Deborah A. Lubin

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.

Acute cocaine alters oxytocin levels in the medial preoptic area and amygdala in lactating rat dams : implications for cocaine-induced changes in maternal behavior and maternal aggression

Acute cocaine administration has been correlated with disruptions in the onset and maintenance of maternal behavior as well as decreases in maternal aggressive behavior in rat dams. A growing body of evidence suggests that cocaine may alter oxytocin levels leading to impairments in maternal behavior and aggression. The current study assessed whether acute cocaine injections alter oxytocin (OT) levels in the medial preoptic area (MPOA), ventral tegmental area (VTA), amygdala (AMY), and hippocampus (HIP) on postpartum day (PPD) 1 or PPD 6. On PPD 1, 30 mg/kg cocaine reduced OT levels by approximately 26.9% (picograms/milligram) in the MPOA (t (18) = 3.44, P<.01) compared to saline. On PPD 6, 30 mg/kg cocaine significantly increased OT levels by approximately 20.9% (picograms/brain area) in the AMY (F (2,25) = 3.44, P=.05) relative to saline. These findings suggest that acute cocaine may disrupt maternal behavior and maternal aggression at least in part through its action on the oxytocinergic system.

Dose-Dependent Effects of Multiple Acute Cocaine Injections on Maternal Behavior and Aggression in Sprague-Dawley Rats

Rat dams, which had no prior drug treatment, were either nontreated controls or were injected subcutaneously 4 times during a 10-day period with a single dose of 30, 15 or 7.5 mg/kg of cocaine hydrochloride HCl, or normal saline. Injections were given immediately postpartum following delivery of their final pup (PPD 1), and again on postpartum day 3 (PPD 3), postpartum day 6 (PPD 6) and postpartum day 10 (PPD 10). Dams were observed 30 min following injections for maternal behavior (MB) towards 8 surrogate male pups on PPD 1 and PPD 3 and for aggression towards a male or female intruder in the presence of their litter on PPD 6 and PPD 10. Compared to saline and untreated controls, cocaine-treated dams exhibited more disruptions in MB on both PPD 1 and PPD 3 and were less aggressive towards an intruder, regardless of intruder sex, on PPD 6 and PPD 10. In most cases MB was altered in a dose-dependent manner with the higher doses of cocaine resulting in a greater disruption of behavior.

Chronic gestational cocaine treatment decreases oxytocin levels in the medial preoptic area, ventral tegmental area and hippocampus in Sprague-Dawley rats

We examined the effects of gestational cocaine treatment on oxytocin levels in the whole hippocampus (HIP), ventral tegmental area (VTA), medial preoptic area (MPOA) and amygdala (AMY) in rat dams on postpartum days (PPDs) 1 and 2. Cocaine treatment significantly reduced oxytocin levels in the MPOA within 12-16 h of delivery (PPD 1), but had no significant effect on the other brain areas. Oxytocin was significantly reduced in the HIP and VTA but not in the AMY or MPOA on PPD 2. These data provide the first evidence for the reduction of oxytocin levels in the VTA, HIP and MPOA as a result of gestational cocaine treatment.

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.

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.

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-HT1A receptor development in the forebrain, diencephalon, midbrain and pons using radiolabel immunocytochemistry. Findings revealed gender and age differences in developmental regulation of 5-HT1A 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-HT1A) receptors across postnatal ages, demonstrating a fundamentally different pattern of development of 5-HT1A receptors between males and females.

Dose-related effects of chronic gestational cocaine treatment on maternal aggression in rats on postpartum days 2, 3, and 5.

Gravid Sprague-Dawley rats received subcutaneous injections of saline, 3.5, 7.5 or 15 mg/kg of cocaine, twice daily, throughout gestation. On postpartum days 2, 3, and 5, dams and their litters (surrogate or natural) were videotaped for 10 minutes in the presence of a male rat for assessment of aggression towards the intruder. Oxytocin levels in discrete brain areas were assayed on postpartum day 5. The 30 mg/kg dose group had a significantly greater increase in the frequency of threats from postpartum day2 through postpartum day 5 than the 7.5 mg/kg cocaine and the non-yoke-fed saline control groups. Dams with natural litters exhibited a significantly greater frequency of receptive behavior compared to dams with surrogate litters. There were no significant differences in oxytocin levels between the 30 mg/kg cocaine-treated group and the other treatment or control groups on postpartum day 5. There are very few statistically significant cocaine-induced increases in maternal aggressive behavior and no dose-dependent decreases in amygdaloid OT levels in the early postpartum period.

Effects of chronic cocaine on monoamine levels in discrete brain structures of lactating rat dams

Chronic gestational cocaine administration has been correlated with high levels of postpartum maternal aggression towards intruders and altered levels of oxytocin in the amygdala. Cocaine may alter both oxytocin and maternal aggression either directly or indirectly through changes in monoamine levels in relevant brain regions. In this study, pregnant female rats were randomly assigned to one of four groups; three cocaine dose groups (7.5, 15 or 30 mg/kg), or a saline-treated group (0.9% normal saline) and given subcutaneous injections twice daily (total volume 2 ml/kg) throughout gestation. Behavioral responses to an inanimate object placed in the homecage were assessed on Postpartum Day (PPD) 6. Immediately following testing, animals were sacrificed and four brain regions implicated in maternal/aggressive behavior (medial preoptic area [MPOA], ventral tegmental area [VTA], hippocampus, and amygdala) were removed for monoamine level analyses using high-performance liquid chromatography. Dams given 30 mg/kg cocaine throughout gestation had significantly higher levels of dopamine (DA) and nonsignificantly elevated serotonin (5-HT) levels relative to saline-treated controls. These dams also exhibited higher frequencies of defensive behavior toward an inanimate object compared to saline-treated controls. Potential mechanisms mediating cocaine-induced increases in responding are proposed.

Effects of chronic cocaine administration on aggressive behavior in virgin rats

Virgin Sprague-Dawley rats received subcutaneous injections of saline, 3.5, 7.5 or 15 mg/kg of cocaine, twice daily, for 20 consecutive days. Females were videotaped for 10 minutes in the presence of a male rat for assessment of aggression towards the intruder 2, 3, and 5 days following cessation of cocaine or saline administration. Oxytocin levels in discrete brain areas were assayed following behavioral testing, 5 days following cessation of cocaine or saline administration. The 30 mg/kg-dose group tended to have a lower frequency of fight attacks and aggressive postures compared to saline-treated controls across sessions. The frequency of most of the behaviors analyzed were represented by quadratic functions across time, such that the highest frequency of behavior occurred 2 days following the final injection with relatively less activity 3 and 5 days following cessation of saline or cocaine administration. The 30 mg/kg cocaine-treated group had significantly lower hippocampal OT levels than the 15 mg/kg group 5 days following cessation of cocaine or saline administration.