Cheryl H. Walker

Oxytocin activates the postpartum onset of rat maternal behavior in the ventral tegmental and medial preoptic areas.

Oxytocin binding (Bmax) was found to be higher in the ventral tegmental area (VTA) and the medial preoptic area (MPOA) at midparturition compared with Pregnancy Days 15-17 or Postpartum Days 5-7 in rat dams. Pup retrieval and assuming a nursing posture over pups were blocked in parturient dams by infusions of an oxytocin antagonist into the VTA or MPOA and by infusions of a vasopressin (V1) antagonist into the MPOA. These results implicate oxytocin in the VTA and MPOA and vasopressin in the MPOA, as well as a parturition-associated rise in oxytocin binding in these sites in the postpartum activation of maternal 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.

L-triiodothyronine: is this peripheral hormone a central neurotransmitter?

L-triiodothyronine (T3) has previously been shown to substance fast-phase, depolarization-induced 45Ca uptake and [3H-gamma-aminobutyric acid release by rat brain synaptosomes at low nanomolar concentrations comparable to those reported for whole brain. Neverthless, the physiologic importance of these nonnuclear-mediated effects of T3 has remained uncertain, a part because specific mechanisms and the presence of T3 at pesumptive sites of action have not been demonstrated. Isotopic studies showing that L-tetraiodothyronine thyroxine, T4) and T3 are concentrated in synaptosomes, and that T4 is deiodinated to T3 suggested that endogenous levels of T3 in nerve terminals are probably much higher than in other compartments of the brain. In the present study we confirmed that endogenous levels of T3 in nerve terminals are at least eightfold higher, and may be as much as 60-fold higher, than in whole brain. More importantly, we showed that both 125I-labeled T3 and endogenous T3, but not 125I-T4 or endogenous T4, are released from depolarized synaptosomes, primarily by a Ca2+-dependent process. This demonstrates a mechanism for raising the level of T3 within the synapse, where the hormone may interact with pre- and postsynaptic binding (or uptake) sites, and suggests that the peripheral hormone T3 may be a neurotransmitter.

The effects of dopaminergic/serotonergic reuptake inhibition on maternal behavior, maternal aggression, and oxytocin in the rat

Studies using dopaminergic and serotonergic agonists or antagonists implicate involvement of these systems in various aspects of early maternal behavior and postpartum aggression towards an intruder in rats, both of which are associated with the presence of oxytocin in specific brain regions. It is unclear however, if or how long-term uptake inhibition of either neurotransmitter system alone or in combination, affects oxytocin system dynamics or maternal behavior/aggression. Pregnant women frequently take drugs (antidepressants, cocaine) that induce long-term reuptake inhibition of dopamine and/or serotonin, thus it is important to understand these effects on behavior and biochemistry. Rat dams were treated throughout gestation with amfonelic acid, fluoxetine, or a combination of both, to investigate effects of reuptake inhibition of dopamine and serotonin systems respectively, on maternal behavior, aggression and oxytocin. The more appetitive aspects of maternal behavior (nesting, licking, touching) and activity were increased by the low dose of amfonelic acid, high dose of fluoxetine, or the high dose combination more than other treatments. Aggression was decreased by amfonelic acid and somewhat increased by fluoxetine. Dopamine uptake inhibition appears to have a strong effect on hippocampal oxytocin levels, while receptor dynamics may be more strongly affected by serotonin uptake inhibition.

Cocaine Treatment and Prenatal Environment Interact to Disrupt Intergenerational Maternal Behavior in Rats

The link between impaired maternal behavior (MB) and cocaine treatment could result from drug-induced decreases in maternal reactivity to offspring, prenatal drug exposure (PDE) in offspring that could alter their ability to elicit MB, or the interaction of both, which could subsequently impair MB of the 1st-generation dams. Following chronic or intermittent cocaine or saline treatment during gestation, rat dams rearing natural or cross-fostered litters were compared along with untreated dams for MB. Untreated 1st-generation females with differentially treated rearing dams and PDE were tested for MB with their natural litters. The authors report disruptions in MB in dams and their 1st-generation offspring, attributable to main and interaction effects of maternal treatment, litter PDE, and rearing experience.

Estrogen increases affinity of oxytocin receptors in the medial preoptic area-anterior hypothalamus

Analysis of binding data from saturation experiments using a radiolabeled oxytocin antagonist ([125I]OTA) demonstrated an increase in binding affinity after treatment with 5 micrograms estradiol benzoate (EB) for 3 days in membrane fractions from the medial preoptic area-anterior hypothalamus (MPOA-AH) of ovariectomized (OVX) rats. Analysis of data from competition experiments revealed high- and low-affinity [125I]OTA binding sites in the MPOA-AH, the medial basal hypothalamus (MBH), and hippocampus of OVX controls. Three days of EB treatment reduced low-affinity binding sites in the MPOA-AH and MBH, but not in the hippocampus. Treatment of membrane fractions from the MPOA-AH of oil-treated OVX rats in vitro with 100 nM OT or with estrogen or progesterone conjugated to bovine serum albumin (E-BSA and P-BSA) also reduced low-affinity [125I]OTA binding sites but BSA alone did not.

Chronic Cocaine Treatment Alters Social/Aggressive Behavior in Sprague-Dawley Rat Dams and in Their Prenatally Exposed Offspringa

Maternal cocaine abuse during pregnancy has been correlated with a greater incidence of maternal neglect and problems with maternal-infant bonding.1 Children of mothers who have abused cocaine during pregnancy have exhibited signs of increased irritability and altered state liability as newborns2,3 and are aggressive, show poor social attachment, and display abnormal play behavior in unstructured environments as young children.4 These data suggest cocaine-induced, abnormal development of socioemotional behavior, but it is difficult to determine if these deficits are a direct result of cocaine or are related to living in an unstable or abusive environment. Animal research on the effects of prenatal cocaine exposure suggest that offspring exposed prenatally to cocaine exhibit signs of behavioral abnormalities including increased “emotionality” and neophobia5,6 and aggression towards an intruder or other untreated conspecifics.7–9 Long-term changes in specific neurotransmitter systems may be related to behavioral alterations. On the basis of previous findings,7–9 we focused our research on cocaine-induced alterations of both maternal and offspring social/aggressive behavior. The following data include a summary of results from several recent experiments.

Neonatal stress transiently alters the development of hippocampal oxytocin receptors

The development of brain oxytocin (OXT) receptors was examined following the mild stress of daily, 20 min separations of infant rats from their mothers (repeated separation condition) or in undisturbed controls. Changes in OXT receptors were characterized in cell membrane preparations, using the OXT receptor ligand [125I]d(CH2)5[Tyr(Me)2Thr4Tyr-NH9(2)]-ornithine vasotocin ([125I]OTA), from rats at 4, 8, 14, 22 postnatal days of age or as adults. In the hippocampus of control animals, [125I]OTA binding was highest at day 4 or 8 and declined thereafter. Repeated separation decreased the Bmax of [125I]OTA binding in whole hippocampus at day 8, an effect that did not persist into adulthood. This effect was found to be confined to the rapidly proliferating, dorsal hippocampus. It has been suggested that brain OXT is involved in both affiliative/social and stress-related behaviors. While the specific function of OXT receptors in hippocampus is currently unknown, mild stress to the infant and the disruption of infant-mother contact transiently alters the normal development of this system.