Gestational treatment with cocaine and fluoxetine alters oxytocin receptor number and binding affinity in lactating rat dams.

Cocaine administered chronically throughout gestation has been correlated with deficits in maternal behavior, increased maternal aggressive behavior and decreased oxytocin levels in rats. In addition to its effects on oxytocin levels, cocaine is a potent serotonergic, dopaminergic and noradrenergic reuptake inhibitor. Alterations in the dopaminergic and serotonergic systems have been suggested as possibly having a role in cocaine-induced maternal aggression. This study was in part, an attempt to understand some of the mechanisms by which cocaine increases postpartum aggression, particularly as they relate to changes in the oxytocin system. Oxytocin receptor number and binding affinity in the medial preoptic area of the hypothalamus, ventral tegmental area, hippocampus and amygdala were determined for lactating rat dams on postpartum day 6 (PPD 6) that were gestationally treated with cocaine, fluoxetine, saline or an amfonelic acid/fluoxetine drug combination. Cocaine and fluoxetine treatment both resulted in a significant up-regulation of oxytocin receptor number and lower receptor affinity in the amygdala of lactating rat dams compared to saline controls and the amfonelic acid/fluoxetine combination treatment group. Cocaine treatment also resulted in a significant down-regulation of oxytocin receptors in the medial preoptic area and both cocaine and fluoxetine treated dams had the highest affinity for oxytocin receptors in this brain region. Results of the present study support previous data indicating that alterations in oxytocinergic and perhaps serotonergic system dynamics in the amygdala may play a role in cocaine-induced postpartum aggression.

An oxytocin antagonist infused into the central nucleus of the amygdala increases maternal aggressive behavior.

Decreased oxytocin levels in the amygdalas of rat dams following chronic gestational cocaine exposure have been correlated with heightened maternal aggressive behavior. In this experiment, drug-naive dams were implanted with bilateral cannulas into the central nucleus of the amygdala (CNA) or control area and infused with 1,000 or 500 ng of an oxytocin antagonist (OTA) or buffer, 4 hr before testing. Behavior was compared among dams infused with OTA into target areas just outside the CNA and cocaine-treated dams (infused with buffer). Dams infused with 1,000 ng OTA attacked intruders significantly more often than buffer-infused dams. OTA did not affect other behaviors, suggesting that disruption of oxytocin activity in the CNA may be sufficient to selectively alter maternal aggressive behavior.

Presynaptic dopaminergic function is largely unaltered in mesolimbic and mesostriatal terminals of adult rats that were prenatally exposed to cocaine.

Fast-scan cyclic voltammetry in brain slices and postmortem tissue content assessment were used to evaluate presynaptic dopaminergic function in the caudate putamen and nucleus accumbens of adult male rats (180+ days old) that were prenatally treated with either cocaine or saline. Experiments were carried out to test whether there were differences in dopamine release, reuptake, autoreceptor function or the tissue levels of dopamine and its metabolites between cocaine- and saline-exposed rats. We report that presynaptic dopaminergic function remains largely intact in adult rats that were prenatally exposed to cocaine. The ability of terminals in the caudate putamen and nucleus accumbens to release and regulate dopamine is unaltered by prenatal cocaine exposure. However the tissue content of dopamine in the caudate putamen was decreased, representing a diminution in the dopamine storage pool. We conclude, therefore, that behavioral changes that have previously been observed in rats that were prenatally exposed to cocaine are not mediated through alteration of presynaptic dopaminergic mechanisms in these brain regions.

Developmental effects of prenatal cocaine exposure on 5-HT1A receptors in male and female rat offspring.

Prenatal cocaine exposure results in behavioral abnormalities throughout development in rats, but little is known regarding the biological mechanisms underlying these abnormalities. Pregnant rats received subcutaneous twice-daily injections (1 ml/kg) of normal saline or 15 mg/kg of cocaine hydrochloride throughout gestation (gestation days 1-20). Following delivery, pups were placed with untreated surrogates. Male and female pups were killed on postnatal days 30, 60 or 120 for assessment of 5-HT(1A) receptor development in the forebrain, diencephalon, midbrain and pons using radiolabel immunocytochemistry. Findings revealed gender and age differences in developmental regulation of 5-HT(1A) receptors, indicating that male rats are more susceptible to long-term consequences of prenatal cocaine exposure in comparison to females. This study also demonstrates gender-specific development of serotonin (5-HT(1A)) receptors across postnatal ages, demonstrating a fundamentally different pattern of development of 5-HT(1A) receptors between males and females.