Field-specific changes in hippocampal opioid mRNA, peptides, and receptors due to prenatal morphine exposure in adult male rats.

Alterations in the opioid system in the hippocampal formation and some of the possible functional consequences were investigated in adult male rats that were prenatally exposed to either saline or morphine (10 mg/kg twice daily on gestational days 11-18). In situ hybridization and Northern blots were used to measure proenkephalin and prodynorphin mRNA, and radioimmunoassays quantified proenkephalin- and prodynorphin-derived peptide levels in the dentate gyrus, CA3, and CA1 subfields of the hippocampal formation. Prenatal morphine exposure in male rats decreases proenkephalin and increases prodynorphin mRNA selectively in the granule cell layer of the dentate gyrus. Similarly, met-enkephalin peptide levels are decreased and dynorphin B peptide levels are increased in the dentate gyrus but not CA3 or CA1 of prenatally morphine-exposed males. In addition, there are decreases in dynorphin-derived peptides in the CA3 subfield. Receptor autoradiography revealed increases in the density of micro but not delta receptor labeling in discrete strata of specific hippocampal subfields in morphine-exposed males. Because alterations in the hippocampal opioid system suggest possible alterations in the excitability of the hippocampal formation, changes in opioid regulation of seizures were examined. Morphine exposure, however, does not alter the latency to onset or number of episodes of wet dog shakes or clonic seizures induced by infusion of 10 nmol [D-Ala2, MePhe4, Gly-ol5]enkephalin into the ventral hippocampal formation. Interestingly, a naloxone (5 mg/kg) injection 30 min before bicuculline administration reverses the increased latency to onset of clonic and tonic-clonic seizures in morphine-exposed males. Thus, the present study suggests that exposure of rats to morphine during early development alters the hippocampal opioid system, suggesting possible consequences for hippocampal-mediated functions.

A critical role for beta-endorphin in cocaine-seeking behavior.

Endogenous beta-endorphin levels in the brain are elevated in response to cocaine and are downstream of the mesolimbic dopaminergic system. However, beta-endorphin's direct involvement in cocaine reinforcement has not been demonstrated. In the present study, a single bilateral microinjection of anti-beta-endorphin antibodies (4 microg) to the nucleus accumbens during the maintenance phase of cocaine self-administration (1 mg/kg/infusion) significantly increased the number of active and inactive lever responses. The increase in lever responses is reminiscent of rat behavior during extinction of cocaine self-administration. Further, a cocaine dose-response demonstrates that the increased lever presses in anti-beta-endorphin antibody-injected rats was still present after substitution with a lower dose of cocaine. These findings support a critical role for beta-endorphin in the cocaine brain reward system.

Bicuculline seizure susceptibility and nigral GABAA alpha1 receptor mRNA is altered in adult prenatally morphine-exposed females.

Prenatal morphine exposure (5-10 mg/kg twice daily on gestation days 11-18) can adversely affect neurological development, including seizure susceptibility. The present study examines the effects of prenatal morphine exposure on seizure susceptibility to the GABA antagonist and convulsant bicuculline and GABA(A) alpha(1) receptor mRNA in the substantia nigra (SN) of female rats. The results demonstrate that prenatally morphine-exposed ovariectomized (OVX) females and OVX females with estradiol benzoate (EB) replacement have an increased latency to seizure onset compared to controls. In addition, prenatal morphine exposure decreases the area covered by grains of GABA(A) alpha(1) receptor mRNA in the anterior SN in both OVX and EB+progesterone (P)-treated groups, and decreases the number of GABA(A) alpha(1) receptor mRNA-labeled cells/field in EB females. Furthermore, prenatally morphine- and saline-exposed EB and EB+P females had decreased GABA(A) alpha(1) receptor mRNA-labeled cells/field in the anterior SN compared to OVX animals of the same prenatal exposure. These results demonstrate that the long term effects of prenatal morphine exposure in female rats is dependent on their hormonal status, and suggest that seizure susceptibility may be altered via neuropharmacological changes in the GABA system in the SN.

Prenatal morphine exposure decreases susceptibility of adult male rat offspring to bicuculline seizures.

The purpose of this study was to investigate the effect of prenatal exposure to morphine (5-10 mg/kg twice daily on days 11-18 of gestation) on bicuculline seizure susceptibility and to examine the interaction of prenatal morphine exposure and hormonal background in adult male rats. The data demonstrate that prenatal morphine exposure does not affect clonic but decreases susceptibility to tonic-clonic bicuculline seizures in intact male rats. Thus, the present data support our previous work demonstrating alterations in seizure susceptibility of adult morphine-exposed animals.

Prenatal morphine exposure differentially alters learning and memory in male and female rats.

The present study tested the hypothesis that exposure to morphine on prenatal days 11-18 impairs performance on tasks requiring learning and memory in adult male and female rats. In Experiment 1, a symmetrical maze was used to measure learning. In Experiment 2, an eight-arm radial maze was used to assess working spatial memory. The results of Experiment 1 demonstrated that prenatal morphine exposure reduces the time needed to complete the trials, but does not affect the accuracy of performance in male rats. In contrast, prenatal drug treatment had no effects on either the time or the accuracy of performance in female rats. In Experiment 2, both male and female morphine-exposed rats needed more time to complete regular trials (no delay) than controls; however, morphine exposure in male rats did not affect performance on tasks requiring memory, measured with delay trials, but hindered it in ovariohysterectomized (OVX) female rats. In OVX females, replacement injections of both estrogen and progesterone restored the impairment of performance on delay trials produced by prenatal morphine exposure. Thus, the present study demonstrates that prenatal morphine exposure differentially alters performance of adult male and female rats on tasks requiring learning and spatial memory.

Prenatal morphine exposure alters susceptibility to bicuculline seizures in a sex- and age-specific manner.

Bicuculline was used to investigate seizure susceptibility in pre- and peripubertal male and female rats exposed prenatally to morphine. Morphine-exposed males showed increased seizure susceptibility at prepubertal and decreased susceptibility at peripubertal ages. There was no difference in seizure susceptibility in morphine-exposed females at either age. Therefore, the present data suggest that males are more vulnerable than females to morphine-induced insults during prenatal brain development.