Alterations in Biodistribution of Cocaine May Explain Differential Toxicity in Pregnant and Postpartum Rats

Dwivedi, Chandradhar; Vaughan, Stuart L.

doi:10.1006/taap.1993.1018

Cited by 12 publications

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“…The IV concentration vs. time profile is markedly distinct from that observed in rats when cocaine is administered via the SC (13,64), IP (11,16), or PO (12,13) routes. Not only were the peak levels comparable or lower than those of the alternative routes (~2500 vs. ~2300, 2200, or ~5400 ng/ml, respectively) and obtained more rapidly (30 s vs. 120, 30, or 15 min, respectively), but they were also followed by a precipitous clearance.…”

Section: Discussionmentioning

confidence: 69%

“…The study of maternal cocaine abuse via an IV rodent model would similarly benefit from removing absorption and distributional factors (46). The existing models with pregnant rats are characterized by sustained absorption with plasma levels greater than 1000 ng/ml for several hours (SC) (13,64), extraplacental absorption (IP) (11,16), and delayed absorption (15-min peak levels) with sustained plasma levels through 1 h (PO) (12,13). Furthermore, given that pharmacokinetic data in the pregnant woman are not obtainable, cross-species comparisons between humans and rats might be facilitated by a dose-response pharmacokinetic analysis of IV cocaine in the male rat.…”

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confidence: 99%

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Dose-response cocaine pharmacokinetics and metabolite profile following intravenous administration and arterial sampling in unanesthetized, freely moving male rats

Booze

Lehner

Wallace

et al. 1997

Neurotoxicology and Teratology

105

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Despite the wealth of experimental data on cocaine abuse, there are no published dose-response pharmacokinetic studies with bolus i.v. cocaine injection in the male rat. The present study examined the pharmacokinetics of arterial plasma concentrations of cocaine and metabolite profile [benzoylecgonine (BE), ecgonine methyl ester (EME), norcocaine (NC)] following a single i.v. injection of 0.5, 1.0, or 3.0 mg/kg cocaine. Male Sprague-Dawley rats (N = 25) were anesthetized and surgically instrumented with both jugular vein (drug administration) and carotid artery (blood withdrawal) catheters and allowed to recover for at least 24 h. Arterial plasma samples (200 microliters) were obtained at eight time points (0.5, 1.5, 2.5, 10, 20, 30 min) following i.v. bolus injection (15-s injection, 15-s flush) and analyzed by single ion monitoring using GC/MS. Nonlinear regression and noncompartmental pharmacokinetic analysis were employed. Mean +/- SEM peak plasma concentrations of cocaine occurred at 30 s in a dose-response manner (370 +/- 14,755 +/- 119,2553 +/- 898 ng/ml for 0.5, 1.0, and 3.0 mg/kg groups, respectively). T1/2 alpha was < 1 min for all groups, but inversely related to dose. T1/2 beta was independent of dose 13.3 +/- 1.6, 13.0 +/- 1.5, and 12.0 +/- 2.0 min for 0.5, 1.0, and 3.0 mg/kg groups, respectively). MRT (16.0, 15.9, 14.5 min), VdSS (3.3, 3.2, and 2.8 l/kg), and ClTOT (204, 201, and 195 ml/min/kg) also provided little evidence of dose-dependent effects. Although the metabolic profile of i.v. cocaine was similarly ordered for all dose groups (BE > EME > NC), a quantitative shift in metabolite profile was evident as a function of increasing dose. This metabolic shift, perhaps attributable to saturation of plasma and liver esterases, suggests that the recently reported pharmacodynamic effects positively correlated with i.v. cocaine dose are unlikely attributable to NC, a minor but pharmacologically active metabolite. In sum, the i.v. pharmacokinetic profile in rats is distinct from that observed via the SC, IP, and PO routes of administration and offers the potential to provide a reasonable clinically relevant rodent model.

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Section: Discussionmentioning

confidence: 69%

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confidence: 99%

Dose-response cocaine pharmacokinetics and metabolite profile following intravenous administration and arterial sampling in unanesthetized, freely moving male rats

Booze

Lehner

Wallace

et al. 1997

Neurotoxicology and Teratology

105

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“…In the only other studies known to us that include postpartum females, Dwivedi et al (1993Dwivedi et al ( , 1996 found that postpartum dams have higher brain concentrations of cocaine and lower serum-to-brain ratios of cocaine compared with pregnant and virgin female rats.…”

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confidence: 93%

Plasma cocaine levels, metabolites, and locomotor activity after subcutaneous cocaine injection are stable across the postpartum period in rats

Wansaw

Lin

Morrell

2005

Pharmacology Biochemistry and Behavior

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Plasma levels of cocaine (COC) and two of its principle metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME) were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS) in samples collected up to 3 h after a subcutaneous injection of cocaine (10 mg/kg) on six different days between days 4 and 24 postpartum, a period of dramatic change in the endocrine state of the female rat. Locomotor activity was measured in the same animals during this period using automated animal activity monitors. Additional measures in males provide a link to existing literature. We found that plasma levels of cocaine and its metabolites, as well as their respective time courses, are remarkably uniform across the postpartum period in female rats, as are the effects of cocaine on locomotor activity. Data from males show accord with prior published values. COC and BE, but not EME levels, were higher in males, and the time courses of COC and BE levels after injection varied somewhat between postpartum females and males; however, neither baseline nor cocaine-induced locomotor activity differed between postpartum females and males. We conclude that in the postpartum rat, there are no significant differences in the peripheral processing or general accessibility of cocaine to the brain to activate motor systems across the postpartum period. These data are critical to our understanding of differences in the reward salience of cocaine across the postpartum period and in other adult rat models [Mattson BJ, Williams S, Rosenblatt JS, Morrell JI. Comparison of two positive reinforcing stimuli: pups and cocaine throughout the postpartum period. Behav Neurosci 2001;115:683-94, Mattson BJ, Williams SE, Rosenblatt JS, Morrell JI. Preferences for cocaine-or pup-associated chambers differentiate otherwise behaviorally identical postpartum maternal rats.

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“…Using animal models involving predetermined, fixed levels of cocaine exposure does not, of course, provide information regarding how the reinforcement value of cocaine may vary as a consequence of the physiological changes associated with the reproductive process. Yet, pregnancy alters the pharmacokinetic and pharmacodynamic profiles of cocaine , with pregnant females showing progressively lower serum/brain cocaine levels than nonpregnant females (Dwivedi, Engineer, & Vaughan, 1993). The neuroendocrine changes associated with pregnancy may also modulate responsivity to cocaine.…”

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confidence: 99%

Changes in progressive ratio responding for intravenous cocaine throughout the reproductive process in female rats

Hecht

Spear

1999

Dev. Psychobiol.

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Operant responding on a progressive ratio (PR) schedule for intravenous cocaine as well as sucrose reinforcement was examined in female rats throughout the reproductive process. Self-administration sessions began before mating, and continued throughout pregnancy and until lactational Day 8; following parturition, litters were present with dams during operant sessions. Physiological changes associated with the reproductive process dramatically altered PR responding for cocaine, while PR responding for sucrose was relatively stable throughout pregnancy and lactation. Female animals exhibited the highest number of responses/session for cocaine during estrus and the 1st trimester of pregnancy and the lowest responding near parturition, with levels only partially recovering during lactation. Dams selfadministering cocaine exhibited notably different patterns of maternal behavior in the operant chambers than dams responding for sucrose. Thus, cocaine's reinforcing efficacy may be influenced by (a) the changing physiological profile associated with the reproductive process and (b) competition from the reinforcing properties of offspring during lactation.Epidemiologic data indicate a high frequency of cocaine use in some populations of pregnant women, with estimates that 18 -20% (Zuckerman et al., 1989) to 31% (

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Alterations in Biodistribution of Cocaine May Explain Differential Toxicity in Pregnant and Postpartum Rats

Cited by 12 publications

References 0 publications

Dose-response cocaine pharmacokinetics and metabolite profile following intravenous administration and arterial sampling in unanesthetized, freely moving male rats

Dose-response cocaine pharmacokinetics and metabolite profile following intravenous administration and arterial sampling in unanesthetized, freely moving male rats

Plasma cocaine levels, metabolites, and locomotor activity after subcutaneous cocaine injection are stable across the postpartum period in rats

Changes in progressive ratio responding for intravenous cocaine throughout the reproductive process in female rats

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