Comparison of heroin and cocaine concentrations in saliva with concentrations in blood and plasma

Saliva is an alternate biological matrix for drug testing that has several advantages over more traditional fluids such as blood and urine. Collection is rapid, noninvasive, and relatively easy to obtain. Several reports have detailed the appearance of drugs of abuse in saliva, but few have compared the excretion profiles of drugs administered by different routes. In this study, subjects were administered three smoked and three intravenous doses of heroin in an ascending dose design. Blood and saliva were collected periodically after drug administration and analyzed by gas chromatography-mass spectrometry (GC-MS) for heroin, 6-acetylmorphine, and morphine. In a second study, subjects were administered a single, smoked dose of 40 mg cocaine base and an intravenous dose of 44.8 mg cocaine HO on separate occasions. Plasma and saliva were collected and analyzed by CC-MS for cocaine, anhydroecgonine methyl ester (AEME), and seven additional metabolites. Heroin and 6-acetylmorphine were detected in the first saliva sample collected (2 min) following drug administration by both routes. Peak heroin concentrations were achieved quickly, between 2 and 5 min after intravenous administration and at 2 min after smoke heroin. Peak heroin concentrations in saliva after smoking heroin base ranged from 3534 (2.6 mg) to 20,580 ng/mL (5.2 mg), and after intravenous administration, concentrations ranged from 6 (10 mg heroin HCl to 30 ng/mL (12 mg heroin HCl. Saliva concentrations of heroin declined rapidly after intravenous administration, reaching the limit of sensitivity of the assay (1 ng/mL) by 60 min. Heroin concentrations in saliva after smoking declined slowly; detection times ranged from 4 to 24 h. Cocaine was the major analyte detected in saliva and plasma after smoked and intravenous administration. Peak saliva cocaine concentrations after intravenous administration ranged from 428 to 1927 ng/mL (N = 7); after smoking, they ranged from 15,852 to 504,880 ng/mL (N = 7). Peak plasma cocaine concentrations after intravenous administration ranged from 122 to 442 ng/mL A = 7), and after smoking, concentrations ranged from 46 to 291 ng/mL A = 7). The thermal degradation product of cocaine, AEME, was detected in saliva but not in plasma after smoking. Peak saliva AEME concentrations were achieved at 2 min and ranged from 558 to 4374 ng/mL (N = 7). These are the first reported observations of heroin and metabolites in saliva following heroin smoking and of AEME in saliva after smoking cocaine base. The presence of AEME in saliva may be useful as a marker of the smoked route following cocaine administration.     

Acute activation of circulating polymorphonuclear neutrophils following in vivo administration of cocaine. A potential etiology for pulmonary injury

Crack cocaine has become a major drug of abuse in the United States and its use is associated with a broad spectrum of pulmonary complications. The present study was conducted to determine whether controlled in vivo administration of cocaine (inhaled or IV) alters the function of circulating inflammatory cells in a manner capable of contributing to acute lung injury. Subjects who regularly smoked crack cocaine were asked to abstain from illicit drug use for at least 8 h, and were then administered one of the following treatments on each of 4 study days: inhaled cocaine base (45 mg), inhaled placebo (4.5 mg cocaine base, a subphysiologic dose), IV cocaine HCl (0.35 to 0.50 mg/kg), or IV placebo (saline solution). Samples of blood were obtained from a peripheral venous catheter and blood cells were isolated before and 10 to 45 min after treatment. The administration of either cocaine base or cocaine HCl, but not their corresponding placebos, resulted in the activation of circulating polymorphonuclear neutrophils (PMNs). Exposure to cocaine in vivo enhanced the antibacterial activity of PMNs, as measured by their ability to kill Staphylococcus aureus. Antitumor activity, as measured in an antibody-dependent cell-mediated cytotoxicity assay, also increased following short-term administration of cocaine. Finally, short-term exposure to cocaine enhanced production of interleukin 8, a potent PMN chemoattractant and neutrophil-activating factor associated with both acute and chronic lung injury. These studies demonstrate that short-term in vivo exposure to cocaine activates the effector function and cytokine production of circulating PMNs. Therefore, it is possible that bursts of acute inflammatory activity resulting from crack use could contribute to lung injury.     

Evaluation of the reinforcing and discriminative stimulus effects of cocaine in combination with (+)-AJ76 or clozapine

Because self-administration and discrimination of a drug by animals correlate with its abuse and subjective effects in humans, interventions that modify the reinforcing and discriminative stimulus effects of the drug may be useful in the treatment of its abuse. The present study was designed to evaluate the effects of the putative dopamine autoreceptor antagonist (+)-AJ76 (AJ) or the atypical antipsychotic clozapine (CLZ) on the reinforcing and discriminative stimulus effects of cocaine in monkeys. One group of rhesus monkeys (n = 6) was allowed to self-administer cocaine (0.03 or 0.1 mg/kg/injection i.v. fixed-ratio 10, 2 hr/day). A second group of monkeys (n = 5) was trained to discriminate cocaine (0.2 or 0.4 mg/kg i.m., 10 min presession) from saline in a two lever, food-reinforced, drug discrimination paradigm. When behavior was stable, AJ or CLZ was administered i.m., 15 or 30 min presession. Intermediate doses of both compounds (1.0-3.0 mg/kg of AJ; 0.3-1.0 mg/kg of CLZ) increased cocaine self-administration, while responding remained evenly distributed over the session. A higher dose of CLZ decreased cocaine self-administration in an apparently nonspecific manner. When combined with saline, partial substitution for cocaine was seen in one of three monkeys with AJ and in none with CLZ. In combination with the training dose of cocaine in the discrimination experiment, both AJ and CLZ decreased drug appropriate responding by at least 50% in two of four monkeys, but had little or no effect in the other monkeys up to doses that completely suppressed lever pressing (6.4 mg/kg of AJ; 3.2 mg/kg of CLZ). Taken together, the present findings suggest that any blockade of the reinforcing and discriminative stimulus effects of cocaine by AJ and CLZ was, at best, partial. Furthermore, the stimulant effects of AJ observed in rats were not prominent in monkeys.     

Drug-induced reinstatement to heroin and cocaine seeking: A rodent model of relapse in polydrug use.

The authors investigated several features of polydrug use in rats. Heroin and cocaine were self-administered following responses on different levers, with only 1 drug and 1 lever available on alternate days of training. Four doses of each drug (heroin: 25, 50, 100, and 200 μg/kg/infusion; cocaine: 0.25, 0.5, 1, and 2 mg/kg/infusion) were tested, and each rat was exposed to a single dose combination. Rats readily developed drug-specific and dose-related responding. During extinction, rats displayed a significant bias for responding on the cocaine-associated lever. Priming injections of either cocaine (20 mg/kg) or heroin (0.25 mg/kg) reinstated responding that was selective for the lever previously associated with each drug These results suggest that in this type of polydrug use, drugs have the capacity to activate drug-seeking behavior selectively oriented toward stimuli previously associated with their administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Polydrug self-administration in rats: cocaine-heroin is more rewarding than cocaine-alone

The i.v. self-administration by rats of a polydrug combination of cocaine and heroin was explored. The rewarding efficacies of a range of cocaine doses (0.25-8 mg/kg/injection) alone or in combination with heroin (12.5 or 25 microg/kg/injection) were compared using a progressive ratio (PR) schedule of reinforcement. Breaking points (BP) for one group of rats were determined at each dose of cocaine alone and for two other groups at each of the same cocaine doses plus one of the heroin doses, respectively. The cocaine-heroin combination was associated with higher BPs than cocaine alone at all doses of cocaine. These data demonstrate that cocaine-heroin combinations (speedballs) are more rewarding than the identical doses of cocaine alone. Some possible mechanisms by which heroin increases cocaine reward are discussed.     

Effects of naltrexone on response to intravenous cocaine, hydromorphone and their combination in humans

This study evaluated the effects of i.v. cocaine, hydromorphone and their combination, and assessed the ability of oral naltrexone, an opioid antagonist, to modulate these effects. Volunteers with cocaine and heroin abuse histories (n = 8) participated in this placebo-controlled, cross-over study while residing on a closed research unit. Daily treatment with capsules containing placebo or naltrexone in ascending doses (3.125, 12.5, 50 and 200 mg) were given for 7-day periods. In thrice weekly experimental sessions, cocaine, hydromorphone and their combination were given in random order. Drug doses were given in an ascending order 1 hr apart as follows: cocaine at 0,20 and 40 mg, hydromorphone at 0, 1.5 and 3.0 mg, and the combination of 0 and 0 mg, 20 mg cocaine and 1.5 mg hydromorphone and 40 mg cocaine and 3.0 mg hydromorphone. Hydromorphone and cocaine produced distinct pharmacodynamic profiles, and the combination produced effects similar to both drugs. In some cases, the magnitude of effects produced by the combination was greater than that produced by either drug alone. Naltrexone produced dose-related blockade of hydromorphone effects, but did not after any of the physiological or subjective effects of cocaine. All naltrexone doses partially attenuated the effects of the combination and this appeared to be attributable to selective opioid blockade. These data do not support the use of naltrexone as a treatment for cocaine abuse, but suggest it may be useful for treating patients with concurrent cocaine and heroin abuse.     

Interaction of buprenorphine with cocaine-morphine combinations.

Sixteen nonheroin dependent drug abusers, who identified intravenous cocaine and heroin as their drug combination of choice, participated in a study assessing the efficacy of buprenorphine in altering the subjective and cardiovascular effects of such combinations. A sublingual dose of buprenorphine (none, 2, or 4 mg) was administered 50 min before the intravenous administration of morphine sulfate (0, 5, or 10 mg/70 kg) in combination with cocaine hydrochloride (0, 8, or 32 mg/70 kg). Buprenorphine had minimal effects on the response to cocaine alone but decreased cardiovascular activity produced by morphine alone. Buprenorphine decreased ratings of drug liking when given before combinations of 32 mg of cocaine and morphine. The greater effect of buprenorphine on cocaine-morphine combinations suggests that buprenorphine may be effective as a treatment medication for individuals who use such combinations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cocaethylene formation following ethanol and cocaine administration by different routes.

Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene. Because of first pass metabolism, oral drug administration might be expected to produce relatively larger concentrations of cocaethylene than would intravenous or smoked administration. We, therefore, compared the effects of route of cocaine administration on the formation and elimination of cocaethylene. Six experienced cocaine users were tested in 6 sessions, approximately 1 week apart. Deuterium-labeled cocaine (d?) was administered in all conditions. Oral cocaine-d? 2.0 mg/kg, intravenous cocaine-d? 1.0 mg/kg, and smoked cocaine-d? (200 mg) were administered after oral ethanol 1.0g/kg or placebo. A small, intravenous dose of deuterated cocaethylene (d?) also was administered with all conditions for determination of cocaethylene formation. Physiologic and subjective effects were recorded and plasma cocaine-d?, cocaethylene-d?, cocaethylene-d?, and benzoylecgonine-d? were measured by gas chromatography-mass spectrometry. About 24% (± 11) of intravenous cocaine was converted to cocaethylene. The oral route (34% ± 20) was significantly greater than from the smoked route (18% ± 11) and showed a trend toward significance for greater formation of cocaethylene compared to the intravenous route. Within each route, the cocaine-ethanol combination produced greater increases in heart rate and rate-pressure product than cocaine alone. Global intoxication effects across time after smoking or intravenous administration were significantly greater when cocaine and ethanol were both given. Administration of cocaine by different routes alters the amount of cocaethylene formed through hepatic first-pass effects. Increased cardiovascular and subjective effects might explain the toxicity and popularity of the combined drugs. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Column-switching high-performance liquid chromatographic assay for determination of apigenin and acacetin in human urine with ultraviolet absorbance detection

Postweaning social isolation can influence the sensitivity of rats to several effects of drugs of abuse. The present study investigated the influence of postweaning housing conditions on the sensitivity of rats to the aversive effects of a number of psychoactive agents using a conditioned taste aversion (CTA) test procedure. Development of a CTA was assessed by pairing administration of the drug with the consumption of a 0.05% (weight/volume) saccharin solution in water-deprived (18 h) rats in a 20 min drinking period. Saccharin consumption was then measured in 20 min test sessions over the next 4 consecutive days. Consumption of saccharin solution was significantly reduced in both isolated and enriched rats following administration of d-amphetamine (2 mg/kg), cocaine (30 mg/kg), morphine (10 mg/kg), nicotine (1.0 mg/kg), caffeine (20 mg/kg), alcohol (1.5 g/kg), and LiCl (0.15 M, 4 ml/kg). There was no significant effect of housing conditions on the CTA induced by cocaine, nicotine, alcohol, or LiCl; however, isolation-reared rats were found to be less sensitive to the aversive effects of d-amphetamine, morphine, and caffeine in this paradigm. These results suggest that rearing rats in social isolation induces an attenuation in sensitivity to the aversive effects of some psychoactive agents.     

Clubgoers and their trendy cocktails: Implications of mixing caffeine into alcohol on information processing and subjective reports of intoxication.

Alcoholic drink preferences in college students have made an interesting shift recently, with trends in consumption leaning toward caffeinated alcohol in various forms (e.g., Red Bull and vodka or caffeinated beers such as Anheuser-Busch's B-to-the-E). Despite the dramatic rise in popularity of these beverages, little research has examined the combined effects of alcohol and caffeine, which is problematic for adequately informing the public about the risk or lack thereof of these drinks. The purpose of this study was to directly investigate the acute effects of alcohol and caffeine, alone and in combination, on well-validated measures of cognitive performance and subjective intoxication in social drinkers. Participants (N = 12) performed a psychological refractory period task that measured dual-task interference as the prolonged reaction time to complete the 2nd of 2 tasks performed in close temporal sequence. Performance was tested under 2 active doses and 1 placebo dose of caffeine (0.0 mg/kg, 2.0 mg/kg, and 4.0 mg/kg) in combination with 1 active dose and 1 placebo dose of alcohol (0.0 g/kg and 0.65 g/kg). As expected, alcohol impaired task performance by increasing dual-task interference and increasing errors. The coadministration of caffeine counteracted the effects of alcohol on interference but had no effect on the degree to which alcohol increased errors. Subjective measures of intoxication showed that coadministration of caffeine with alcohol reduced participants' perceptions of alcohol intoxication compared with administration of alcohol alone. The results highlight the complexity of drug interactions between alcohol and caffeine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative characteristics of high and low cocaine administration: effect of other psychostimulants

Two groups of N/Nih male rats were trained to discriminate saline vehicle from either 2.0 mg/kg (n = 10) or 10.0 mg/kg (n = 10) cocaine in a food-motivated, two-lever operant paradigm. The rats trained at the low-dose cocaine took a significantly longer training period to reach criterion performance than did the high-dose cocaine group. In addition, the ED50 value for the 2.0 mg/kg cocaine-trained animals (0.465 mg/kg) was significantly lower than the ED50 value (2.105 mg/kg) for those animals trained at the 10.0 mg/kg dose of cocaine. This correlation of ED50 values for stimulus generalization decreasing with reduction in training dose was in contrast to the time-course of the two groups when tested from 15 to 240 min post-injection; this experimentation indicated that there was a non-significant difference in half-life for the 2.0 mg/kg (t1/2: 97.1 min) vs. that of the 10.0 mg/kg cocaine-trained group (t1/2: 83.4 min). Generalization tests with other purportedly dopaminergically-active drugs of abuse including 0.05-0.8 mg/kg d-amphetamine, 0.125-1.5 mg/kg methamphetamine and 0.125-1.0 mg/kg methcathinone indicated that the highest doses of each produced generalization and, with the exception of methcathinone, the ED50 values were significantly lower in the low-cocaine trained group. The stimulus properties of cocaine, as they generalize to amphetamine, methamphetamine and methcathinone, can be explained by effects upon central dopaminergic neurons and may be qualitatively different in low-and high-dose trained rats.     

Dopamine 'D2-like' receptor agonists in combination with cocaine: absence of interactive effects on locomotor activity

This study examined interactions between cocaine and drugs that act as direct agonists at subtypes of "D2-like" dopamine receptors. The drugs 7-OH-DPAT, quinpirole and RU24213 were studied alone and in combination with cocaine for their effects on locomotor activity in non-habituated mice. Locomotor activity was measured by photobeam crossings over 140 min. At the doses given (7-OH-DPAT: 0.006-6.4 mg/kg; quinpirole: 0.001-1 mg/kg; RU24213: 0.008-8 mg/kg) all three direct agonists dose-dependently reduced locomotor activity throughout the test, whereas cocaine (0.6-20 mg/kg) produced dose-related hyperactivity. Next, for each direct agonist, a series of doses was selected (up to threshold behaviourally-active doses) as pretreatments to a sub-maximally stimulant dose of cocaine (15 mg/kg). 7-OH-DPAT and quinpirole did not modulate the effects of cocaine; RU24213 produced, at best, a very modest attenuation of the effects of cocaine. Finally, a series of cocaine doses (below stimulant threshold) was given before a single dose of each direct agonist (the lowest dose to reduce activity significantly). Cocaine did not reliably alter the hypoactivity produced by any of the D2-like agonists. By demonstrating negligible interactions between cocaine and D2-like agonists, the results fail to demonstrate any necessary involvement of D2-like receptors in one of the behavioural effects of cocaine.     

Tocopherols, retinol, beta-carotene and fatty acids in fat globule membrane and fat globule core in cows'' milk

To develop and characterize a murine model for investigating the long-term effects of prenatal cocaine exposure, the present study established the route of drug administration and the doses to be used for pregnant C57BL/6 mice. Comparison of the effects of a high dose of cocaine (60 mg/kg) when gavaged or injected subcutaneously (SC) established patterns of pathology characteristic of administration route but no dominating logic for selecting one over the other route for prenatal studies; however, because of the fourfold greater brain levels, with no evidence of greater pathology, the SC route was selected. When injected daily during gestation days 12-18, the period of prenatal development of dopamine systems, cocaine at doses producing plasma concentrations consistent with its stimulatory effects reduced food ingestion and weight gains during pregnancy and fetal body and brain weights at term. The extent of these reductions was comparable to reports on babies exposed to cocaine prenatally. Furthermore, the present study suggests that maternal undernutrition is not a likely mediator of these perinatal effects and that differences in the amount of cocaine exposure may cause the contrasting effects of maternal cocaine noted in the human literature.     

Effects of phentermine on responding maintained under multiple fixed-ratio schedules of food and cocaine presentation in the rhesus monkey

Drugs that decrease drug-maintained responding at doses that do not decrease other behaviors in animals may be suitable candidates for development as medications to treat drug abuse in humans. The present study examined whether this effect could be obtained with phentermine, a drug that has been reported to decrease cocaine intake in humans. Rhesus monkeys were trained under multiple fixed-ratio 30-response schedules of food and i.v. cocaine delivery. Phentermine was always given as a slow, i.v. infusion. Acute treatment with phentermine (0.3-10 mg/kg) decreased cocaine-maintained responding at doses that did not decrease, or decreased less, food-maintained responding for each of three unit doses of cocaine (10-100 microg/kg/injection). Subacute treatment with phentermine (3 or 5.6 mg/kg, daily) also decreased cocaine-maintained responding more than food-maintained responding. After subacute treatment was terminated, rates of cocaine-maintained responding generally recovered to levels comparable to those seen during untreated control sessions. Phentermine (0.3-3 mg/kg) did not generally increase responding associated with a very low (1 microg/kg/injection) unit dose of cocaine, suggesting that the decrease in cocaine-maintained responding at higher unit doses was not the result of a leftward shift in the cocaine unit dose-effect function. Phentermine (0.1-3 mg/kg) decreased responding maintained by 1-[2-[bis(4-fluorophenyl) methoxy]ethyl]-4-[3-phenylpropyl] piperazine (GBR 12909) (30 microg/kg/injection) at doses similar to those that decreased food-maintained responding. These results show that phentermine is effective in decreasing cocaine self-administration and suggest that it may be an effective medication for cocaine abuse.     

Determination of the place conditioning and locomotor effects of amperozide in rats: A comparison with cocaine.

Amperozide promotes social interactions in rats (Rattus norvegicus) and reduces craving for cocaine and alcohol without producing adverse side effects. Amperozide administration produced a place preference in the dose range from 3.0 to 10.0 mg/kg. Locomotor behavior tended to be suppressed on the days of amperozide pairings, elevated on the days of vehicle pairings, and elevated on test days. Administration of 20.0 mg/kg but neither 2.0 nor 0.2 mg/kg cocaine produced place preference. Rats exhibited a greater place preference for the chamber paired with 2.0 mg/kg and 20.0 mg/kg but not 0.2 mg/kg cocaine compared to the chamber paired with 5.0 mg/kg amperozide. The results indicate that amperozide is appetitive. The most appetitive dose of amperozide (5.0 mg/kg) is less appetitive than the most appetitive dose of cocaine (20.0 mg/kg). More research is needed before conclusions regarding the degree of abuse potential for amperozide can be made. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Deficits in D-fenfluramine-sensitive pool of brain 5-HT following withdrawal from chronic cocaine exposure

Recent head-twitch response (HTR) studies in mice have indicated that withdrawal from chronic cocaine exposure produces deficits in CNS conversion of L-tryptophan to 5-HT. In the present study, the ability of 5-HT releaser, d-fenfluramine, was utilized to induce the HTR in mice following abstinence from chronic cocaine exposure. d-Fenfluramine-induced HTR, is a 5-HT2A receptor-mediated phenomenon and its induction frequency can be regarded as an indirect but in vivo measure of basal brain 5-HT concentration. Thus, different groups of mice were injected with cocaine twice daily (0, 0.1, 0.5, 2.5, 5 or 10 mg/kg, i.p.) for either 7 or 13 days. At 24 h after last cocaine injection, the treated mice received d-fenfluramine (5 mg/kg, i.p.) and the induced HTR (mean+/-SEM) was recorded for the next 30 min. Cocaine attenuated the d-fenfluramine-induced HTR frequency by 30-37% in the 13-day regimen and significant effects were observed from 0.5 mg/kg dose. At 24 h withdrawal in the 7-day cocaine exposure group, the mean HTR frequencies were attenuated, however, they did not achieve statistical significance. Extended abstinence studies (i.e. 24, 48, 72 and 96 h postwithdrawal) from chronic cocaine exposure (0, 0.5 and 5 mg/kg/day for either 7 or 13 days) indicated that in the 7-day exposure group, significant reductions (26, 39 and 22%) in HTR frequency occurred at 48, 72 and 96 h following withdrawal from 0.5 mg/kg cocaine, whereas its 5 mg/kg dose failed to induce a significant effect. In the 13-day exposure group significant reductions in HTR frequency were observed at 24 h abstinence (27%) for the 0.5 mg/kg cocaine dose and at 24 and 48 h for the 5 mg/kg. Overall, these results indicate that abstinence from chronic exposure to cocaine produces enduring deficits in basal 5-HT concentration. Lastly, serotonergic function appears to be uniquely sensitive to chronic administration of low doses 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.     

Apoptosis mediated by Fas and its related diseases]

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

Effects of cocaine administration during early organogenesis on prenatal development and postnatal growth in mice

Cocaine use has been associated with adverse developmental effects in humans. However, clinical reports both confirm and deny an association between cocaine use and malformations. Similarly, differences in species and strain, as well as route and timing of cocaine administration, have added to the difficulties in determining the teratogenicity of cocaine in animal models. This study was undertaken to compare the effects of dose, route, and timing of cocaine administration in ICR mice during early organogenesis. A single intraperitoneal (ip) administration of cocaine ( > or = 60 mg/kg) on Day 9 of gestation (plug day = 1) produced maternal lethality. The predominant developmental effect of cocaine administration was an increase in the percentage of litters exhibiting an enlarged renal pelvis. Despite a high incidence of affected pups at these doses, the enlargement was not severe. These results, in agreement with previous reports, provide further evidence that the developing urogenital system is sensitive to cocaine administration. When cocaine was administered using a subcutaneous route, pup weights were greater and the incidence of enlarged renal pelvis was lower than when an ip route was used. To better mimic human binge cocaine abuse, the toxicity of a "split dose" was determined. A 60 mg/kg dose was administered using one administration of 60 mg/kg, two treatments of 30 mg/kg, or three administrations of 20 mg/kg with 1 hr separating the treatments. The incidence of enlarged renal pelvis was similar when cocaine was administered as one or two but was decreased when cocaine was administered as three treatments. Both the route and split-dose studies suggest that high-peak serum concentrations are required to perturb development. There were no differences in the incidence or severity of enlarged renal pelvis when cocaine was administered on Day 8, 9, or 10 or on all 3 days of gestation. This suggested that the increase in enlarged renal pelvis may not be a specific teratogenic effect of cocaine administration but may be a delay of normal development induced by cocaine exposure during this early period of organogenesis. To address this hypothesis, cocaine was administered on Day 9 using an ip route and the pups were allowed to be naturally born. In pups whose mothers received cocaine there was an increase in postnatal deaths and a trend toward a reduction in pup body weight/litter at Postnatal Day 21. However, when renal morphology was assessed on Postnatal Day 21 no abnormal kidneys were seen. This supports the hypothesis that enlarged renal pelvis produced by cocaine administration during early organogenesis represents a developmental delay and not a persistent teratogenic defect. These studies suggest that high peak cocaine concentrations are required to delay normal kidney morphogenesis in mice.     

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)