in the acquisition of learned food aversions. Exp II compared vagotomized Ss consuming familiar laboratory chow with those consuming a novel diet. In contrast to the novel diets, learned aversions to the familiar chow did not develop and hypophagia was less persistent and severe. It is concluded that learned food aversions can contribute to the appetite and weight loss exhibited by vagotomized animals. Consideration of the conditions under which these aversions arise after vagotomy surgery may allow for the design of studies so as to minimize the aversions and thereby separate these nonspecific effects from direct regulatory deficits produced by vagotomy. (22 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of long-term cocaine administration to pregnant ewes on fetal hemodynamics, oxygenation, and growth

OBJECTIVE: To assess uterine and fetal blood flows by Doppler velocimetry and fetal growth and oxygenation in pregnant ewes treated daily with cocaine and to determine whether cocaine impairs fetal cardiac and cerebral reactivity. METHODS: The study groups received 70 mg (n = 7) or 140 mg (n = 7) of cocaine and the control group (n = 7) received placebo injected intramuscularly daily on days 60-134. Hemodynamic data were measured at rest and during two acute hypoxic tests at cesarean delivery performed on day 134. RESULTS: The fetal heart rate (FHR) and umbilical and uterine resistance indices (RIs) were higher in the cocaine groups than in the control group (FHR: 187 +/- 8 and 166 +/- 8 beats per minute at 83 and 123 days, respectively, in controls and 9-11% higher in cocaine groups; umbilical RI: 0.79 +/- 0.06, 0.60 +/- 0.04, and 0.52 +/- 0.06, at 83, 105, and 123 days, respectively, in controls and 11-17% higher in the cocaine groups [P < .01]; and uterine RI: 0.40 +/- 0.05, 0.40 +/- 0.04, and 0.37 +/- 0.04, at 83, 105, and 123 days, respectively, in controls and 13-35% higher in cocaine groups [P < .05]). At delivery on day 134, the following characteristics were found to be different in the cocaine groups: fetal weight (4.03 +/- 0.2 kg in controls and 15-21% lower in the cocaine groups [P < .02]), partial pressure of oxygen (26.5 +/- 1.4 mmHg in controls and 15-16% lower in cocaine groups [P < .05]), umbilical RI (0.40 +/- 0.03 in controls and 11-17% higher in cocaine groups [P < .01]), cerebral RI (0.61 +/- 0.03 in controls and 9-15% lower in cocaine groups [P < .01]), and cerebral-umbilical ratio (1.52 +/- 0.04 in controls and 22-23% lower in cocaine groups [P < .001]). During the hypoxic tests, the cerebral RI (P < .05) and the cerebral-umbilical ratio (P < .05) decreased significantly less in the two cocaine groups. The FHR response was reduced significantly in the two cocaine groups (P < .05). CONCLUSION: Long-term exposure to cocaine induces uterine and fetal blood flow disorders, fetal growth restriction, and hypoxia. It reduces the capability of the cerebral vessels to vasodilate and the heart rate to increase during acute hypoxia.     

Systemic and coronary hemodynamic effects of repetitive cocaine administration in conscious dogs

The cardiovascular actions of cocaine are complex, and previous studies suggest that tachyphylaxis to the positive chronotropic and pressor effects of cocaine may develop after repetitive administration. We examined changes in systemic and coronary hemodynamics when single or multiple doses of intravenous (i.v.) cocaine were administered to conscious dogs. Dogs were chronically instrumented for measurement of aortic blood pressure (BP) and left ventricular pressure (LVP), LV dP/dtmax and dP/dt50, subendocardial segment length (%SS), diastolic coronary blood flow (CBF) velocity, and cardiac output (CO). Myocardial oxygen consumption was estimated by the pressure-work index (PWI). In one series of experiments, a single dose of cocaine (0.1, 0.2, 0.4, 0.8, or 1.6 mg/kg) was administered on 5 consecutive days in random fashion and peak changes in systemic and coronary hemodynamics were recorded. These doses were then randomly repeated in a second group of experiments with a 1-h interval between doses on the same day. Peak and steady-state changes in cardiovascular variables were recorded within and between each dose, respectively. In other experiments, higher doses of cocaine (0.8 or 1.6 mg/kg; separate groups) were administered four times at 1-h intervals in the same dogs and peak and steady-state changes in hemodynamics were determined. Cocaine caused dose-related increases in heart rate (HR), mean arterial pressure (MAP), LV systolic pressure (LVSP) and end-diastolic pressure (LVEDP), PWI, CO, and diastolic coronary vascular resistance and decreases in %SS when administered on different days. Cocaine also caused significant increases in baseline HR, MAP, LVSP, and PWI between doses given on the same day at 1-h intervals, but the absolute value of the peak response to cocaine of these hemodynamic parameters was independent of dosing regimen. These results were confirmed when we administered four doses of 0.8 mg/kg cocaine at 1-h intervals. The results indicate that baseline changes in systemic hemodynamic variables are a predominant feature of repetitive administration of lower doses of cocaine (< or = 0.8 mg/kg), but administration of higher doses of cocaine (> or = 8 mg/kg) at 1-h intervals caused tachyphylaxis to the hypertensive actions and myocardial oxygen consumption effects of cocaine.     

Intravenous gestational cocaine in rats: effects on offspring development and weanling behavior

Pregnant rats were injected with cocaine (CN; 6 mg/kg) or an equal volume of saline (SAL), via the tail vein, on gestation days 8-20. A third group was untreated (UT). Maternal weight gain was not affected by dam treatment despite slight differences in food intake. Litter characteristics (e.g., litter size, pup weight) did not differ among groups. Indices of fetal mortality were not affected by the treatments. Developmental tests, initiated on postnatal day (PND) 2, indicated slight delays in the negative geotaxic response and eye opening in cocaine-exposed pups. Open-field and tail-flick tests were performed on PND 21. Pups were acutely injected with cocaine (10 mg/kg, IP), saline, or received no treatment before placement in a novel open field; morphine (1.5 mg/kg, SC) or saline was injected prior to the tail flick test. Pups from CN dams exhibited a significant decrease in spontaneous exploratory behavior compared to both controls, and a time-dependent increase in rearing compared to pups from UT dams. The acute cocaine injection prior to placement in the open field did not alter locomotion or rearing among dam treatment groups. However, the acute cocaine injection did increase stereotypy ratings for female pups from CN dams compared to similarly treated males, and females from SAL and UT dams. No differences were observed among groups in the tail-flick test. These data suggest that the IV route of administration provides a viable method of cocaine delivery in pregnant rats, and provides further evidence of the developmental and behavioral teratogenicity of prenatal cocaine exposure.     

Characterization of the effects of the partial dopamine agonist terguride on cocaine self-administration in the rat

One notable functional abnormality in murine and human systemic lupus erythematosus (SLE) is the defect in the production of IL-2 in association with the deficit in naive CD4+ T cells. The mechanism is unknown, but one idea is that naturally occurring autoantibodies with specificities to the naive CD4+ T cell subpopulation are related to this event. We selected hybridoma monoclonal autoantibodies from SLE-prone (New Zealand Black (NZB) x New Zealand White (NZW))F1 mice that reacted with restricted populations of CD4+ T cells. One of these, H32, was specific for L-selectin, as determined by 1) distribution of Ag H32 on lymphoid cells similar to Mel-14, an epitope of L-selectin; 2) shedding of 80-kDa molecules with epitope H32 from the surface of lymph node cells coincidentally with Mel-14, when stimulated with phorbol ester; 3) cross-inhibitory activities on Ag binding between H32 and Mel-14; and 4) reactivity of H32 with recombinant mouse L-selectin. Pretreatment of 51Cr-labeled lymphocytes from BALB/c mice with H32 significantly inhibited their homing to lymph nodes in vivo. The BALB/c splenic H32+ CD4+ T cell subset produced few cytokines except IL-2, thus corresponding to naive ThP-type cells. This subset was markedly selectively depleted in aged (NZB x NZW)F1 mice. There was an age-associated increase in frequencies and titers of anti-L-selectin autoantibodies in sera from (NZB x NZW)F1 mice. Thus, abnormalities of naive CD4+ T cell subset, including IL-2 production in subjects with SLE, are at least partly attributed to the generation of autoantibodies to L-selectin.     

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)     

Within-subject variability in cocaine pharmacokinetics and pharmacodynamics after intraperitoneal compared with intravenous cocaine administration.

Performance in rats (Rattus norvegicus) was measured on a differential reinforcement of low-rate schedule (DRL 45-s) in 1.5-hr sessions after 2 mg/kg intravenous (IV) or 10–20 mg/kg intraperitoneal (IP) cocaine administration, with each dose given twice and separated by 3–5 days. For successive IV doses, cocaine effects were similar, with minimal within-subject variability. For IP cocaine, the effects were not always similar; performance was variable and sometimes remained at baseline level. These diminished effects occurred following either the 1st or 2nd IP injection. A parallel pharmacokinetic study of cocaine confirmed that within-subject variability existed in cocaine concentration-time profiles after IP cocaine, and that a low serum cocaine concentration-time profile could account for the diminished effects. The IP route for cocaine administration should be used with caution. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Central administration of saikosaponin-d increases corticotropin-releasing factor mRNA levels in the rat hypothalamus

The free radicals nitric oxide (.NO) and superoxide (O2-) are known to react to form peroxynitrite (ONOO-), a highly reactive species. Peroxynitrite has been suggested to play an important role in the cellular damage associated with the overproduction of .NO, but there are very limited data regarding its in vivo formation. Here we demonstrate that injection of endotoxin into rats leads to the expression of an inducible isoform of .NO synthase (iNOS) in the thoracic aorta at 6 h and an increase in the circulating levels of nitrite/nitrate. Moreover, at the same time point, there is a marked increase in the immunoreactivity of nitrotyrosine, a marker of peroxynitrite in the aorta. The formation of nitrotyrosine was prevented by inhibiting the activity of NOS by NG-methyl-L-arginine in vivo. Our data suggest that during endotoxin shock, part of .NO, produced following the induction of iNOS, is converted into peroxynitrite in the vicinity of large blood vessels. The demonstration of the in vivo formation of peroxynitrite at sites of .NO overproduction may necessitate the development of novel and additional approaches for limiting or preventing .NO-related cytotoxic or vasodilatory actions during circulatory shock.     

Discrimination behavior in the rat: Differential effects of reinforcement and nonreinforcement.

Gave information to a total of 12 male Sprague-Dawley albino rats in 3 experiments about the location of reinforcement and nonreinforcement. Ss then performed a discrimination task choosing among reinforced, nonreinforced, and a 3rd location. In all cases, avoidance of nonreinforcement was substantially greater than approach to reinforcement, indicating the crucial role of nonreinforcement in directing this discrimination behavior. Results of introducing a 50-min delay between information and discrimination trials and presenting other combinations of information confirm these conclusions. (23 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of cocaine on fetal and postnatal development in mice

The goal of the current investigation was to study the effect of in utero exposure of cocaine on fetal and postnatal development. 48 adult female NIH Swiss mice were used as experimental animal models. Each of the 24 mice were injected intraperitoneally with cocaine HCl at a daily dose level of 45 mg/kg (body weight). Each of the 24 control animals were daily injected with saline. One week after the treatment started, one male was introduced into each female cage. The day the vaginal plug was found was recorded as day one of pregnancy. Both cocaine treated and saline treated animals were subdivided into three subgroups each with 8 animals in each subgroup. Subgroup one was used to obtain midgestational (11 day) fetuses, subgroup two was used to obtain full term fetuses (18 day) and subgroup three was used to obtain pups. Individual fetal weights were taken and each fetus was examined for developmental anomalies. Midgestational fetuses exposed to cocaine had lower body weights than those of the controls. The full term fetuses, however, had similar weight in both experimental and control groups. The pups were weighed every 2 days from day 2 to day 16. The pups showed a slightly wider range of weights in the cocaine treated group as they matured to 16 days. All fetuses and pups revealed no soft tissue anomaly which, along with the weight data, supported our earlier findings.     

Proliferation in the rat olfactory epithelium: age-dependent changes

Vertebrate olfactory sensory neurons are replaced continuously throughout life. We studied the effect of age on proliferation in olfactory epithelium in postnatal rats ranging in age from birth (P1) until P333. Using BrdU to label dividing cells, we determined the proliferation density of basal cells, i.e., the number of labeled nuclei/unit length (240 microm) of olfactory epithelium in coronal sections from six different anterior-posterior levels from each animal. A total length of >1 m of olfactory epithelium was counted in each age group. We observed a dramatic decrease of proliferation density from P1 through P333. At P1, proliferation density is 151 cells/mm; it decreases to approximately half at P21 (70 cells/mm), and half again at P40 (37 cells/mm). At P333 the proliferation density was only 8/mm, approximately 5% of that seen at P1. The changes were clearly related to age and not to body weight, because the values were essentially identical for males and females of the same age but of different body weight. Proliferating cells appear in patches that, after P40, become more separated from one another and contain fewer cells. In 6- and 11-month-old rats, 30 and 45% of all units contained no labeled cells. We confirmed the data of others that the olfactory surface area continuously increases with age; we showed that there is a reciprocal relationship between proliferation density and surface area. The proliferating cells provide neurons to sustain growth as well as to replace dying cells.