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.Maternal aggressive behavior is a robust type of offensive aggressive behavior found in lactating female rats (Erskine, Barfield, & Goldman, 1978;Flannelly & Flannelly, 1987;Olivier & Mos, 1992). It has been characterized by a set of postures, threats, and attacks used by mothers to protect their young from intruders that may attack or kill them (Numan, 1994). Although specific components may vary across species, virtually all mammals systematically protect their offspring (Nelson, 1995). Therefore, maternal aggressive behavior is generally considered to be adaptive, helping to ensure that pups survive what would otherwise be the most vulnerable period of their lives.However, following chronic gestational cocaine administration, rat dams can become highly aggressive toward an intruder (relative to saline-treated dams), leaving their young unprotected and vulnerable or allowing, and in some cases causing, offspring to be injured during the interaction (Johns, Faggin, Noonan, Li, Zimmerman, & Pedersen, 1995;Johns, Noonan, Zimmerman, Li, & Pedersen, 1994, 1997. This heightened level of maternal aggressive behavior is evidenced by a decreased latency to attack intruders and an increased frequency of attacks (Heyser, Molina, & Spear, 1992;Johns et al., 1994Johns et al., , 1995 (Johns, Noonan, et al., 1997). Chronic cocaineinduced increases in maternal aggressive behavior have been reported to occur during the midlactational period, on post-partum days (PPDs) 6 and 10 (Heyser et al., 1992;Johns et al., , 1995Johns, Noonan, et al., 1997), but not during the early postpartum period (Lubin, Meter, Walker, & Johns, 2001) when cocaine-induced disruptions of maternal behavior have been reported . Potentiated aggressive behavior during the midlactational period has been consistently correlated with decreased levels of the neuropeptide oxytocin (OT), specifically in the amygdala (Johns et al., 1995;Johns, Noonan, et al., 1998), a structure implicated in both normal maternal behavior (Fleming, Vaccarino, & Luebke, 1980), and pup cannibalism and viciousness (Grossman, Grossman, & Walsh, 1975).A growing body of literature reveals that pregnant rats given cocaine daily throughout gestation have decreased amygdala OT levels and incre...

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...

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.

SummaryWe 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.

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