Craig Howard Kinsley

Prenatal stress has long-term effects on brain opiate receptors

Prenatal stress has been associated with a number of behavioral consequences including altered sensitivity to exogenous opiates. In the present study, mu opiate receptors were compared in the 42-day-old offspring from females stressed on days 15-22 of gestation and from females who were unstressed controls. Membrane homogenates from the prenatal stress group showed less binding of the mu opiate receptor ligand, [3H]DAGO in striatum but not in several other brain regions. Saturation studies suggest this difference is due to fewer striatal mu opiate receptors in offspring of prenatally stressed females. Using in vitro receptor autoradiography, the decreased binding in striatum was found mostly in the rostral striatum, extending into the nucleus accumbens with conservation of the normal anatomic distribution of receptor rich patches.

Prenatal stress alters morphine- and stress-induced analgesia in male and female rats.

Prenatal stress affects the expression of many opioid-regulated behaviors in adulthood, e.g., aggressive, maternal, regulatory, and sexual. In the present report we examined two forms of analgesia, morphine-induced (opioid receptor-mediated), and stress-induced [cold-water swim (CWS), nonopioid] analgesia in adult prenatally-stressed (P-S) male and female rats to determine whether and to what extent these analgesic responses might be altered. Timed-mated Sprague-Dawley females were exposed to heat and restraint stress (three daily 1/2 hour sessions, 0830, 1230, and 1630 hr) from days 15-22 of gestation. Control animals remained undisturbed throughout pregnancy. Between 120-150 days of age, baseline pain sensitivities were determined using a tail-flick monitor. P-S and Control animals were then exposed to 3.5 min cold-water swims (2 degrees C) and pain thresholds were again determined at 30 min intervals for 120 min. P-S females exhibited significantly lower pain thresholds than Control females at the 30 and 60 min marks, whereas P-S and Control males did not differ. Six to eight days later, analgesia was measured for 180 min following morphine (5.0 mg/kg) administration. P-S females exhibited significantly greater analgesia at each time-point after morphine treatment than Controls. Conversely, P-S males were significantly less analgesic than Control males from 60 to 180 min. These data suggest that prenatal stress alters the status of endogenous opiate systems. Such prenatal stress-induced alterations in opiate function may help account for some of the behavioral effects reported in P-S animals.

Opioid Receptor Subtype Involvement in Maternal Behavior in Lactating Rats

Central or systemic administration of morphine disrupts maternal behavior in steroid-primed, pup-induced virgin and lactating rats. Morphine, the prototypical mu agonist, also interacts with different opioid receptor subtypes. The present study examined the effectiveness of five receptor-selective agonists, in addition to morphine, to disrupt maternal behavior in primiparous lactating rats following intracerebroventricular (i.c.v.) infusions in order to characterize opioid receptor subtype involvement in maternal behavior in the female rat. Virgin, Sprague-Dawley rats were mated and implanted with lateral ventricle cannulae on days 13-15 of gestation. On postpartum day 5, mothers were tested for maternal behavior 30 min after i.c.v. vehicle infusion (5 microliters). On day 6, rats received one of the following opioid receptor agonists 30 min before testing: beta-endorphin (mu/epsilon receptor subtype; 0.29, 0.72, 1.45, 2.9 nmol), DAGO (mu; 0.29, 0.72, 1.45, 2.9 nmol), morphine (mu; 0.29, 0.72, 1.45, 2.9, 14.5 nmol), DPDPE (delta; 2.9, 29 nmol), U50488H (kappa l; 2.9, 29, 145 nmol) and SKF10047 (sigma; 2.9, 29, 145 nmol). Only activation of mu opioid receptors dose-dependently disrupted maternal behavior in primiparous lactating rats. DPDPE, U50488 and SKF10047 had no discernible effect on maternal behavior. DAGO, a highly selective mu agonist, was even more potent than beta-endorphin and morphine in disrupting maternal behavior suggesting that maternal behavior is regulated by opioids interacting with the mu opioid receptor.

Long-term effects of parity on opioid and nonopioid behavioral and endocrine responses

Parity (number of parturitions) affects the endogenous opioid system. Multiparous lactating rats are less sensitive to the effects of morphine (MOR) on maternal behavior (MB) and analgesia than primiparous lactating rats. In order to determine whether these changes in opiate sensitivity persist beyond the lactational state, the present study compared the sensitivity of ovariectomized nulliparous and nonlactating primiparous rats to MORs effects on MB (Experiment 1), analgesia (Experiment 2) and prolactin release (Experiment 3) in addition to stress-induced analgesia (Experiment 2). In Experiments 1 and 2 primiparous rats were allowed to give birth and remain with their litter (culled to 6 pups) until weaning. At that time the pups were removed and the dams and age-matched nulliparous rats were ovariectomized. Four weeks later animals were exposed to foster pups daily in order to induce MB (Experiment 1). On day 5 or 6 of full MB the primiparous and nulliparous rats received either saline or one of four doses of MOR (0.625, 1.25, 2.5, or 5.0 mg/kg, SC) and 60 min later MB was assessed. MOR, at the 2.5 mg/kg dose, disrupted MB in a significantly greater percentage of nulliparous as compared to primiparous animals (100% vs. 55%, respectively). In Experiment 2, nulliparous and nonlactating primiparous animals received 2.5 mg/kg of MOR four weeks after ovariectomy. Analgesia was assessed on a tail-flick apparatus 30, 60, 90, 120 and 150 min postinjection. One week later the same animals were exposed to cold-water swims (CWS, 2 degrees C, 3.5 min) and tail-flick latencies were again recorded.(ABSTRACT TRUNCATED AT 250 WORDS)

Opiate involvement in postpartum aggression in rats

Opiates and the endogenous opioids mediate maternal behavior and various forms of aggression. The present study sought to investigate the role of opiates in postpartum aggression (PPA), an intense form of agonistic behavior displayed by lactating females. Primiparous rats were screened for their PPA against adult males on day seven postpartum. They were then randomly assigned to one of four treatment groups [morphine, 5.0 mg/kg; naloxone alone, 0.5 mg/kg; morphine (5.0 mg/kg) plus naloxone (0.5 mg/kg); and saline] and tested for PPA on postpartum days eight and nine following the respective treatments. Morphine significantly lowered PPA, and naloxone antagonized the effect. Whereas the morphine plus naloxone, naloxone alone, and saline groups exhibited higher levels of PPA than that shown by the morphine group, there were no differences in PPA found among the morphine plus naloxone, naloxone alone, or saline groups. These results, in conjunction with evidence describing the state of the endogenous opioid system in the postpartum rat, suggest that some aspect of the endogenous opioid system may be involved in another form of maternal behavior, postpartum aggression.

Prolactin modulation of the maternal-like behavior displayed by juvenile rats

Reports of elevated prolactin (Prl) levels in juvenile rats of the same strain and approximate age, together with the established role of Prl in maternal behavior in adult female rats, prompted us to examine the possible involvement of Prl in the expression of maternal-like behavior in juvenile Sprague-Dawley males and females. Experiment 1 showed that at 25 days of age both sexes exhibited a rapid onset of full maternal behavior (FMB), with males (median = 2.0 days) responding significantly more quickly than females (median = 4.0 days). Moreover, blood sampled for Prl revealed that males had significantly higher levels of circulating Prl than females, (21.0 vs 10.4 ng/ml, respectively). In Experiment 2, CB-154 treatment significantly delayed the onset of FMB in males only, causing latencies to increase to 5.0 days vs 2.0 days for Controls. Female latencies were unaffected by CB-154, 7.0 and 7.5 days for CB-154 and Control groups, respectively. A second set of both male and female juveniles was treated with either CB-154 or vehicle. CB-154 reduced Prl levels in both sexes. In the Controls, the sex difference in Prl levels (males greater than females) was again evident. In Experiment 3 juvenile males were treated with either ovine Prl (0.5 mg) + CB-154, CB-154 + Vehicle, or Vehicle + Vehicle and tested for FMB. Males treated with Prl + CB-154 required 3.0 days to exhibit FMB, significantly faster than CB-154 + Vehicle males which responded in 8.0 days. The response of Vehicle + Vehicle males was intermediate, with a latency of 5.0 days. These results provide support for the idea that Prl is involved in the maternal-like responsiveness shown by 25 day old juvenile males, but that in females a maturational factor may have prevented both heightened responsiveness to pups by 25 days of age and sensitivity to the Prl releasing mechanism(s)/Prl feedback involved in the exhibition of maternal behavior.

Prenatal stress reduces estradiol-induced prolactin release in male and female rats.

Prenatal stress is a potent disruptor of the normal course of sexual differentiation, affecting both males and females. In the present study, we wished to examine a sexually dimorphic endocrine response, estradiol (E2)-induced prolactin (Prl) release, in prenatally-stressed (P-S) males and females. Sprague-Dawley female rats were timed-mated (+ sperm = Day 1). From gestation days 15-22 one group of females was subjected to a thrice-daily regimen of heat and restraint stress (0830, 1230, and 1630 hr) consisting of placing the rats into a Plexiglas restraint tube over which were poised two 100 W floodlights. Control females remained undisturbed throughout pregnancy. At parturition all offspring were cross-fostered to untreated, recently-parturient dams and weaned at 25 days of age. Separate groups of P-S and Control males and females were gonadectomized and, for males, paired testes weights and body weights were recorded. Four days later the animals were implanted with Silastic capsules containing E2, and fitted with intra-atrial cannulae. The following day, blood samples were taken at 0900, 1300, 1500, and 1700 hr for a total of five days. Beginning with the 1700 hr sample on Day 2, and with the exception of the 1500 hr sample on Day 3, P-S males had significantly lower plasma Prl values than Control males through Day 4, and at the 1500 hr sample on Day 5. Moreover, at no point did P-S males exhibit a significant daily afternoon increase in Prl values, whereas Control males did so on Days 2 and 4.(ABSTRACT TRUNCATED AT 250 WORDS)