Morphine exposure prevents up-regulation of MR and GR binding sites in the brain of adult male and female rats due to prenatal stress.

Our previous work demonstrated that the hormone response to stress and the negative feedback inhibition to these hormones are sex-dependently altered by prenatal morphine exposure in adult rats. An alteration in the glucocorticoid negative feedback inhibition is mediated by glucocorticoid receptors (GR) that are distributed throughout the brain, and mineralocorticoid receptors (MR) localized mainly in the hippocampus and involved in a tonic influence of brain functions. Therefore, the present study examined the binding characteristics of MR and GR in young adult male and female rats exposed prenatally (E11-E18) to morphine (10 mg/kg/2 x /day), saline or no treatment at all (controls). At 60-90 days of age, animals were adrenalectomized (ADX) 24 h prior to decapitation. The hippocampus and hypothalamus were dissected for saturation binding assays. The data demonstrate that prenatal stress due to maternal saline injections up-regulates MR and GR binding in the hippocampus of adult male rats and this effect is prevented by prenatal morphine exposure. There is no effect of prenatal morphine exposure on GR binding in the hypothalamus of males. In female rats, prenatal morphine exposure does not affect the binding of MR and GR in the hippocampus or GR in the hypothalamus relative to controls; however, they are affected by ovarian hormone fluctuation. Moreover, prenatal stress decreases MR binding in the hippocampus of diestrous females and GR binding in the hypothalamus of estrous females. Both decreases are prevented by prenatal morphine exposure. Thus, the present study demonstrates that: (1) prenatal stress due to maternal saline injections alters MR and GR binding of adult male and female rats and is prevented by prenatal morphine exposure; (2) the MR and GR binding in adult female rats are affected by ovarian hormone fluctuations.

Mid- to late gestational morphine exposure does not alter the rewarding properties of morphine in adult male rats.

Prenatal exposure to drugs of abuse often leads to physiological and neurobiological abnormalities including decreased brain and body weight, cognitive deficits and behavioral alterations. A handful of studies showed increased vulnerability to drug abuse in prenatally drug-exposed offspring. Our work also demonstrated that prenatal exposure to analgesic doses of morphine during gestation days 11-18 increases mu-opioid receptor density in the nucleus accumbens and central amygdala of adult male rats. Both the nucleus accumbens and central amygdala play important roles in modulating drug-induced reward via the mesolimbic dopaminergic system. Therefore, two types of behavioral paradigms were used to test the hypothesis that the same prenatal morphine exposure would enhance the rewarding effects of morphine, making drug-exposed offspring more vulnerable to abuse this drug in adulthood. All experiments were performed with adult male offspring of saline-injected, morphine-injected or non-injected (control) dams. (1) The unbiased conditioned place preference (CPP) paradigm was used to investigate whether prenatal morphine exposure sensitizes adult male rats to non-contingent morphine reward. These adult animals were conditioned with 0.1, 0.3, 1, 3 or 5 mg/kg morphine. All control, prenatally saline- and morphine-exposed male rats preferred the morphine-paired compartment relative to the saline-paired compartment. However, the magnitude of morphine CPP in adult male rats was not dependent on the conditioning dose of morphine or prenatal morphine exposure. (2) Intravenous morphine self-administration was used to assess the behavioral response to contingent morphine reward. Each rat self-administered one of four doses of morphine (0.3, 1, 2 or 3 mg/kg/infusion). Morphine self-administration was not altered in prenatally morphine-exposed adult male offspring. Control males self-administered significantly less morphine at the lowest dose of morphine than both prenatally saline- and morphine-exposed males. Although our data show that prenatal exposure to an analgesic dose of morphine during the time of opioid receptor appearance does not enhance morphine CPP or self-administration, they do not exclude the possibility that this prenatal morphine exposure enhances the rewarding properties of other drugs of abuse.

Quantitative peptidomics in mice: effect of cocaine treatment.

We recently developed a quantitative peptidomics method using stable isotopic labels and mass spectrometry to both quantify and identify a large number of peptides. To test this approach and screen for peptides regulated by cocaine administration, 32 Cpefat/fat mice and 16 wild-type mice were treated twice daily for 5 d either with saline or 10 mg/kg cocaine. Peptides were extracted from striatum, hypothalamus, hippocampus, and prefrontal cortex, and extracts from groups of eight mice were labeled with the N-hydroxysuccinimide ester of trimethylammonium butyrate containing either nine deuterium or nine hydrogen atoms. Pools of heavy- and light-labeled peptides were combined, purified on an anhydrotrypsin affinity column, and analyzed on a reversephase column coupled to an electrospray ionization quadrapole time-of-flight mass spectrometer. Changes in peptide levels upon cocaine treatment were determined from the relative peak intensities of the cocaine versus saline peaks, and peptides were identified from collision-induced dissociation spectra. Ten peptides were found to increase or decrease in each of two separate analyses from distinct groups of mice. Peptides found to increase corresponded to fragments of proenkephalin, prothyrotropin-releasing hormone, provasopressin, proSAAS, secretogranin II, chromogranin B, and peptidyl-glycine-alpha-amidating mono-oxygenase in the hypothalamus. The same peptidyl-glycine-alpha-amidating mono-oxygenase peptide decreased in the prefrontal cortex, along with striatal neurokinin B and two unidentified peptides. Thirty other peptides were not substantially affected by cocaine treatment in both replicates. Taken together, the quantitative peptidomics approach provides an efficient method to screen for changes in a large number of peptides.

Mifepristone (RU486) inhibits lateral perforant path long-term potentiation in hippocampal slices from prenatally morphine-exposed female rats.

In brain slices from prenatally saline-exposed female rats during proestrus and diestrus, long-term potentiation (LTP) can be induced in the lateral perforant pathway (LPP). Prenatal morphine exposure suppresses LTP induction in the LPP during proestrus. Here we studied synaptic plasticity in the LPP in slices from female rats prenatally exposed to morphine. Two additional factors were investigated: the role of the estrous cycle and role of glucocorticoid receptors. Hippocampal slices were prepared from adult, prenatally saline- or morphine-exposed female rats. One hour prior to decapitation, vaginal smears were obtained and the rats either in proestrus or diestrus were treated with a non-specific glucocorticoid receptor antagonist mifepristone (RU486) or with a vehicle. LPP was stimulated with high-frequency stimulation. Short-tem plasticity (STP) and the induction and maintenance of long-term potentiation (LTP) were assessed. In all groups of prenatally saline-exposed rats, LTP was induced and maintained with the exception of RU486-treated rats during proestrus where the LTP was induced but not maintained. In prenatally morphine-exposed females in diestrus, both STP and LTP were induced after postnatal vehicle treatment. In morphine-exposed, proestrous females, neither STP nor LTP were induced irrespective of the postnatal treatment. Thus, prenatal morphine exposure suppresses the induction of LTP in the LPP, except during diestrus. Data indicate that the induction and maintenance of LTP in the LPP in hippocampal slices from female rats is multifactorial: ovarian steroids and functionality of glucocorticoid receptors cooperation are necessary for induction and maintenance of the LTP, prenatal morphine exposure interferes with this process possibly by its long-term effects on synaptic plasticity.

Alterations of prenatal morphine exposure in mu-opioid receptor density in hypothalamic nuclei associated with sexual behavior.

Our previous work demonstrated that prenatal morphine exposure twice daily during gestational days 11-18 differentially alters male and female sexual behavior. One possible explanation may be that prenatal morphine exposure alters the sexual behavior via alterations of mu-opioid receptors in brain regions involved in reproductive function and behavior, including the ventromedial nucleus of the hypothalamus (VMH), arcuate nucleus (ARC), and medial preoptic area (mPOA). In experiment 1, mu-opioid receptor density was analyzed in three groups of adult male rats: gonadally intact, gonadectomized (GNX), and GNX and testosterone 17beta-propionate-treated (TP). In experiment 2, mu-opioid receptor density was analyzed in four groups of adult female rats: ovariectomized (OVX), OVX and estradiol benzoate-treated (EB), OVX and progesterone-treated (P), and OVX and EB- and P-treated (EB+P). Experiment 1 demonstrated that prenatal morphine exposure lowered the mu-opioid receptor density in the mPOA of adult, gonadally intact and in TP males, while this difference was not apparent in GNX male rats. Experiment 2 demonstrated that prenatal morphine exposure increased mu-opioid receptor density in OVX females, while decreasing it in EB females in the VMH. When compared to our previous sexual behavior data, the present results demonstrate that at least some changes in sexual behavior of adult male and female rats prenatally exposed to morphine may be related to alterations in mu-opioid receptors in brain regions controlling sexual behavior.

Hypothalamo-pituitary-adrenal axis-regulated stress response and negative feedback sensitivity is altered by prenatal morphine exposure in adult female rats.

It has been shown that adult female rats react to stressors more intensely than adult male rats. Our previous work demonstrated that the adrenocorticotropic hormone (ACTH) but not corticosterone (CORT) response to stress is altered by prenatal morphine exposure in adult male rats. Response of the hypothalamo-pituitary-adrenal (HPA) axis to stress is known to be sex specific and dependent on the hormonal fluctuation of the estrous cycle. Therefore, the present study examined the effect of prenatal morphine exposure on the levels of ACTH and CORT before and after restraint stress in adult female rats. Experiment 1 tested ACTH and CORT plasma levels before and after restraint stress in prenatally morphine- and saline-exposed, adult diestrus and proestrus female rats. Prenatal morphine exposure suppressed the restraint stress-induced ACTH levels in both diestrus and proestrus females, but did not have any effects on the basal or stress-induced CORT levels. Experiment 2 examined the sensitivity of negative feedback using the dexamethasone (DEX) (0.001, 0.01, 0.1 and 1.0 mg/kg) suppression test in adult, prenatally morphine- and saline-exposed female rats. In saline-exposed, proestrus but not diestrus females, all doses of DEX were effective in suppressing the restraint stress-induced increase in CORT levels. In both diestrus and proestrus, morphine-exposed females, only the two highest doses of DEX (0.1 and 1.0 mg/kg) were successfully suppressing the stress-induced CORT levels. The stress-induced increase in the ACTH level was suppressed only by the highest dose of DEX (1.0 mg/kg) in both saline- and morphine-exposed, diestrus and proestrus females. Thus, the present study demonstrates that prenatal morphine exposure alters the HPA axis-regulated stress response and the sensitivity of negative feedback that are affected by the fluctuation of ovarian hormones.

Cholera toxin B decreases bicuculline seizures in prenatally morphine- and saline-exposed male rats.

Prenatal morphine exposure on gestation days 11-18 alters bicuculline-induced seizures in rats during development and in adulthood. Adult, morphine-exposed male progeny exhibit an increased latency to bicuculline seizures, which can be reversed by administration of the opioid receptor antagonist naloxone. In chronically morphine-treated adult mice, cholera toxin B (CTX-B) can reverse the effects of chronic morphine administration. Therefore, the present study investigated whether prenatally morphine-exposed rats show a similar response to CTX-B as chronically morphine-treated adult rodents. Prenatally morphine-, saline- and unexposed male progeny were tested for seizure susceptibility with a 7.5-mg/kg intraperitoneal injection of bicuculline in adulthood. CTX-B or saline was injected subcutaneously at 24, 12, and 0.5 h before bicuculline injection. CTX-B decreased the occurrence of bicuculline-induced seizures in both prenatally saline- and morphine-exposed but not unexposed rats. Furthermore, three, but not one, saline injections administered at 12-h intervals prior to bicuculline administration reversed the increase in seizure latency in prenatally morphine-exposed adult males, suggesting an altered responsiveness of the stress system. The present study demonstrates that CTX-B can decrease the occurrence of bicuculline seizures in prenatally stressed rats and that increased seizure latencies in prenatally morphine-exposed male rats may be related to stress responses.

Adrenocorticotropin stress response but not glucocorticoid-negative feedback is altered by prenatal morphine exposure in adult male rats.

The present study was designed to investigate the effects of prenatal morphine exposure on the hypothalamic-pituitary-adrenal (HPA) axis-regulated stress responses by measuring restraint stress-induced changes in the adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels. In experiment 1, plasma levels of ACTH and CORT in prenatally morphine-, saline-exposed and control male rats were determined before and at several times after restraint stress. There were no statistically significant differences in plasma ACTH and CORT levels before restraint stress between the groups. However, prenatal morphine exposure dampened the stress-induced increase and spontaneous recovery of ACTH levels after the restraint stress. There were no differences in plasma CORT levels between the three groups either before or at any time after restraint stress. Experiment 2 was designed to investigate the sensitivity of negative feedback of glucocorticoids using the dexamethasone (DEX) suppression test. DEX was administered at different doses (0.001, 0.01, 0.1 and 1.0 mg/kg) and ACTH and CORT plasma levels were measured before and at several times after restraint stress in prenatally morphine- and saline-exposed males. DEX pretreatment eliminated the differences observed in ACTH responses to stress in morphine- and saline-exposed males. DEX pretreatment dose dependently suppressed the restraint stress-induced increased plasma ACTH concentration. In plasma CORT levels, DEX pretreatment dose dependently suppressed the restraint stress-induced increased plasma CORT concentration regardless of prenatal drug exposure. Thus, the present study demonstrates that prenatal morphine exposure alters the ACTH and CORT responses to stress but not the sensitivity of negative feedback of glucocorticoids.

Cortical and striatal mu-opioid receptors are altered by gonadal hormone treatment but not by prenatal morphine exposure in adult male and female rats.

The cerebral cortex (CX), cingulate CX (cgCX), and striatum (STR) play an important role in locomotion, cognition, emotion, and reward-motivated behaviors, and are altered by prenatal morphine exposure. We have demonstrated that delta-opioid receptors in the CX and STR of adult male and female rats are altered by prenatal morphine exposure and gonadal hormonal treatment. Because morphine binds with greater affinity to mu- than delta-opioid receptors, the present study examined the effect of prenatal morphine exposure on mu-opioid receptor density in the CX, cgCX, and STR of adult male and female rats using receptor autoradiography. In Experiment 1, three groups of adult male rats were analyzed: intact, gonadally intact; GNX, gonadectomized; and TP, GNX and testosterone propionate (TP)-treated. In Experiment 2, four groups of adult females were analyzed: OVX, ovariectomized; EB, OVX and estradiol benzoate (EB)-treated; P, OVX and progesterone (P)-treated; and EB+P, OVX and EB- and P-treated. In male rats, GNX and TP males had lower mu-opioid receptor densities in all three brain regions than gonadally intact males regardless of prenatal drug exposure. In female rats, OVX, EB+P-treated females had lower mu-opioid receptor density in the STR than OVX only females regardless of prenatal drug exposure. There were no drug or gonadal hormone effects in the CX or in the cgCX of female rats. Thus, the present study demonstrates that gonadal hormones, and not prenatal morphine exposure, alter the density of mu-opioid receptors in the CX, cgCX, and STR of adult male and female rats.

Prenatal morphine exposure suppresses mineralocorticoid receptor-dependent basal synaptic transmission and synaptic plasticity in the lateral perforant path in adult male rats.

The effects of prenatal morphine exposure (E11-18) on mineralocorticoid receptor (MR) modulation of synaptic plasticity were investigated in the lateral perforant path (LPP)-dentate gyrus granule cell synaptic system. Hippocampal slices were prepared from adult, prenatally saline- or morphine-exposed male rats. One hour prior to decapitation, some adult male rats were injected subcutaneously with saline or the MR antagonist, canrenoic acid (50 mg/kg). LPP was stimulated with high-frequency (2x100 Hz/0.5 s) and short-term plasticity (STP) and long-term potentiation (LTP) were evaluated at 5 and 30 min poststimulation, respectively. Prenatally saline-exposed male rats injected with saline 1 h prior to decapitation showed significantly higher levels of baseline, STP, and LTP than prenatally saline-exposed, canrenoic acid-treated males. In contrast, prenatally morphine-exposed male rats regardless of saline or canrenoic acid injection 1 h prior to decapitation were comparable in their baseline, STP, and LTP activities. Thus, the results demonstrate that canrenoic acid decreases the efficacy of the basal synaptic transmission in the LPP as well as suppresses synaptic plasticity in saline-exposed males. However, in adult morphine-exposed male rats, canrenoic acid has no other or further effects than a saline treatment suggesting that prenatal morphine exposure suppresses MR-dependent basal synaptic transmission as well as synaptic plasticity.

Density of mu-opioid receptors in the hippocampus of adult male and female rats is altered by prenatal morphine exposure and gonadal hormone treatment.

The present in vitro autoradiography study demonstrates that prenatal exposure to morphine alters the density of mu-opioid receptors in the hippocampus of adult female but not adult male rats. Prenatal morphine exposure increased the mu-opioid receptor density in the CA1 of ovariectomized (OVX) females and in the CA3 of OVX, estradiol benzoate-plus progesterone (EB+P)-treated females, but decreased it in CA3 of OVX females. There were also hormonal effects on mu-opioid receptor density in adult female rats. In the CA1, only morphine-exposed but not saline-exposed, hormone-treated females (EB, P, or EB+P) had a decrease in mu-opioid receptor density relative to OVX females. Both saline-exposed and morphine-exposed, OVX females after gonadal hormone replacement had a lower density of mu-opioid receptors in the CA3 and in the dentate gyrus (DG) than OVX females. In male rats, there was a decrease in mu-opioid receptor density in the CA1 and CA3 of gonadectomized (GNX), testosterone 17beta-proprionate (TP)-treated males relative to GNX males regardless of prenatal morphine exposure. In the DG, the mu-opioid receptor density was reduced only in morphine-exposed but not in saline-exposed, TP-treated males compared with GNX males. Thus, our data demonstrate that mu-opioid receptor density in the hippocampus is affected by prenatal morphine exposure and by male and female gonadal hormones.

Autoradiographic evidence that prenatal morphine exposure sex-dependently alters mu-opioid receptor densities in brain regions that are involved in the control of drug abuse and other motivated behaviors.

The present study examined the effects of prenatal morphine exposure on mu-opioid receptor density in young adult male and female rats to assess the long-term alterations in several brain areas including the nucleus accumbens (NAc), bed nucleus of stria terminalis (BNST), and the basolateral (BLA), lateral (LA), central (CeA), and posteromedial cortical (PMCoA) amygdaloid nuclei. These brain areas are involved in motivating and rewarding behaviors of opiates and other drugs of abuse. The reinforcing actions of opiates appear to be mu-opioid receptor dependent. The results demonstrate that in male rats, prenatal morphine exposure significantly increases the density of mu-opioid receptors in the NAc and PMCoA. In contrast, the same prenatal morphine exposure reduces the density of mu-opioid receptors in the BLA, while increasing it in the CeA and without effects in the LA or BNST. In female rats, prenatal morphine exposure has no effects on the density of mu-opioid receptors in the above six brain areas, but the density of these receptors is dependent on the presence or absence of ovarian hormones. Thus, the present study demonstrates that mid- to late gestational morphine exposure induces long-term, sex-specific alterations in the density of mu-opioid receptors in the NAc and amygdala. Moreover, this prenatal morphine exposure also eliminates sex differences in the density of mu-opioid receptors in the NAc, CeA, and PMCoA but not in the BLA, LA, and BNST.

Long-term effects of prenatal morphine exposure on maternal behaviors differ from the effects of direct chronic morphine treatment.

Previous studies have demonstrated that chronic morphine treatment of pregnant rats alters maternal behavior. Other studies have shown long-term effects of prenatal exposure to morphine, including changes in reproductive behavior in adult females. The present study investigated the effects of prenatal morphine exposure on a variety of maternal behaviors such as nursing, maternal activities, nonmaternal activities, and pup retrieval. Prenatal morphine exposure increased active and decreased passive nursing. There were no differences in maternal activities such as presence in the nest, contact with pups, grooming of pups, and/or manipulation of nest shavings. In the retrieval test, prenatally morphine-exposed mothers were faster in carrying the first pup, retrieving the first pup back to the nest, and returning all pups to the nest than prenatally saline-exposed mothers. Maternal and nonmaternal activities also were affected by the light: dark cycle. All saline- and morphine-exposed mothers nursed more, were more often in the nest, and more often in contact with greater than half of their litter during the light than the dark sessions. On the other hand, nonmaternal activities increased during the dark sessions: Mothers cared for themselves (groomed, ate) more and displayed more rearing and sniffing. Mothers spent more time resting with their eyes closed during the light sessions regardless of prenatal drug exposure. The present study demonstrated that the effect of morphine on maternal behavior is different in adult exposed and prenatally exposed mothers. While direct morphine treatment impaired maternal behaviors, prenatal morphine exposure has the opposite effect.

Mu-opioid receptors in seizure-controlling brain structures are altered by prenatal morphine exposure and by male and female gonadal steroids in adult rats.

The present study used autoradiography to examine the effect of prenatal morphine exposure on mu-opioid receptor density in epileptic seizure-controlling brain structures including the substantia nigra pars compacta (SNC), substantia nigra pars reticulata (SNR), superior colliculus (SC), and subthalamic nucleus (STN) of adult male and female rats. The results demonstrate that prenatal morphine exposure increases the mu-opioid receptor density in the SNC and STN, but not in the SNR or in the SC of gonadally intact adult male rats. The density of mu-opioid receptors in the SNC and STN is, however, decreased following gonadectomy in morphine-exposed males, and testosterone treatment fails to restore this decrease to the level of gonadally intact males. Further, in the SC, the density of mu receptors was lower in both saline-exposed, gonadectomized (GNX) and GNX, TP-treated males and in morphine-exposed, GNX, TP-treated males relative to gonadally intact saline- and morphine-exposed males, respectively. In ovariectomized (OVX) female rats, the same prenatal morphine exposure increases the mu-opioid receptor density in the SNC and SNR, but decreases it in the STN. The density of mu-opioid receptors is also decreased in the SNC and SC of OVX estrogen-treated females and in the SNR and SC of OVX, progesterone-treated females. Thus, the present study demonstrates that mu-opioid receptors in seizure-controlling brain structures are sex-specifically altered by prenatal morphine exposure in adult progeny. Further, prenatal morphine exposure alters gonadal hormone effects on the density of mu receptors in adult, OVX females.

Impact of maternal morphine and saline injections on behavioral responses to a cold water stressor in adult male and female progeny.

The purpose of the present study was to test the effects of maternal morphine and saline injections on chronic cold water stress responses in three groups of adult male and female rats: prenatally morphine-exposed adult progeny, prenatally saline-exposed adult progeny, and control groups. All male rats were gonadally intact, and female rats were ovariectomized (OVX) in adulthood, and half of them were injected with estradiol benzoate (EB). All animals were exposed to a cold water stressor daily for 2 weeks and tested before (baseline) and after (stress effects) the chronic cold water stressor in a swim test and an open field test. In the swim test, both adult males and OVX, EB-treated adult females born to mothers injected with morphine or saline displayed more floating behavior during the swim test than their controls, both before and after the cold water stressor. Male rats exposed to morphine or saline prenatally also spent more time struggling during the swim tests than controls, and this was further increased after the cold water stressor. In the open field test, males and OVX, EB-treated females born to morphine- or saline-injected mothers were less active and displayed fewer rearings than controls. No differences were observed in OVX females as a result of prenatal injections. Thus, the present study demonstrates that maternal injections, regardless of injection content, induce long-lasting effects on stress responsiveness in adult progeny.

Differential effects of prenatal morphine exposure on analgesia produced by vaginocervical stimulation or systemic morphine administration in adult rats.

The present study investigated the effects of prenatal morphine exposure on the magnitude of analgesia produced by vaginocervical stimulation (VS) or systemic morphine injection in adult rats. In Experiment 1, an acute subcutaneous morphine (1 mg/kg) injection induced a 124% greater increase in tail-flick latency (TFL) in adult rats exposed prenatally to saline than to morphine. By contrast, in Experiment 2, VS induced a 196% greater increase in TFL in adult rats exposed prenatally to morphine than to saline. Female rats exposed prenatally to morphine also had a greater VS-produced increase in vocalization threshold (VOC-T) to tail shock than those exposed prenatally to saline. Thus, the present study demonstrates that prenatal morphine exposure exerts diametrically opposite effects on analgesia that is produced in adulthood by morphine or VS, attenuating the former while potentiating the latter. These findings provide evidence that the mechanisms underlying the two types of analgesia differ fundamentally.

Gonadal hormone-induced changes in adult male and female rats exposed to early postnatal handling are not altered by prenatal morphine exposure.

The purpose of the present study was to investigate the long-term effects of early postnatal handling in several gonadal hormone conditions in adult male and female rats exposed prenatally to morphine or saline. An open-field apparatus was used to test locomotor activities such as line crossing, rearing, grooming, and anxiety-like behaviors such as visiting squares alongside the walls of the open field and boli dropping. Postnatal handling increased locomotor activities in gonadally intact males and in all groups of hormone-manipulated females, but did not change them in gonadectomized (GNX) males. Additionally, there was a decrease in anxiety-like behavior in ovariectomized (OVX) females after estradiol benzoate (EB) or EB and progesterone (P) replacement due to handling. Handling did not affect anxiety-like behaviors in OVX females or in GNX or gonadally intact males. Prenatal morphine exposure did not alter any open-field measures in handled or nonhandled animals when compared to saline controls. Thus, the present study demonstrates that early postnatal handling induces long-lasting changes in locomotor and anxiety-like behaviors of adult male and female rats regardless of their prenatal exposure to morphine. These changes are gonadal hormone specific.

Prenatal opiate exposure: long-term CNS consequences in the stress system of the offspring.

Our data show that prenatal morphine exposure induces long-term alterations in adult brain and behavior in both male and female rats, and these alterations are sex-specific. It is also evident that the alterations are not restricted to a single brain site or to a single neurotransmitter or neuromodulator. Moreover, there are long-term alterations in both the norepinephrine (NE) and opioid systems in several brain regions involved in stress responses and in the maintenance of homeostatic balance between the external environment, the brain and the rest of the body. Thus, this short paper reviews the prenatal morphine exposure data and highlights gaps in stress response to drug vulnerability/predisposition as an adult.