Anxiogenic effects of acute and chronic cocaine administration: neurochemical and behavioral studies.

The effects of cocaine on defensive withdrawal behavior in rats and elevated plus-maze behavior in mice were investigated. Cocaine (20 mg/kg IP) injected daily for 7 or 14 days induced defensive withdrawal; that is, the latency to emerge from a small chamber in an open field and the mean time in the chamber were both significantly increased. Acute cocaine administration also induced defensive withdrawal, and this effect was prevented by prior treatment with chlordiazepoxide (5 mg/kg IP). Both acute and chronic cocaine treatments significantly increased plasma concentrations of corticosterone and reduced the ratios of 3,4-dihydroxyphenylacetic acid to dopamine and 5-hydroxyindoleacetic acid to serotonin in several brain regions. Further evidence for an acute anxiogenic effect of cocaine was obtained from mice studied in the elevated plus-maze. Acute cocaine administration decreased both the number of entries into and the time spent in the open arms of the maze. These results taken together strongly support an anxiogenic action of acute and chronic cocaine administration.     

Cardiovascular responses to cocaine self-administration: acute and chronic tolerance.

The nature and the mechanism of tolerance to the cardiovascular responses to cocaine self-administration were studied in rats implanted with telemetric devices. The first infusion of cocaine (1 mg/kg/infusion) on day 1 of testing produced rapid and brief increases in mean arterial blood pressure and in heart rate. Subsequent infusions in the same session produced minimal effects. With chronic testing, there were gradual reductions in cardiovascular responses to the first infusion in the daily session and enhancements in the daily cocaine intake, with significant changes occurring by the fourth week of the testing. Following saline extinction testing (for 5 days), reinstatement of cocaine during week 6 led to a partial and short lasting (相似文献   

Sex differences in locomotor activity after acute and chronic cocaine administration.

Adult, intact and gonadectomized male and female Wistar rats (n = 9) were exposed to an automated open field to assess the behavioral effects of acute cocaine administration (saline, 1.0 and 10.0 mg/kg subcutaneous). The subjects were exposed to the open field for 10 min, removed to be injected and returned to the open field for another 30 min. Three saline and two drug sessions were run in counterbalanced order. Locomotor activity in intact and castrated male rats and ovariectomized female rats decreased following injection, irrespective of the dose of cocaine. The locomotor activity of intact female rats was higher than that of any other group of subjects. It decreased during the session after saline and 1.0 mg/kg cocaine, but increased towards the end of the 30 min session after 10.0 mg/kg. Rearing measures paralleled the observations on locomotor activity. To determine the effects of chronic, home-cage, cocaine administration, five of the subjects in each group were injected with 10.0 mg/kg cocaine for 9 consecutive days. The remaining four subjects received saline injections. On day 10, all subjects were re-exposed to the open-field for 10 min, removed, injected with 10.0 mg/kg cocaine and returned to the open field for another 30 min. Chronic home cage cocaine administration produced an increase in cocaine's effects on locomotor activity and rearing in intact female rats only. However, behavioral sensitization was also observed in intact female rats who had been treated with saline for 9 consecutive days, suggesting that behavioral sensitization to cocaine in intact female rats may develop very rapidly and independent of environmental context.     

Cardiovascular effects and toxicities of cocaine.

Cocaine exerts a myriad of adverse cardiovascular effects which are dependent on the dose, rate of administration, and duration of use. The drug has two primary pharmacologic actions: it is a powerful sympathomimetic agent and a local anesthetic. The drug blocks the presynaptic reuptake of catecholamines resulting in the marked hormonal increase at the postsynaptic receptor sites. These effects, in turn, lower the threshold for coronary vasoconstriction and vasospasm, myocardial ischemia and infarction. In addition, the drug's multiple pharmacologic and electrophysiologic cardiovascular actions can promote arrhythmias, myocarditis, cardiomyopathy, as well as unmasking subclinical diseases. Long-term cocaine use can cause autonomic disturbances and alter catecholamine homeostasis: chronic cocaine addicts face serious cardiovascular sequelae from the drug's multiple adverse effects. It is important to assess the prevalence of cocaine-related cardiovascular diseases, to understand how the drug affects the autonomic nervous system, and to determine its long-term effects on the cardiovascular system.     

Behavioral effects of acute and chronic cocaine administration in male and female rats: effects of fixed-ratio schedule parameters

Intact and gonadectomized male and female rats pressed a lever to obtain food on different fixed-ratio (FR) schedules in a three-component multiple schedule. The values of a small, intermediate and large FR schedule were individually determined and were higher for intact male rats than for most subjects in the other groups. Acute cocaine administration (1.0-30.0mg/kg) dose-dependently decreased response rates maintained by all three schedules, but responding maintained by the large FR schedule was more sensitive to the rate-decreasing effects of acute cocaine administration. Response rates of intact male rats were less sensitive to the rate-decreasing effects of cocaine than those of the other groups, at least at higher doses during the small and intermediate FR schedules. Cocaine's dose-effect curve was redetermined after chronic administration of a behaviorally active dose of cocaine. Differences between groups of subjects were not evident. Behavioral tolerance was consistently observed when responding was maintained by the small FR schedule. Effects varied between subjects within groups when responding was maintained by the intermediate FR schedule, but behavioral tolerance was frequently observed. Behavioral sensitization was evident during the large FR schedule, but these data were difficult to interpret because of a considerable shift in response rates after vehicle administration. The data suggest that the comparison of drug effects in male and female rats requires a systematic analysis of the contribution of behavioral parameters. They also provide additional evidence for the notion that reference to reinforcement-loss alone is not sufficient to explain the development of tolerance to the behavioral effects of cocaine.     

The influence of route of administration on the acute cardiovascular effects of cocaine in conscious unrestrained pregnant rats

The intravenous route of administration, accessed via a subcutaneous vascular access port, has been recently suggested as an animal model for studying the developmental effects of maternal cocaine abuse in the pregnant and/or group-housed rat. The present study (1) assessed the cardiovascular effects of intravenous (IV) cocaine, delivered via bolus injection, in chronically catheterized near-term pregnant rats, and (2) compared the IV cardiovascular responses to those following cocaine delivered via the commonly employed subcutaneous (SC) and intragastric (IG) routes of administration. Pregnant gestation day 15 (GD15) young adult female Sprague-Dawley rats (n = 21) were anesthetized and catheters surgically implanted into the carotid artery, jugular vein, fundus of the stomach, and a subcutaneous pouch. On GD17-19, heart rate (HR) and mean arterial pressure (MAP) were assessed, using a within-subjects design, prior and subsequent to IV (3 mg/kg), IG (60 mg/kg), and SC (40 mg/kg) cocaine. An interval of 6 h separated IV and IG cocaine administration and an interval of 18 h separated IG and SC cocaine administration. The peak responses of HR (23% downward arrow) and MAP (37% upward arrow) following IV cocaine were noted within 0.5 min. In contrast, the peak responses of HR (4% downward arrow, 6% downward arrow) and MAP (2% upward arrow, 15% downward arrow) after IG (23 min) or SC (26 min) cocaine, respectively, were significantly smaller and markedly delayed. No significant change in aortic blood flow velocity was detected following cocaine via any route of administration, although phasic flow velocities (PFV) were differentially sensitive to route of administration (PFV(dias) not PFV(sys)); IV cocaine increased (55% upward arrow) whereas IG or SC cocaine decreased approximately 35% downward arrow) PFV(dias). The pressor effects of an equimolar dose of IV cocaine methiodide (3.9 mg/kg) were indistinguishable from those of IV cocaine (38% upward arrow vs. 37% upward arrow), as were the effects on PFV(dias) (83% upward arrow vs. 55% upward arrow). The lack of an effect of cocaine methiodide on HR was consistent with the bradycardia effect of cocaine attributable to central mediation of the baroreflex. Finally, the pressor effects of IV cocaine paralleled the rapidly peaking arterial plasma levels of cocaine noted within 30 s after the initiation of drug injection. In sum, prominent effects of IV cocaine on maternal cardiovascular physiology are noted; as such, the recent reports of a lack of maternal/fetal toxicity following daily (3-6mg/kg) IV cocaine during GD8-21 are not due to use of an ineffective drug dose. It was equally clear that the SC and IG routes of exposure did not reproduce the cardiovascular component(s) of the expected physiological response to cocaine.     

Cardiovascular effects of acute oxygen administration in healthy adults

Supplementary oxygen is commonly administered in current medical practice. However, attention has recently been drawn to the potentially disadvantageous hemodynamic consequences in certain patients. Possible mechanisms underlying the cardiovascular responses to acute hyperoxia are unclear. The effects of acute oxygen administration on heart rate, blood pressure, cardiac output, systemic vascular resistance, and baroreflex sensitivity were studied in a series of randomised, placebo-controlled studies in healthy individuals, using validated, non-invasive techniques. The effects of oxygen administration on forearm blood flow responses to locally administered acetylcholine, an endothelium-dependent vasodilator, sodium nitroprusside, an endothelium-independent vasodilator, and l-NG-monomethylarginine, a nitric oxide synthase inhibitor, were studied using venous occlusion plethysmography. Oxygen administration for 1 hour caused a reduction in heart rate (P < 0.01) and cardiac index (P < 0.05), and an increase in mean arterial pressure (P < 0.01), systemic vascular resistance (P < 0.05), large artery stiffness (P < 0.05), and baroreflex sensitivity (P < 0.05). There were no effects on vascular responses in the isolated forearm bed. These findings indicate that oxygen administration causes acute effects on cardiovascular function, which might be important in the context of acute illness.     

The effects of chronic cocaine administration on brain neurotransmitter receptors

The nonmedical use of cocaine has continued to increase during the past decade, resulting in considerable interest in the clinical and neurobiological implications of this behavior. A better understanding of the complex neurobiological changes associated with chronic cocaine intoxication may assist in the search for improved methods of treatment in the clinic. In this investigation, chronic daily injections of cocaine for 15 days resulted in opposite effects on dopamine receptor number measured with [^3H]sulpiride in the striatum and nucleus accumbens of rats. Binding was increased in the nucleus accumbens but decreased in the striatum. By contrast, benzodiazepine receptors measured with [³H]Ro 15-1788 were increased in the striatum and cerebellum but decreased in the frontal cortex. Intraventricular injections of 6-hydroxydopamine resulted in a decrease in the number of benzodiazepine receptors measured in the striatum and reduced the effects of cocaine on these receptors. These data suggest that while chronic cocaine administration may induce changes in dopaminergic activity and dopaminergic receptors, opposite effects may be observed in benzodiazepine receptor number induced either directly by cocaine or indirectly through changes in dopaminergic neuronal activity. Although the significance of these findings is not clear, the results of this investigation suggest a different noncatecholaminergicavenue for future studies to follow.     

Sex differences in plasma cocaine levels and subjective effects after acute cocaine administration in human volunteers

Gender differences after acute cocaine administration have received little attention in spite of the fact that males and females respond differently to many drugs. Seven male and seven female occasional cocaine users received both an intranasal dose of cocaine hydrochloride (0.9 mg/kg) and placebo powder in a randomized order and reported subjective effects via an instrumental joystick device and various questionnaires. Blood samples were withdrawn at 5-min intervals to assess pharmacokinetic differences. Male subjects achieved the highest peak plasma cocaine levels (144.4 ± 17.5 ng/ml), detected cocaine effects significantly faster than females and also experienced a greater number of episodes of intense good and bad effects. Women studied during the follicular phase of their menstrual cycle had peak plasma cocaine levels of 73.2 ± 9.9 ng/ml, which was significantly higher than when they were studied during their luteal phase (54.7 ± 8.7 ng/ml), but there were no differences in their subjective reports of cocaine effects. In spite of the different cocaine blood levels and subjective effects, peak heart rate increases did not differ between males and females suggesting that women may be more sensitive than males to the cardiovascular effects of cocaine. These data suggest that there are significant gender and menstrual cycle differences in the response to acute intranasal cocaine administration and these differences may have implications for the differential abuse of this drug.This paper is dedicated to Xavier Lamas, MD, PhD, who lost his life while ascending Mt. Everest, August 1995     

Heart rate dynamics after acute cocaine administration.

We examined heart rate (HR) patterns after a bolus intravenous (i.v.) administration of a high (10 mg/kg) dose of cocaine in unrestrained cats. Mean R-R intervals, SD, and other measures of variability were assessed in three periods: waking baseline, early postcocaine administration, and later recovery periods. Cocaine resulted in initial tachycardia and reduced HR variability. This reduction in variability was independent of changes in the average rate: during the recovery period, HR returned to baseline values, but the reduced variability persisted. Nonlinear methods of assessment yielded additional results: Cocaine introduces a high correlation between one beat and the next and a tendency for cardiac accelerations to be followed immediately by decelerations and vice versa. The overall effect of the drug is to restrict deviation from a fixed rate.     

Proconvulsant and anticonvulsant effects in mice of acute and chronic treatment with cocaine

The proconvulsant and anticonvulsant effects of acute and chronic exposure to cocaine were investigated in adult, male, CF-1 mice. The proconvulsant effects of cocaine in mice only manifested themselves after daily exposure to motor-stimulant doses. Although daily treatment decreased electroshock convulsion threshold, no motor convulsions were observed. Animals in the proconvulsant state, however, kindled to electrically-induced convulsions more rapidly than did controls. Furthermore, daily treatment with cocaine and electroshock also enhanced the development of electrical kindling. These results illustrate that the excitatory properties of cocaine in the CNS can enhance phenomena which cause a persistent increase in excitability of the CNS. In contrast to the proconvulsant activity after chronic exposure, cocaine, administered acutely, in motor-stimulant doses, was anticonvulsant in a variety of tests using electroshock and chemically-induced convulsions. The drug elevated electroshock thresholds for both minimal and maximal convulsions and these responses were not blocked by haloperidol. In tests for minimal chemically-induced convulsions, cocaine elevated the threshold to N-methyl-DL-aspartate, but not to bicuculline; against maximal convulsions, the drug was anticonvulsant against both N-methyl-DL-aspartate and bicuculline. Cocaine did not affect convulsion thresholds for strychnine, arecoline or aminophylline; these data suggest that the anticonvulsant action of cocaine is relatively selective for the gamma-aminobutyric acid (GABA) and glutamate systems.     

Brain and plasma levels of cocaine and benzoylecgonine in lead-exposed and cadmium-exposed rats following acute or chronic intraperitoneal administration of cocaine

Previous investigations of metal/cocaine interactions have shown that chronic oral exposure to inorganic lead or cadmium attenuates the psychoactive effects of acute or repeated administration of cocaine. The purpose of this investigation was to assess the possibility that such interactive effects may derive from metal-induced disturbances in cocaine pharmacokinetics, i.e., delivery of cocaine to critical biologic sites may be disrupted by metal contamination. In this study, adult male rats were exposed to purified diets containing 250 ppm lead acetate (Group Lead), 100 ppm cadmium chloride (Group Cadmium), or unadulterated laboratory chow (Group Control); n=48/exposure condition. Following ad libitum access to their respective diets in the home cage for 45 days, half the animals from each exposure regimen received single daily IP injections of 5, 10, or 20 mg/kg cocaine HCl for a period of 7 days (n=8/group). The remaining half the animals received repeated daily injections of saline during this pretreatment phase. On the day following pretreatment, animals previously receiving cocaine injections were administered a single cocaine test challenge at a dose equal to that received in pretreatment. Similarly, saline pretreatment animals received either 5, 10, or 20 mg/kg cocaine. The results of this investigation did not reveal reliable evidence of metal-related differences in brain levels of cocaine. Plasma cocaine and benzoylecgonine (BE) levels also were essentially the same for control and metal-exposed animals. The failure to show that lead or cadmium alters the disposition of cocaine in brain or plasma underscores the need to pursue alternative accounts of metal/cocaine interactions.     

Potentiation of the behavioral and convulsant effects of cocaine by chronic administration in the rat

The effect of chronic administration on the behavioral response to cocaine was studied in male Sprague-Dawley rats. In experiment 1 five groups of rats received daily intraperitoneal injections of either saline, 20 mg/kg, or 40 mg/kg cocaine hydrochloride for 10 days, or of higher doses of cocaine until either one or three convulsions occured. Following this initial treatment, all animals were left untreated for seven days, and then sensitivity to cocaine was assessed in all animals by a test injection series (daily injections of increasing doses of cocaine). Animals which had received 40 mg/kg cocaine during the initial treatment exhibited a greater behavioral response (stereotyped behavior) to cocaine during the test injection series than did animals treated with saline; both the 40 mg/kg and one — convulsion treatments during the initial stage of the experiment resulted in greater sensitivity to the convulsant effect of cocaine during the test injection series. In experiment 2 animals were injected intraperitoneally with either saline or 40 mg/kg cocaine for 10 days and then tested with a series of daily cocaine injections of increasing dosage after remaining untreated for 4, 8, 16 or 32 days. The results indicated that the initial treatment with 40 mg/kg cocaine augmented both the behavioral and convulsant effects of cocaine during the subsequent test injection series. The sensitization to the convulsant effect of cocaine was significant at all intervals after initial treatment except 16 days, while the duration of sensitization to the behavioral effects of cocaine could not be determined due to apparent age-related changes in the response of control animals to cocaine. The sensitization which was observed was attributed to the effects of cocaine per se rather than to convulsions produced by the drug.     

Behavioural and neurochemical effects of repeated administration of cocaine in rats.

The effects of repeated administration of cocaine (15 mg/kg, i.p. twice daily at 8-hr intervals) were investigated on the spontaneous motor activity (SMA) and stereotypy (ST) as well as on the various neurotransmitters (e.g. norepinephrine, NE; dopamine, DA; serotonin, 5-HT; acetylcholine, ACh) in different brain areas (e.g. diencephalon-midbrain, DM; pons-medulla, PM; caudate nucleus, CN) in rats.Following repeated injections of cocaine, both SMA and ST gradually increased, reaching a peak in each case on about the 9th day, then gradually decreased up to the 18th or 20th day, after which the activities were maintained at minimum level which was slightly higher than normal levels. Concomitantly, the DA level in the CN and DM increased and 5-HT in the DM and PM decreased reaching their maximum or minimum levels following cocaine injections on the 9th day; these changes were gradually minimized by the 18th day and remained so up to the 30th day. There were also slight changes in NE and ACh levels. It thus appears that, following repeated cocaine administrations, the changes in the drug-induced behavioural effects can be correlated roughly with the changes in the DA level in the CN and the 5-HT levels in the DM and PM.     

Metoclopramide pharmacokinetics in pregnant and nonpregnant sheep

The pharmacokinetics of metoclopramide was studied in chronically instrumented pregnant and nonpregnant sheep. Metoclopramide was administered to the ewe by intravenous bolus injections (on a crossover basis) of 10, 20, and 40 mg, with an additional 80-mg dose to the nonpregnant animals. Transfer of the drug to the fetus was rapid with significant concentrations in fetal plasma 1 min after maternal dosing. The ratio of fetal-to-maternal area under the plasma concentration-time curves averaged 0.74, indicating significant fetal exposure to the drug. Maternal metoclopramide administration resulted in minimal fetal effects, with no change in arterial pressure, heart rate, or arterial pH or PCO2, and only a small (approximately 1.8 mmHg) transient decline in PO2. Plasma concentrations in maternal and fetal plasma in most animals were best described by a biexponential equation with rapid distribution and elimination phases. The terminal elimination half-lives in maternal and fetal plasma averaged 71.3 and 86.8 min, respectively, with fetal half-life being significantly longer. The number of fetuses present had no consistent effects on either maternal or fetal pharmacokinetic parameters. Total body clearance and volume of distribution averaged 3.5 L/h/kg and 5.8 L/kg, respectively, in the pregnant ewe, and 4.5 L/h/kg and 6.9 L/kg, respectively, in the nonpregnant animals. The terminal elimination half-life in the nonpregnant ewes averaged 67.5 min. Pharmacokinetic parameters were compared in the pregnant and nonpregnant ewes at the 10-, 20-, and 40-mg doses, and no significant differences were observed in the distribution or elimination rate constants, elimination half-life, or volume of distribution.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular effects of apamin and BRL 34915 in rats and rabbits.

1. The cardiovascular effects of apamin, a selective blocker of certain calcium-activated potassium channels, and BRL 34915, a vasodilator thought to act by opening of potassium channels, have been investigated in vivo in rats and rabbits. 2. In anaesthetized normotensive rats, apamin (0.05 and 0.15 mg kg-1, i.v.) potentiated angiotensin II pressor responses but did not modify baseline blood pressure or heart rate. 3. Apamin (0.15 mg kg-1, i.v.) was without cardiovascular effects in rabbits. 4. BRL 34915 (0.1 and 0.3 mg kg-1, i.v.) lowered blood pressure in rats dose-dependently and caused reflex tachycardia. The heart rate increase was abolished by prior administration of the beta-adrenoceptor blocker bopindolol (0.1 mg kg-1, i.v.). 5. In anaesthetized rabbits, regional blood flow measurements (with radioactive tracer microspheres) showed that BRL 34915 (3 to 30 micrograms kg-1, i.v.) caused marked vasodilatation in the stomach, with increases in flow also to the heart and small intestine. Brain blood flow also tended to increase. Blood flow to the kidneys was reduced by BRL 34915, whereas flow to skeletal muscle was unchanged. 6. Apamin pretreatment did not modify the blood pressure lowering activity of BRL 34915 in rats. The site at which BRL 34915 acts to cause vasodilatation in vivo thus appears to be apamin-insensitive.     

Comparison of the pharmacokinetics of iron in pregnant and nonpregnant women after oral administration of Vitaferro

In this paper we represent results concerning pharmacokinetics and bioavailability of iron after the oral application of Vitaferro to women in the second half of pregnancy suffering or not from anaemia in comparison to nonpregnant women. The significance of different parameters used to proof an iron deficiency is discussed. In all pregnant probands the bioavailability of Vitaferro is about twice as high as in nonpregnant women. Also the parameters of elimination refer to an enhanced retention of iron during pregnancy. We conclude from our investigations that an iron deficiency may be diagnosed well by the determination of haemoglobin values, iron concentration in serum, binding capacity and resorption of iron. During pregnancy the preparation Vitaferro is well resorbed and does not cause incompatibilities. Thus it is suitable for the treatment of anaemia during pregnancy.