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.

The link between impaired maternal behavior (MB) and cocaine treatment could result from druginduced 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. Pregnant women who use cocaine perpetrate child abuse and neglect more often than women who do not use cocaine during pregnancy (Hawley, Halle, Drasin, & Thomas, 1995; Tyler, Howard, Espinosa, & Doakes, 1997; Wasserman & Leventhal, 1993). Maternal cocaine abuse during pregnancy has also been strongly associated with deficits in maternalinfant bonding (Burns, Chethik, Burns, & Clark, 1991), and mothers with a history of substance abuse often exhibit poor mother-infant interactions (Bauman & Dougherty, 1983;Bays, 1990; Howard, Beck-with, Espinosa, & Tyler, 1995;Johnson & Rosen, 1990). Though studies with human participants are helpful in understanding the connection between cocaine use and maternal neglect, these experiments are correlational. There is a necessary lack of control over many important variables that could confound the results, such as socioeconomic issues, lack of family support, multidrug abuse, and poor general prenatal care (Chasnoff et al., 1998;Koren et al., 1998). Studies that use numerous controls have shown a strong correlation between reported history of child maltreatment and the perpetration of maltreatment and/or neglect in next-generation mothers (Egeland, Jacobvitz, & Papatola, 1987;Hunter, Kilstrom, Kraybill, & Loda, 1978).In order to appropriately investigate and describe the characteristics of cocaine-induced disruption of maternal behavior and potential neglect, as well as possible intergenerational effects of such disruptions, a nonhuman cocaine abuse model offers several advantages. The laboratory rat is a particularly good model for the study of maternal behavior. Their offspring are born blind, unable to thermoregulate, defecate, urinate, or protect themselves from attack (Numan, 1994), thus needing considerable maternal care to survive (Stern, 1997). Behaviorally and neurologically, maternal behavior in the rat has also been relatively well characterized (Numan, 1994;Pedersen, Ascher, Monroe, & Prange, 1982;Pedersen, Caldwell, Walker, Ayers, & Mason, 1994) so that any insult to normal maternal behavior can be easily determined.Maternal separation studies also support a rat intergenerational model of behavior showing that cross-fostering results in behavior of offsp...

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 newborns 2,3 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 neophobia 5,6 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.a These studies were supported in part by the National Institute on Drug Abuse Grant R29-DA08456-01 (to J.M.J.) and the UNC METHODS Treatment GroupsDams received 15 mg/kg of cocaine-HCL (Sigma Chemical Co., St. Louis, Missouri) in a saline solution (CC) or an equal volume of (0.9%) normal saline (Sal) twice daily at approximately 9:00 AM and 4:00 PM from gestational days 1-20. An intermittent cocaine group received the same dose of cocaine on 2 consecutive days every 4 days throughout gestation (days 2-3, 8-9,14-15, and 19-20), and the amfonelic acid-treated (AFA, a selective dopamine uptake inhibitor) dams received 1.5 mg/kg of AFA dissolved in a pH 10 solution (Sterling Winthrop Labs, Rensselaer, New York) once daily (9:00 AM) on gestational days 1-20. ProcedureTreatment dams were either yoke fed or fed ad libitum, were weighed daily, and had their daily food consumption measured. Dams were tested on postpartum days 6, 8, and 10 for aggression towards an intruder during a 10-minute period. On postpartum days 8 or 11, dams were killed and the ventral tegmental area, hippocampus, and amygdala were removed for oxytocin radioimmunoassay. Details of aggression testing procedures were published elsewhere. 10 Pups were placed with surrogates immediately after birth, weaned at 21 days of age, and separated into same sex groups of three for behavioral testing on postnatal days 30, 60, 90, and 180. Pups from three of the test periods (30, 60, and 180 days) were used for HPLC analyses of monoamines, and several pups were killed on postnatal days 1, 4, and 10 for assessment of 5-HT 1A receptor development using immunobinding assays (using a specific 5-HT 1A antipeptide antibody, which was a gift of John Raymond) and quantitative, competitive RT-PCR using internal standar...

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 longterm 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.

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.