Cocaine‐induced inhibition of process outgrowth in locus coeruleus neurons: role of gestational exposure period and offspring sex

Abstract

Cocaine use during pregnancy is associated with neurobehavioral problems in school-aged children that implicate alterations in attentional processes, potentially due to impairments in the noradrenergic system. We analyzed locus coeruleus (LC) neurite outgrowth characteristics following the administration of a physiologically relevant dose of cocaine (3.0 mg/kg) issued during critical phases of gestation (gestational day (GD)8-14, GD15-21, GD8-21). Results showed that cocaine inhibits LC neurite outgrowth and development, as evidenced by a decrease in total neurite length, a decrease in neurite length per cell, and a decrease in the percentage of cells with neurites. Morphological differences between cultures treated with and without cocaine were also evident. Further, the specific gestational exposure period effects were also dependent upon sex of the fetus. Finally, a discriminant function analysis suggested that the pattern and magnitude of alterations that defined the GD8-14 exposure were significantly different from that of the GD15-21 or GD8-21 exposures. Collectively, these data demonstrate a direct, disruptive effect of cocaine on noradrenergic neurons and may provide a neurobiological basis for changes in attentional function seen in offspring exposed to cocaine in utero.

Prenatal intravenous cocaine and the heart rate‐orienting response: a dose–response study

“…The neurochemical specificity suggests that prenatal IV cocaine exposure, at least when delivered by the IV route of administration, has an effect on the development and/or integrity of the noradrenergic system. This view is also consistent with recent in vitro work from our laboratory showing locus coeruleus cell survival and neurite outgrowth are altered if exposed to cocaine during development (Snow et al, 2001(Snow et al, , 2004. It is well-known that the locus coeruleus is the primary source of noradrenergic fibers in the central nervous system.…”

“…With the assessment in adulthood of long-term alterations in attentional proceeses, sex differences are also noted, albeit the adverse effects of cocaine are noted on different measures in the two sexes of animals (Gendle et al, 2003). In a direct examination of LC neurons in vitro, following in vivo exposure, measures of neurite outgrowth consistently demonstrated far more pervasive effects in female, relative to male offspring (Snow et al, 2004). In an examination of the brain metabolic response to prenatal cocaine there were clear treatment-related regional differences, however, in each of the four regions where a treatment by sex interaction was confirmed, this outcome was primarily attributable to cocaine eliminating the sex difference normally observed.…”

Cocaine exposure in vitro induces apoptosis in fetal locus coeruleus neurons by altering the Bax/Bcl-2 ratio and through caspase-3 apoptotic signaling

“…Further, numerous studies have defined a clear role for the noradrenergic system in attentional deficits following prenatal cocaine exposure (Mactutus, 1999;Bayer et al, 2002;Foltz et al, 2004). Consistent with these data, our previous in vivo and in vitro studies show that cocaine exposure specifically impairs the basic cell biology of locus coeruleus (LC), neurons that mediate attention, by inhibition of LC neurite initiation, elongation and branching during early periods of gestation (Snow et al, 2001;Foltz et al, 2004;Snow et al, 2004;Dey et al, 2006).…”

“…This study took a reductionist approach to examine the effects of a single pharmacologically active dose of cocaine administered over a short period of time, to two critical isolated cell types in vitro within the limitations of this type of experimental design. We have identified potential targets for cocaine mediated deficits of LC morphology and outgrowth (Snow et al, 2001;Snow et al, 2004) and survival via apoptotic mechanisms (current studies). These data highlight the importance of identifying critical signal transduction elements in cocaine-mediated cell death to ultimately develop vital treatments and therapeutic drug abuse interventions.…”

“…When a dose response study was conducted, the treatment factor had 4 levels (cocaine dose -0, 250 ng/ml, 500 ng/ml, 1 μg/ml). Planned comparisons and orthogonal decompositions of main effects were employed and justified given the a priori hypothesized greater vulnerability to cocaine of LC, relative to SN neurons (Mactutus, 1999;Snow et al, 2001;Bayer et al, 2002;Snow et al, 2004; Dey et al., in press) regardless of the presence of significant two-and three-way interaction terms. Correlational analyses and bivariate plots were further employed to examine the degree of relationship between the effects of cocaine on LC vs. SN neurons.…”