Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

Abstract

Children exposed to cocaine during gestation have a higher incidence of neurobehavioral deficits. The neurochemical bases of these deficits have not been determined, but the pharmacology of cocaine and the nature of the abnormalities suggest that disruptions in catecholaminergic systems may be involved. In the current study, we used a rat model of prenatal cocaine exposure to examine the impact that this exposure has on the locus coeruleus (LC) noradrenergic system in offspring. Pregnant rats received twice-daily intravenous injections of cocaine (3 mg/kg) or saline between gestational days 10 and 20, and progeny were tested as juveniles. Exposure to a mild stressor elevated an index of norepinephrine turnover in the prefrontal cortex and also increased Fos expression in tyrosine hydroxylase-positive LC neurons in rats exposed to prenatal cocaine but not in rats exposed to prenatal saline. No change in the number of tyrosine hydroxylase-positive neurons in the LC was observed between the two prenatal treatment groups. Specific binding of [ 125 I]-para-iodoclonidine, a radioligand with specificity for high affinity α2A-adrenergic receptors, was decreased in the LC of rats exposed to prenatal cocaine compared to prenatal saline controls. As α 2 -adrenergic receptors on LC norepinephrine neurons function as autoreceptors, their down-regulation by prenatal cocaine exposure provides a plausible mechanism for the observed heightened reactivity of norepinephrine neurons in these animals. These data indicate that prenatal cocaine exposure results in lasting changes to the regulation and responsivity of rat LC norepinephrine neurons. A similar dysregulation of LC norepinephrine neurons may occur in children exposed to cocaine during gestation, and this may explain, at least partly, the increased incidence of cognitive deficits that have been observed in these subjects.

Chronic cold exposure increases RGS7 expression and decreases α2‐autoreceptor‐mediated inhibition of noradrenergic locus coeruleus neurons

“…Whether repeated restraint leads to enhanced NE activity is unknown, but this different stress paradigm or the much higher doses of clonidine (Aghajanian & VanderMaelen, 1982; Pavcovich et al ., 1990; Lacroix et al ., 1991; Pineda et al ., 1997) may explain the contrasting leftward shift of the dose–response curve for clonidine‐evoked inhibition of LC neurons reported following repeated restraint (Pavcovich et al ., 1990). The present demonstration of decreased autoreceptor function is consistent with the reduction of autoinhibitory control over LC neuronal activity, as suggested by decreased autoreceptor antagonism following repeated tail shock exposure (Simson & Weiss, 1988) and in a prenatal cocaine model leading to enhanced noradrenergic activation (Elsworth et al ., 2007). Furthermore, it complements previous neurochemical and electrophysiological changes in the noradrenergic system following cold exposure (Nisenbaum et al ., 1991; Nisenbaum & Abercrombie, 1992; Gresch et al ., 1994; Finlay et al ., 1997; Mana & Grace, 1997; Jedema et al ., 1999, 2001; Jedema & Grace, 2003).…”

Interactions of nitric oxide with α2‐adrenoceptors within the locus coeruleus underlie the facilitation of inhibitory avoidance memory by agmatine

“…There is good evidence for the involvement of the noradrenergic system in the retrieval of memory (Sara and Devauges, ). Presynaptic α 2 ‐adrenoceptors function as autoreceptors in the LC (Elsworth et al , ) and the α 2 ‐adrenoceptor agonist clonidine, per se, impaired the memory retention (Jafari‐Sabet et al , ). We also found that clonidine administered within the LC inhibited memory retrieval.…”

Effects of prenatal cocaine exposure on pubertal development

“…While the underlying mechanisms for these findings remain unknown, the noradrenergic system may be involved. PCE has been shown to affect the noradrenergic system (Elsworth, et al 2007; Foltz, et al 2004; Seidler and Slotkin 1992; Snow, et al 2004), which in turn may influence pubertal development. Norepinephrine plays a role in regulating the hypothalamus (Christman and Gisolfi 1985; Oishi 1979; Tsigos and Chrousos 2002), which contains cells that produce gonadotropin releasing hormones that regulate pubertal development, particularly the onset of puberty (Plant 2002).…”