Long-term learning deficits and changes in unlearned behaviors following in utero exposure to multiple daily doses of cocaine during different exposure periods and maternal plasma cocaine concentrations

Vorhees, Charles V.; Reed, Tracy M.; Acuff‐Smith, Karen D.; Schilling, Mary A.; Cappon, Gregg D.; Fisher, J. Edward; Pu, Cunfeng

doi:10.1016/0892-0362(94)00061-h

Cited by 59 publications

(43 citation statements)

References 43 publications

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“…Attempts to establish an animal model for the teratogenic effects of gestational cocaine exposure on the neurobiology and behavior of the offspring have yielded much information on plasma cocaine and metabolite levels in the pregnant female rat. Plasma cocaine and metabolite levels have been studied in pregnant rats and mice after subcutaneous (Collins et al, 1999;Spear et al, 1989;Vorhees et al, 1995), intraperitoneal (DeVane et al, 1989Shah et al, 1980), intragastric (Dow-Edwards, 1990, and intravenous (Robinson et al, 1994) cocaine administration.…”

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confidence: 99%

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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confidence: 99%

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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“…In animal models, similar deficits have been noted. Prenatal cocaine exposed rats performed more poorly than controls in tests of spatial memory (Choi et al 1998a;Cutler et al 1996;Heyser et al 1995;Levin and Seidler 1993;Tonkiss et al 1997;Vorhees et al 1995) and non-spatial memory (Morrow et al 2000b). Deficits in attention have also been noted (Garavan et al 2000;Mactutus 1999;Romano and Harvey 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Behavioral studies in animal models of prenatal cocaine exposure have demonstrated similar deficits in memory (Choi et al 1998a;Cutler et al 1996;Heyser et al 1995;Levin and Seidler 1993;Morrow et al 2000b;Tonkiss et al 1997;Vorhees et al 1995) and attention (Garavan et al 2000;Mactutus 1999;Romano and Harvey 1996). The identification of the sites and the underlying biochemical changes induced by in utero exposure to cocaine, however, remain elusive.…”

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Male Rats Exposed to Cocaine in utero Demonstrate Elevated Expression of Fos in the Prefrontal Cortex in Response to Environment

Morrow

Elsworth

Roth

2002

Neuropsychopharmacology

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Prenatal cocaine exposure has been associated with disruption in attention and short-term memory in exposed children and in animal models. The biochemical change or changes responsible for these cognitive deficits are not known. An intriguing possibility, however, is that cocaine exposure during development disrupts the morphology or function of the frontal cortex, a region thought to contribute to cognitive and executive functions. In this report, we examined the effects of intravenous prenatal cocaineThe abuse of cocaine during pregnancy has not been associated with major anatomical birth defects; however, a significant numbers of children exposed to cocaine in utero go on to develop select cognitive deficits, such as memory deficits, impulsivity, and difficulties in modulating attention (Delaney-Black et al. 1998; DowEdwards et al. 1999). Behavioral studies in animal models of prenatal cocaine exposure have demonstrated similar deficits in memory (Choi et al. 1998a;Cutler et al. 1996;Heyser et al. 1995;Levin and Seidler 1993;Morrow et al. 2000b;Tonkiss et al. 1997;Vorhees et al. 1995) and attention (Garavan et al. 2000;Mactutus 1999;Romano and Harvey 1996). The identification of the sites and the underlying biochemical changes induced by in utero exposure to cocaine, however, remain elusive. Understanding the biochemical substrates of the behavioral deficits induced by prenatal cocaine is necessary if logical treatments for the condition are to be developed. We have chosen to use the expression of the immediateearly gene, c-fos , as a marker of neuronal activation. NO . 3 Many researchers, including in our own laboratory, have successfully used this marker to map and study stress responses (Kovacs 1998). The expression of Fos, however, does not solely indicate that the neuron has been activated but indicates that the neuron is in the process of undergoing longer-term adaptation brought about by activation.One potential candidate site for the cognitive effects of prenatal cocaine is the frontal cortex. Dysfunction in this region has been associated with disruption in cognitive processes, including memory and attention (Goldman-Rakic 1998). Additionally, deficits in shortterm working memory can be observed with altered dopaminergic function in the prefrontal cortex of rats and non-human primates (Goldman-Rakic 1998;Morrow et al. 2000c;Murphy et al. 1996). One obvious mechanism by which prenatal cocaine exposure could impact on the frontal cortex is by blockade by cocaine of the monoamine transporters, including that of dopamine, in that region. Fetal changes in monoamine levels in the developing frontal cortex could potentially result in an anatomical or functional disruption (Levitt 1998;Pendleton et al. 1998). Wang and colleagues reported changes in the GABAergic neurons in the cortex, leading to the hypothesis that prenatal cocaine exposure could result in a disruption of the excitatory/inhibitory balance (Wang et al. 1995(Wang et al. , 1996. In this current report, we investigate potential changes in th...

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“…In utero, exposure to cocaine has been shown to cause various detrimental consequences including, but not limited to congenital malformations and postnatal neurobehavioral changes (Young et al, 1992;Plessinger and Woods, 1993;Vorhees et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Nitric Oxide Synthase Enhances Cocaine's Developmental Toxicity: Vascular and CNS Effects

Mendoza-Baumgart

Pravetoni

Sparber

2006

Neuropsychopharmacol

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Ischemia and/or reperfusion injury from free radicals may cause cocaine's toxicity, including its effect upon neurobehavioral development. We previously used salicylate to measure hydroxyl free radicals in chick embryos exposed to cocaine. The combination was more toxic than cocaine alone. We postulated that salicylate enhanced the vasoconstriction and toxicity via inhibition of compensatory processes (eg by inhibition of the synthesis of vasodilatory prostanoids and/or nitric oxide). A nontoxic dose of N(G)-nitro-L-arginine methyl ester (L-NAME) was used to inhibit nitric oxide synthase to test this hypothesis. In one experiment, cocaine was injected every 1.5 h (total dose ¼ 67.5 mg/kg egg) on day 15 of development, 1 h after injection of L-NAME (200 mg/kg egg) to determine viability and hatchability, which are measures of toxicity. Another experiment measured diameters of blood vessels after L-NAME injection, followed by NaCl or cocaine infusion (0.23 mg/egg/min; total dose ¼ 67.5 mg/kg egg) at 15 and 5 min afterwards. Lastly, brains of embryos pretreated with L-NAME before cocaine injections were analyzed for nitric oxide synthase activity. Cocaine decreased viability and hatchability. L-NAME enhanced cocaine's effect upon both parameters. Blood vessel diameters were decreased by cocaine after 15 min of infusion. L-NAME + cocaine caused a decrease in vessel diameter as soon as 5 min into the infusion and was greater with time, compared with other groups. Enzyme activity in brains was decreased only in the L-NAME + cocaine group. Thus, inhibition of nitric oxide synthesis interferes with the embryos' capacity to mount a compensatory vasodilatory response. Neuropsychopharmacology (2007) 32, 940-945.

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Long-term learning deficits and changes in unlearned behaviors following in utero exposure to multiple daily doses of cocaine during different exposure periods and maternal plasma cocaine concentrations

Cited by 59 publications

References 43 publications

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

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

Male Rats Exposed to Cocaine in utero Demonstrate Elevated Expression of Fos in the Prefrontal Cortex in Response to Environment

Inhibition of Nitric Oxide Synthase Enhances Cocaine's Developmental Toxicity: Vascular and CNS Effects

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