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Biomedical subjects

J W Simpkins

Publications and source records attributed to J W Simpkins.

At least 109 records · Page 6Linked to original sources
PubMed1987

Evidence for the reestablishment of copulatory behavior in castrated male rats with a brain-enhanced estradiol-chemical delivery system.

We have developed a redox-chemical system for brain-enhanced drug delivery of estradiol based on an interconvertible dihydropyridine in equilibrium with pyridinium salt carrier. Estradiol, when combined with the carrier, readily crosses the blood-brain barrier and upon oxidation of the carrier is "locked" in the brain. The aim of this study was to evaluate the effects of an estradiol-chemical delivery system (E2-CDS) versus an equimolar dose of estradiol-17-valerate (E2-VAL) on copulatory behavior in orchidectomized rats. The data revealed that a single dose of E2-CDS was more efficacious than E2-VAL in stimulating mounting behavior (percent responding) and the effect was 100% through 5 weeks. E2-CDS increased intromission behavior more than E2-VAL through 28 days. Mount and intromission latencies were reduced by E2-CDS to a greater extent and for a longer time (28 days) than E2-VAL. Neither form of estradiol restored ejaculation parameters or penile reflexes. These data suggest that E2-CDS causes a potent and long-acting stimulation of proceptive and consummatory components of male sexual behavior, presumably acting through the local brain-release of estradiol.

Animals↗
PubMed1987

Effects of central application of naloxone on the skin temperature response in morphine-dependent rats.

This study was designed to identify if the surge in tail skin temperature (TST) observed following systemic administration of naloxone to morphine-dependent rats is mediated by a specific brain locus. Female rats were fitted with cannula located either in the preoptic area-anterior hypothalamus, locus coeruleus, or the frontal cortex. TST was monitored every 5 min for 60 min following central administration of naloxone (1-40 micrograms/0.4 microliters), in morphine-dependent rats. Regardless of the central site of naloxone injection, TST was significantly increased 4-5 degrees C. A threshold dose of 20 micrograms/0.4 microliters (10 micrograms/0.2 microliters, bilaterally) of naloxone was identified to produce this surge in TST in all three brain regions. These results suggest that morphine dependency sensitizes several brain regions to administration of naloxone such that the narcotic antagonist produces a similar change in TST as is observed following its systemic administration. These data further support the use of our morphine-dependent rat model to study the central mechanisms of the menopausal hot flush, and provide additional evidence that the flush response is centrally mediated.

Animals↗
PubMed1987

Role of hypothermia in the pentobarbital-induced blockade of luteinizing hormone secretion in female rats.

Studies were conducted to determine if the hypothermic effects of barbiturates were responsible for their ability to suppress luteinizing hormone (LH) secretion in rats following ovariectomy or treatment with gonadal steroids. In both ovariectomized rats and rats treated with estradiol and progesterone, pentobarbital caused a marked hypothermia and blocked LH hypersecretion. In ovariectomized rats, the LH-suppressing effects of pentobarbital could be prevented by maintaining normal core body temperature. However, in steroid-treated rats, the maintenance of normal core body temperature did not prevent the pentobarbital-induced blockade of the steroid-induced LH surge. These data indicate that the pentobarbital-induced reduction of LH secretion in ovariectomized rats is temperature-dependent, while its blockade of the steroid-induced LH surge is not. Additionally, this study provides further evidence for the differential neuronal regulation of LH secretion following ovariectomy and during the steroid-induced surge in LH.

Animals↗
PubMed1987

Effects of early pregnancy and acute 17 beta-estradiol administration on porcine uterine secretion, cyclic nucleotides, and catecholamines.

This study investigated acute effects of 17 beta-estradiol (E) on ions, cyclic nucleotides, and catecholamines and their association with temporal changes in uterine secretory products in pregnant, cyclic, and nonpregnant gilts. Uterine flushings (UTF) and endometrium (ENDOM) from one uterine horn of nonpregnant and pregnant gilts (n = 9) were collected on days 10, 12, and 14 (n = 3). Protein, plasma inhibitor (P less than 0.05), Na+, and K+ (P less than 0.01) increased linearly in UTF of pregnant gilts. Ca2+ changed biphasically, with higher concentrations (P less than 0.01) in pregnant gilts on day 12. Endometrial cAMP and cGMP (P less than 0.05) increased between days 12 and 14 of pregnancy. The UTF norepinephrine (NE) concentrations increased (P less than 0.01) in cyclic gilts between days 12 and 14, while endometrial NE increased between days 10 and 12 and then decreased on day 14. The UTF of pregnant gilts had higher (P less than 0.05) concentrations of dopamine (DA), which peaked on day 12 and then decreased (P less than 0.01) by day 14. DA in UTF of nonpregnant gilts decreased between days 10 and 12 and remained low on day 14. A catecholamine metabolite, 3,4-dihydroxyphenylglycol, in ENDOM (P less than 0.05) and UTF (P less than 0.01) decreased linearly between days 10 and 14. The turnover rate of endometrial catecholamines was 2.4-fold higher (P less than 0.05) during early pregnancy compared with that in cyclic gilts. Effects of acute administration of exogenous E (0.5 mg) were also studied. The UTF and ENDOM were from day 11 nonpregnant gilts 0, 30, 60, and 360 min (n = 3) post-E or post-saline-ethanol (C) injection (n = 9). Potassium, plasma inhibitor (P less than 0.01), and cGMP (P less than 0.05) increased rapidly (30 min) after E injection. The K+ level changed biphasically, with increased concentrations again at 360 min. Plasmin inhibitor returned to levels similar to controls by 60 min, whereas cGMP remained elevated until 360 min postinjection when E, Ca2+, K+ (P less than 0.01), and Na+ (P less than 0.03) were increased. ENDOM NE (P less than 0.05) and UTF DA (P less than 0.05) were lower in E-treated gilts. Additionally, the turnover rate was significantly lower (P less than 0.05) for NE and DA in the UTF of E-treated gilts. An increase in Ca2+ in UTF preceded increases in protein secretions (except plasmin inhibitor) and may play a role in E-stimulated endometrial epithelial secretory vesicle exocytosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Acid Phosphatase↗
PubMed1987

Chronic morphine treatment enhances the negative and positive feedback effects of estradiol on gonadotropin secretion in ovariectomized rats.

Studies were undertaken to evaluate the effects of chronic morphine exposure on the negative and positive feedback effects of estradiol (E2) on LH and FSH secretion in ovariectomized rats. Two days of E2 exposure reduced at 1000 h and stimulated at 1600 h the serum LH concentration at each dose tested. Chronic exposure (4 days) to morphine enhanced both the inhibitory effects of E2 on LH secretion at 1000 h and E2 induction of the midafternoon surge in LH. A detailed time course of the afternoon LH response to E2 revealed that chronic morphine exposure advanced its time of onset and increased its magnitude. The response of FSH to E2 and the interaction between E2 and morphine on FSH secretion were similar to those observed for LH, albeit lower in magnitude. With extension of the E2 exposure period from 2 to 4 days, the synergistic interaction between E2 and morphine persisted for the negative, but not the positive, feedback action on LH. Chronic morphine exposure in ovariectomized rats, without E2 replacement, was ineffective in altering the LH levels at 1000 h, but had a slight stimulatory effect on LH at 1600 h, indicating an E2 requirement for the observed suppression and stimulation of LH in the morning and afternoon, respectively. The response of the anterior pituitary to exogenously administered LHRH in the morning (1000 h) and during the midafternoon hypersecretion of LH (1800 h) was markedly enhanced in animals exposed chronically to morphine. Thus, the chronic stimulation of opiate receptors with morphine enhances the inhibition and subsequent hypersecretion of LH in E2-exposed rats, advances the time of onset and enhances the magnitude of the E2-induced LH surge, and augments the response to LHRH when LH levels are low in the morning and during the E2-induced hypersecretion of LH. These data support an important role for opioid neuronal systems in the mechanism that switches the E2 signal for gonadotropin secretion from inhibitory to stimulatory and, hence, in the series of neuronal events that leads to phasic secretion of gonadotropins.

Animals↗
PubMed1987

Influence of age on neurotransmitter function.

Regulation by neurotransmitters of anterior pituitary hormone secretion is complex and a thorough understanding of their normal role in hormone secretion is a prerequisite to understanding their involvement in age-related changes in endocrine function. To date, uncertainties far out-number demonstrated causative relationships between alterations in neurotransmitter release and resulting age-associated changes in hormone secretion. The best demonstrated relationships are the following. First, a decline in function of the TIDA system is responsible, in part, for the age-related elevation in prolactin secretion and may be involved in the decline in LH secretion. Second, the age-related decrease in hypothalamic norepinephrine turnover plays a role in the decline in LH and GH secretion and may be involved in alterations in TSH secretion during aging. Third, the decline in circadian activity of suprachiasmatic nucleus serotoninergic neurons may account for the blunting of circadian rhythms in the secretions of several anterior pituitary hormones in old animals. Fourth, evidence exists for an age-related decline in function of LHRH neurons, which may contribute to the observation of blunted LH secretion in old animals. Finally, somatostatin release may be increased in old animals, which likely contributes to the age-related decline in GH secretion. Other hypothalamic-releasing hormones have only recently been isolated and characterized; thus, little research on their age-related alterations has been done. Research on these neuropeptides will contribute further to our understanding of the role of neurotransmitters in age-related alterations in hormone secretion.

Aging↗
PubMed1986

Effects of opioid antagonists and their quaternary analogs on temperature changes in morphine-dependent rats.

Subcutaneous administration of three opioid antagonists; naloxone, naltrexone and nalmefene, produced a significant rise in tail skin temperature and a subsequent fall in rectal temperature in morphine dependent rats. However, subcutaneous administration of equimolar concentrations of the quaternary derivatives of these opioid antagonists (naloxone methobromide, naltrexone methobromide and n-methylnalmefenium iodide) failed to produce any significant alterations in either tail skin or rectal temperatures in the morphine dependent rat. At doses of naloxone methobromide 6 to 9 times greater than naloxone, there was a slight reduction of rectal temperatures with no significant elevation of skin temperature. However, the fall in rectal temperature was still significantly less than that achieved with administration of naloxone. When each of these six agents were administered centrally (20 micrograms/5 microliter, icv) in the morphine dependent rat, similar increases in tail skin temperature and decreases in rectal temperature were observed. These temperature changes were similar to those observed following systemic administration of the opioid antagonist. Previously, we have suggested that acute withdrawal in the morphine-dependent rat may serve as an animal model for the mechanism of the menopausal hot flush. Collectively, these results suggest that the temperature changes associated with morphine-withdrawal in our rat model for studying the mechanisms of the menopausal hot flush are centrally mediated.

Animals↗
PubMed1986

Regional skin temperature changes in a rat model for the menopausal hot flush.

Administration of naloxone to morphine-dependent male and female rats produced a significant rise in both tail skin temperature and foot temperature with a subsequent fall in colonic temperature. The magnitudes of the skin temperature surges were similar in the two regions, with the elevation in foot temperature preceding the rise in tail skin temperature. These regional skin temperature surges were similar in magnitude, duration and temporal pattern in both the male and female rat, and are similar to those exhibited in men and women undergoing flushing episodes. Castration of males did not alter these temperature responses. The only difference in response between male and female rats was the more pronounced fall in colonic temperature observed in morphine-dependent female rats following administration of naloxone. Neither the administration of naloxone to placebo-treated animals nor that of saline to morphine-dependent animals produced any changes in skin or colonic temperature in either male or female rats. These results suggest that the pattern of skin temperature alterations associated with morphine withdrawal in both the male and female rat is similar to the pattern of skin temperature surges associated with the hot flush in men and women, which provides additional evidence for the morphine-dependent rat as a model for women who exhibit flushing episodes. Additionally, this is the first report of a potential model for men who exhibit flushing episodes.

Analysis of Variance↗
PubMed1986

Long-term weekly gonadal steroid treatment: effects on plasma prolactin, sexual behavior and hypothalamic-preoptic area catecholamines.

Treatment of intact female rats with weekly injections of estradiol benzoate followed 48 h later by progesterone reliably induced high levels of sexual behavior. After 15-20 treatments, 25% of one group of females became refractory to the sexual-activity-inducing effects of ovarian steroids. The apparent deficit in sexual behavior could not be attributed to variation in prolactin secretion, as long-term steroid treatment resulted in greatly elevated circulating prolactin levels (greater than 1 microgram/ml) which were equivalent in good sexual responders (lordosis quotient, LQ greater than or equal to 90) and sexually refractory females (LQ less than or equal to 20). In control rats, short-term steroid treatment (5 weeks) decreased dopamine (DA) and dihydroxyphenylacetic acid (Dopac) concentrations in the median eminence (ME) and induced good sexual behavior. Interestingly, a similar pattern of decreases in DA and Dopac levels of ME was observed in those long-term-treated rats displaying good sexual behavior but not in the sexually refractory females. Further, a significant increase in DA concentration in the preoptic-anterior hypothalamic area of the sexually refractory females was observed. These data are interpreted to suggest that severe and chronic elevations in circulating levels of prolactin, induced by chronic ovarian steroid treatment, are not universally associated with a disruption of sexual behavior and increased dopaminergic function in the ME, seen in females with normal sexual behavior, was conspicuously absent in female rats that became refractory to the sexual-behavior-inducing effects of ovarian steroids.

Animals↗
PubMed1986

A decline in endogenous opioid influence during the steroid-induced hypersecretion of luteinizing hormone in the rat.

Studies were undertaken to evaluate the influence of endogenous opioid peptides (EOP) on the LH hypersecretion induced in ovariectomized rats by estradiol benzoate (EB) or EB plus progesterone (EBP). Naloxone (0.1-15.0 mg/kg) was injected before (1200 h) and during (1400 and 1530 h) the LH surge induced by EBP treatment and during the LH surge after EB treatment (1600 h). The opiate antagonist readily stimulated LH secretion before the LH surge in EBP-treated rats at 1200 h and during the LH surge in EB-treated rats at 1600 h, but was much less effective during the LH hypersecretion induced by EBP treatment at 1400 and 1530 h. This decline in the LH secretory response to naloxone during the EBP-induced LH surge was not due to changes in the response of pituitary to LHRH. These studies indicate that during the period of LH hypersecretion induced by the sequential administration of EB plus P, the influence of EOP neuronal systems on LH secretion is diminished. Thus, EOP neurons may play a role in the timing and magnitude of the LH surge in EBP-treated rats.

Animals↗
PubMed1986

The influence of chronic morphine treatment on the negative feedback regulation of gonadotropin secretion by gonadal steroids.

The influence of continuous stimulation of opiate receptors with morphine (M) on the negative feedback effects of testosterone (T), 5 alpha-dihydrotestosterone (DHT), and 17 beta-estradiol (E2) on LH and FSH secretion was studied in rats that had been castrated 2 weeks previously. In the absence of gonadal steroids, 4 days of continuous M exposure did not alter LH or FSH levels. Similarly, Silastic capsules containing crystalline T (5 mm) or E2 [5 mm long (75 micrograms E2/ml) to 7.5 mm long (300 micrograms E2/ml)] alone had little effect on LH or FSH release. However, in M-exposed rats, T reduced serum LH by greater than 90%, and E2 reduced LH by more than 75%. Among the doses of DHT evaluated, only the highest dose (7.5-mm Silastic capsules packed with crystalline DHT) reduced LH secretion, and M exposure only slightly enhanced this suppression. M or gonadal steroids alone produced little change in FSH levels in castrated rats. However, the combination of M plus E2 or DHT further reduced FSH levels. Evaluation of pituitary responses to LHRH revealed that when administered alone, T did not alter, DHT reduced, and E2 enhanced the LH response to the decapeptide. Neither M treatment alone nor M plus T or DHT altered the pituitary LH response to LHRH. On the other hand, M appeared to enhance the stimulatory effects of E2 on pituitary responsiveness to LHRH. These findings suggest that the interaction of M and gonadal steroids at the level of the pituitary could not explain the observed marked suppression of gonadotropin secretion by suboptimal T or E2 during opiate receptor stimulation with M. Collectively, these observations are in accord with the view that endogenous opioid peptides may play a role in modulating the sensitivity of the hypothalamus to the negative feedback effects of gonadal steroids.

Animals↗
PubMed1985

Changes in anterior pituitary hormone secretion and hypothalamic catecholamine metabolism during morphine withdrawal in the female rat.

Studies were undertaken to evaluate the acute responses of hypothalamic noradrenergic and dopaminergic neurons and anterior pituitary hormones to naloxone (NAL)-precipitated morphine (MOR) withdrawal in the rat. Ovariectomized female rats were rendered MOR-dependent and injected with NAL (1 mg/kg b.w., s.c.). During precipitated MOR withdrawal, a decline in norepinephrine (NE) concentrations was preceded by an increase in the level of its metabolite normetanephrine (NME) in the medial basal hypothalamus (MBH) as well as the preoptic area-anterior hypothalamus (POA-AH). Both dopamine (DA) and its major acid metabolite, dihydroxyphenylacetic acid (DOPAC), showed increased concentrations in these two hypothalamic regions within 30 min of NAL administration. Elevated luteinizing hormone (LH) and beta-endorphin secretion was evident within 5 min of NAL injection to MOR-dependent rats, while serum prolactin (PRL) increased 15 min into MOR withdrawal. Both growth hormone (GH) and thyroid-stimulating hormone (TSH) were depressed over the course of MOR withdrawal. Although a cause and effect relationship cannot be established, during NAL-precipitated MOR withdrawal, a heightened hypothalamic monoaminergic neuronal activity is accompanied by a differential response of anterior pituitary hormones. The observed responses, which are similar to those seen during acute stress, indicate that MOR withdrawal may activate the same mechanisms which mediate the neuroendocrine response to stress.

Animals↗
PubMed1985

Direct evidence for brain-specific release of dopamine from a redox delivery system.

Dopamine (1) was transformed into a lipoidal redox chemical delivery system which crosses the blood brain barrier and is converted to a quaternary ammonium precursor of 1, thus "locking in" this ionized moiety. Systemic administration of this chemical delivery system for 1 increased concentrations of the major acid metabolite of 1, dihydroxyphenylacetic acid, (6) in several brain regions, and despite sustained inhibition of prolactin secretion, concentrations of 1 were unchanged. Inhibition of monoamine oxidase did not encourage the formation of 1 from this delivery system. When de novo synthesis of 1 was inhibited, however, regional brain concentrations of both 1 and dihydroxyphenylacetic acid acid were increased by systemic administration of the delivery system. This study provides direct evidence for the brain-specific delivery of 1 by a redox chemical delivery system and indicates that the 1 formed is delivered to sites which normally store newly biosynthesized 1.

Animals↗
PubMed1985

Chronic morphine treatment induces hypersensitivity to testosterone-negative feedback in castrated male rats.

Studies were undertaken to determine the effects of chronic stimulation of opiate receptors on the negative feedback effects of testosterone (T) on luteinizing hormone (LH) secretion in the male rat. In an initial study, castrated male rats received replacement levels of T (2 ng/ml) or chronic morphine (M) treatment for 7 days. When initiated at the time of castration, both T and M treatments prevented the castration-induced hypersecretion of LH. However, when the treatments commenced 2 weeks after castration, only T restored LH secretion to the low levels seen in intact rats. In a second study, rats castrated 2 weeks previously were exposed to chronic M or placebo (control) treatment in the presence of various dosages of T. In rats receiving T alone, LH secretion was unaffected at T levels up to 600 pg/ml serum, but thereafter there was a dose-dependent suppression of LH release by T. Serum T levels which reduced LH secretion by 50% were estimated to be 966 pg/ml. In contrast, in castrated rats receiving both M and T treatment, a 50% reduction in LH secretion was estimated to be at 300 pg T/ml serum and maximal inhibition of LH secretion was achieved at serum T levels of greater than 600 pg/ml. Neither T alone nor M plus T treatment altered the responsiveness of the anterior pituitary to LHRH in vitro. These findings indicate that M may enhance the sensitivity of the hypothalamus to T feedback by approximately 3-fold and raise the possibility of the existence of an opioid-sensitive neural component which may modulate the negative feedback effects of T on LH secretion.

Animals↗
PubMed1985

Effects of naloxone on catecholamine and LHRH release from the perifused hypothalamus of the steroid-primed rat.

The purpose of the present investigation was to determine the effects of naloxone on LHRH and catecholamine release from preoptic area-medial basal hypothalamic (POA-MBH) fragments in vitro. Ovariectomized rats were treated with estradiol benzoate, followed 2 days later by progesterone. The rats were killed 2 after progesterone administration and the POA-MBH dissected out and incubated in a perifusion system. After preincubation, medium with or without naloxone (1 mg/ml) was infused into the perifusion chambers and LHRH, norepinephrine, epinephrine and dopamine release were monitored. Naloxone concurrently released LHRH and the three catecholamines during the entire perifusion period. LHRH and catecholamine output returned to the control range within 30-45 min after cessation of naloxone infusion. These data show that naloxone can promptly stimulate catecholamine release and concur with the view that LH release evoked by naloxone in vivo may be due to hypersecretion of LHRH and they further raise the possibility that norepinephrine and epinephrine released in the vicinity of peptidergic neurons in the POA-MBH may participate in LHRH hypersecretion.

Animals↗
PubMed1985

Effects of prenatal exposure to tricyclic antidepressants on adrenergic responses in progeny.

Studies were undertaken to examine the effects on cardiovascular function in progeny of rats treated maternally with the tricyclic antidepressants, doxepin and imipramine. Doxepin was administered once daily during the first trimester (days 1-7), second trimester (days 8-14) or third trimester (days 15-21) of pregnancy, while imipramine was administered during the third trimester only. Exposure to doxepin during the first or second trimester increased infant mortality rate, while third trimester exposure to imipramine, but not doxepin, enhanced infant mortality. Additionally, third trimester imipramine, but not doxepin, exposure reduced birth weight and growth rate of progeny. Tests of cardiac and aortic response to adrenergic stimulation revealed that third trimester exposure to either of these tricyclic antidepressants enhance the responsiveness of the beta-adrenergic system in the aorta, while doxepin exposure during the other trimesters was without effect on aortic beta-response. Prenatal exposure to these antidepressants did not alter blood pressure or the contractile response of aortic tissues to alpha-receptor stimulation. Collectively, these studies reveal that at doses of tricyclic antidepressants which do not cause dysmorphic effects on the fetus, subtle alterations occur in selective adrenergic functions which can persist into adulthood in the rat.

Animals↗
PubMed1984

Chronic hyperprolactinemia causes progressive changes in hypothalamic dopaminergic and noradrenergic neurons.

Studies were undertaken to evaluate the effects of chronic hyperprolactinemia (HYP) on catecholamine concentrations and turnover rates in brain regions of the female rat. HYP was induced by inoculation of tissue derived from the prolactin secreting MtTW15 tumor. When serum prolactin (PRL) levels were moderately elevated, medial basal hypothalamus (MBH) dopamine (DA) turnover was enhanced and DA concentrations were moderately reduced. Later, as serum PRL levels increased to greater than 10 micrograms/ml, DA concentrations were further reduced and DA turnover was concomitantly reduced to below pre-tumor levels. In the preoptic area-anterior hypothalamus (POA-AH), DA concentrations were reduced as PRL levels increased and this was associated with a reduction in DA turnover. Between 5 and 8 weeks of tumor growth, DA turnover remained low, but DA concentrations increased. In the neurointermediate lobe of the pituitary (NIL) the tumor reduced DA turnover at 5 weeks only. Norepinephrine (NE) turnover, but not concentration, was reduced in both the POA-AH and MBH. Surgical removal of the tumor at 5 weeks of growth reduced serum PRL levels to near normal, but MBH DA concentrations and turnover remained depressed while POA-AH and NIL DA levels and turnover increased. Despite removal of the tumor, NE turnover remained depressed in both the MBH and POA-AH. These studies indicate that severe chronic HYP causes progressive alterations in hypothalamic catecholamine neurons which are not reversed by normalization of serum PRL levels. These results suggest that chronic HYP can cause long-lasting effects on some DA and NE neuronal systems.

Animals↗