Biomedical subjects

J W Simpkins

Publications and source records attributed to J W Simpkins.

At least 127 records · Page 7Linked to original sources

PubMed1984

Age-related alterations in dopamine and norepinephrine activity within microdissected brain regions of ovariectomized Long Evans rats.

The ability of several stimuli which augment central catecholamine (CA) neuronal activity to reinitiate estrous cycles in old constant estrous (CE) rats suggests CA neuronal function is impaired with advanced age. We examined the effects of age on dopamine (DA) and norepinephrine (NE) levels and turnover rates within microdissected brain regions of previously normally cycling young (3-4 months old) and middle-aged (10 months old) and CE old (20-22 months old) Long Evans 2 weeks after ovariectomy. Steady-state DA concentrations were significantly decreased in old compared to young rats in the nucleus accumbens (34%), anterior hypothalamic nucleus (54%, NHA ), neurointermediate pituitary lobe (51%, NIL) and median eminence (74%, ME). The rate constant of DA loss, an estimate of neuronal activity, decreased in old versus young rats only in the preoptic area suprachiasmatica (60%, POAs ) and NHA (60%) and was unchanged or augmented in the 7 other regions. In contrast, a decline in DA turnover rate of 29-67% was observed in 6 of 9 regions in middle-aged rats and 45-81% in 5 of 9 regions in old rats. Steady-state NE concentrations similarly were significantly decreased in old versus young rats in the POAs (54%), medial forebrain bundle (44%), nucleus suprachiasmatica (49%) and ME (59%). The rate constant of NE loss progressively decreased with increasing age only in the POAs and was unchanged or augmented in other regions. Turnover rate of NE was decreased from 21 to 98% in 4 of 8 regions from old animals. A strong positive correlation was noted between the rate constant of NE (but not DA) loss measured in young rats and the magnitude of the age-related depletion in NE concentrations within specific brain regions. Collectively these data indicate that with increasing age: CA neuronal function is differentially altered in nuclei located along the preoptico-tuberal pathway; substantial declines in both DA and NE concentrations are the primary contributor to the reduced amine turnover noted in several of these regions; and the observed age-related alterations in CA turnover may contribute to impaired LH response and the persistent hyperprolactinemia in old CE rats.

Aging↗

PubMed1984

Age-related alteration in catecholamine activity within microdissected brain regions of ovariectomized Fischer 344 rats.

The effects of increasing age on catecholamine (CA) metabolism in microdissected brain regions and on serum and pituitary hormone levels were examined in ovariectomized Fischer 344 rats. Young (4 to 5 months old) and middle-aged (9 to 10 months old) normally cycling and old repeated pseudopregnant rats (21-22 months old, PP) were ovariectomized to eliminate the complicating effects of cyclic gonadal steroid fluctuations. CA metabolism was examined 2 weeks later. To determine CA turnover rates, each age-group was subdivided into three groups, which were killed by decapitation 0, 45, or 90 min after administration of alpha-methyl-para-tyrosine (alpha-mpt). Dopamine (DA) and norepinephrine (NE) concentrations were determined in microdissected brain regions by radioenzymatic assay, and turnover rates were estimated. Steady-state concentrations of NE were not altered in middle-aged rats, but NE turnover rates increased in middle-aged rats in five of the six areas examined. While NE concentrations did not change with age in the median eminence (ME), NE turnover rates increased significantly in the two older age groups. These data indicate that the age-related decline in NE concentrations in several ventral diencephalic nuclei is preceded by a period of hyperactivity in noradrenergic neurons. DA concentrations were generally decreased in most areas examined in old versus young rats, with dramatic DA depletions (42-78%) observed in five regions. However, no consistent relationship between DA concentrations and turnover rates was seen either in regions with stable DA levels or in those which showed an age-associated decrease in DA concentrations. In the ME, a 42% decline in DA concentration was associated with an increase in the DA turnover rate in the oldest group of rats. Serum luteinizing hormone (LH) levels were similar in all three age groups of ovariectomized rats, while serum prolactin was elevated four-fold in old compared to younger animals. These data indicate that a complex pattern of regional alterations in CA metabolism accompanies the aging process and these may be related to the pseudopregnant state and hormone secretory capacity of aging Fischer 344 rats.

Age Factors↗

PubMed1984

Cerebral and blood pharmacokinetics of imipramine and its active metabolites in the pregnant rat.

A single IP dose of imipramine (IMI) was administered to pregnant rats. Whole blood, plasma, and brain concentrations of IMI, desipramine (DMI), and their 2-hydroxylated metabolites were separated by high-pressure liquid chromatography and quantified by fluorescence detection. IMI and DMI rapidly appeared in brain tissue in concentrations greatly exceeding those in whole blood and plasma. The much higher concentration and longer persistence of DMI in brain compared to IMI suggests that the predominant central effects from administered IMI result from biotransformation to DMI. The metabolite: "parent" area under the curve ratios for the hydroxylated metabolites indicate that their contribution to the pharmacologic effects of IMI and DMI are probably negligible.

Animals↗

PubMed1984

Regional changes in monoamine metabolism in the aging constant estrous rat.

Studies were undertaken to determine levels of monoamines and their metabolites in brain regions in young (3-4 months) normally cycling and old (25-26 month) constant estrous female rats. Dopamine (DA) concentrations were reduced in old rats in the median eminence (ME), medial basal hypothalamus (MBH), preoptic area-anterior hypothalamus (POA-AH) and the striatum. Similarly, concentrations of dihydroxyphenylacetic acid (DOPAC), the major acid metabolite of DA, were reduced significantly in all 4 regions. In the ME, a strong positive correlation was observed between DA and DOPAC concentrations in both young and old rats. Concentrations of norepinephrine (NE) were reduced in old rats in the MBH and POA-AH but not in the ME or striatum. Concentrations of serotonin (5HT) and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA) were generally unchanged with age in all of the regions examined. These studies indicate the age-related regional alterations in DA and 5HT metabolism can be monitored by methods which quantitate monoamines and their metabolites.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

The effects of chronic naloxone on pituitary hormone secretion in female rats.

The effects of a sustained-release implant for naloxone (NAL) on serum concentrations of prolactin (PRL), immunoreactive beta-endorphin (IR-beta-ENDO), growth hormone (GH) and thyroid stimulating hormone (TSH) were evaluated in ovariectomized female rats. After 9 days of exposure to NAL, serum levels of none of these 4 pituitary hormones were altered. However, the NAL implant antagonized the stimulatory effects of morphine (15 and 30 mg/kg body weight) on PRL and IR-beta-ENDO secretion, enhanced the stimulatory effects of morphine on GH secretion, and had no effect on morphine-induced suppression of TSH secretion. These results indicate that while chronic NAL exposure does not, by itself, persistently alter pituitary hormone secretion, it differentially effects the response of these hormones to morphine exposure. These data suggest that chronic treatment with narcotic antagonists may invoke differential compensatory mechanisms to maintain normal hormone secretion.

Animals↗

PubMed1984

Spontaneous skin flushing episodes in the aging female rat.

It is well known that with the loss of gonadal function most women experience hot flushes, characterized by a rapid regional increase in cutaneous blood flow. Animal models for this vasomotor syndrome have been elusive, thus hampering efforts to evaluate the endocrine and neuronal substrates of the hot flush. In this report, evidence is reported for the occurrence in aging female rats of spontaneous tail skin temperature (TST) fluctuations which are similar in amplitude, duration and frequency to hot flushes reported for peri-menopausal women. Paradoxically, these TST pulses occur in animals with senescent reproductive states in which serum estrogen levels are moderately elevated and ovariectomy eliminates these rat flushing episodes. This demonstration of steroid-dependent, spontaneous flushing episodes indicates that the aging female rat can be used to evaluate the neuronal and hormonal basis of vasomotor instability.

Age Factors↗

PubMed1984

Testosterone raises LHRH levels exclusively in the median eminence of castrated rats.

Although LHRH is widely distributed in the diencephalon, previous studies show that testosterone (T) treatment for 72-96 h of castrated male rats raised LHRH levels only in the medial basal hypothalamus. In the present study, LHRH concentrations were analyzed in microdissected brain regions shown to contain LHRH perikarya and their projections to identify the discrete regions which may display this T-dependent accumulation of luteinizing hormone-releasing hormone (LHRH) and to study the temporal sequence of LHRH changes in those regions. Rats were killed at 12-hour intervals from 60 to 96 h after subcutaneous implantation of Silastic capsules containing T. Results showed that the physiological range of serum T levels attained by these implants suppressed LH release at all times, however, there was no immediate effect on LHRH concentrations in any region. In fact, out of the 9 regions in the preoptic-tuberal pathway examined, 8 regions displayed no change in LHRH concentrations at any time. On the other hand, for up to 84 h, LHRH concentrations in the median eminence region remained unchanged; an additional 12 h of T exposure significantly raised LHRH levels. These results suggest that this T-dependent accumulation of LHRH may arise either by de novo synthesis or by increase in the rate of processing of the precursor LHRH protein into the immunoreactive form within nerve terminals in the median eminence.

Animals↗

PubMed1984

Evidence that chronic hyperprolactinemia effects skin temperature regulation through an opioid mechanism.

Studies were undertaken to evaluate the effects of chronic hyperprolactinemia (HYP) induced by the MtTW15 tumor on the thermoregulatory response of female rats to blockade of opiate receptors with naloxone. Both chronic administration of morphine and HYP cause a mild hyperthermia as evidenced by a 0.8-1.0 degrees C elevation in rectal temperature (Tr). Naloxone-precipitated morphine withdrawal caused a prompt increase (4.9 +/- 0.76 degrees C) in tail skin temperature (TST) and a subsequent decline in Tr (-2.8 degrees C). Similarly, naloxone administration to HYP rats caused a dramatic TST response which was coincident with the onset of severe HYP. This effect of naloxone was maximal at 7 weeks of tumor growth when a TST response of 4.8 +/- 0.3 degrees C was observed but was not evident prior to or 1 week following tumor inoculation, when serum prolactin levels were low. The TST response to naloxone in chronic HYP exhibited distinct pulses with an amplitude of 3.4 +/- 0.4 degrees C and a frequency of 2.2 +/- 0.5 pulses per 120 min. It appears that blockade of opiate receptors in HYP rats induces instability in the regulation of skin temperature as evident by recurrent episodes of TST surges. These effects of chronic HYP on the TST response to naloxone were not influenced by ovariectomy, suggesting that changes in ovarian secretions were not involved in the response. At 4 weeks of tumor growth, immunoreactive beta-endorphin concentrations in the medial basal hypothalamus, preoptic area-anterior hypothalamus and the neurointermediate lobe of the pituitary were decreased by 59, 28 and 47%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

A rapid, quantitative in vivo assay for narcotic antagonists.

Tail skin temperature (TST) response of morphine-dependent rats was evaluated as a potential in vivo assay for the activity of narcotic antagonists. Dependency was produced in rats by repeated subcutaneous implantation of morphine-containing pellets and TST was evaluated by thermistor probes attached to the dorsal surface of the tail. TST was determined prior to and following administration of either naloxone (NAL: 0, 0.01, 0.1, 0.5 or 1.0 mg/kg body weight); naltrexone (NALT: 0.001, 0.005, 0.01, 0.02 or 0.1 mg/kg body weight); or 6-Desoxy-6-methylenenaltrexone (DM-NALT: 0.001, 0.005, 0.01, 0.02 or 0.1 mg/kg body weight). Each of the narcotic antagonists caused a dose-dependent increase in tail skin temperature in morphine dependent rats. The initial TST increase was observed by 5 minutes and the maximal TST response occurred 15 to 25 minutes after drug administration. For each drug evaluated, a linear relationship was observed between the dose and maximal change in TST and between the dose and the area under the TST response curve. Determination of ED50 for the TST response revealed the expected relative potency for the narcotic antagonists evaluated: DM-NALT greater than NALT greater than NAL. Thus, the TST-response test is a rapid and quantitative bioassay for the evaluation of compounds for narcotic antagonistic activity.

Animals↗

PubMed1983

Depletion of tuberoinfundibular dopamine does not restore gonadotropin secretion in ovariectomized hyperprolactinemic rats.

The effect of depleting tuberoinfundibular dopamine (TIDA) on gonadotropin secretion was studied in rats made hyperprolactinemic by implantation of the prolactin and growth hormone secreting Furth MtTW15 tumor. Implants of the pituitary tumor prevented gonadotropin release in response to castration. Daily injection of 100 mg dl-alpha-methyl-para-tyrosine/kg bw which reduced TIDA levels in tumor bearing rats more than 90% did not restore gonadotropin release. It seems likely that the increased activity of the TIDA system does not mediate the suppression of gonadotropins during chronic hyperprolactinemia.

Animals↗

PubMed1983

Redox delivery system for brain-specific, sustained release of dopamine.

Dopamine was transformed into a redox chemical system for delivery to the brain. The lipoidal form allowed penetration of the blood-brain barrier. Oxidative and hydrolytic processes then transformed the delivery form into a quaternary ammonium precursor of dopamine. The quaternary ammonium precursor was rapidly eliminated from the general circulation, whereas that formed in the brain was locked in, thereby providing a significant and sustained brain-specific dopaminergic activity.

Animals↗

PubMed1983

Similarities between morphine withdrawal in the rat and the menopausal hot flush.

Skin temperature, cardiovascular and neuroendocrine responses to morphine withdrawal in the rat were evaluated in an effort to develop a potential animal model for the menopausal hot flush in women. Morphine dependency was produced by s.c. implantation of pellets containing morphine alkaloid. In response to precipitous, naloxone-induced withdrawal, rats showed surges in tail skin temperature (TST) which were similar in magnitude (4.8 to 7.2 degrees C) and duration (60 to 90 min.) to peripheral skin temperature increases reported during menopausal hot flushes. Additionally, a brief period of accelerated heart rate (59%) and a 9-fold hypersecretion of luteinizing hormone (LH) preceded the TST response to morphine withdrawal. These cardiovascular and neuroendocrine responses are observed to precede or coincide with the menopausal hot flush. Additionally, protracted morphine withdrawal subsequent to abstention, resulted in TST instability characterized by spontaneous, high amplitude TST fluctuations. Thus, the alteration in skin temperature, heart rate and LH secretion during precipitated morphine withdrawal in the rat are similar in magnitude, duration and in their temporal relationship to those observed during the hot flush. These data suggest a possible opioid etiology in this vasomotor disturbance. Acute withdrawal in the morphine addicted rats may serve as an animal model by which to study the neural mechanism underlying the menopausal hot flush.

Animals↗

PubMed1983

Age-related decline in adrenergic responsiveness of the kidney, heart and aorta of male rats.

Studies were undertaken to evaluate the rate of loss in beta-adrenergic responsiveness in the kidney, heart and thoracic aorta in aging male rats. The dipsogenic response to isoproterenol (15 micrograms/kg B.W.) was reduced by 53 and 78% in middle-aged (12 to 13 months) and old (24 to 25 months) versus young (4 to 5 month) rats. In contrast, the drinking response to angiotensin I was unaltered with increasing age, indicating that the decline in B-response was not due to an alteration in the processing of or response to angiotensin. The chronotropic response of the heart to isoproterenol (5 micrograms/kg B.W.) was only moderately decreased by middle-age but was reduced by 69% in old versus young rats. Similarly, the isoproterenol-induced relaxation of aortic rings, in vitro was unchanged at 12 to 13 months of age but was severely diminished at 24 to 25 months of age. Thus the decline in beta-adrenergic responsiveness which accompanies the aging process appears to occur at different rates in several peripheral tissues. In vitro, aortic rings exhibited an age-related decline in contractile response to increasing dose of potassium chloride (KCL) and norepinephrine (NE). Maximum contractility in response to KCl was reduced by middle-age and declined further by 24 to 25 months of age. Similarly, the contractile response of aortic rings to low doses of NE (5 X 10(-10) and 1 X 10(-9)M) was significantly reduced at both middle and old age. Thus, both alpha-adrenoceptor mediated as well as non-receptor mediated aortic contractility are reduced progressively with increasing post-maturational age.

Age Factors↗

PubMed1983

Effects of chronic hyperprolactinaemia on experimentally induced thirsts in male rats.

Chronic hyperprolactinaemia was induced in ten male Wistar rats by subcutaneous injection of tissue fragments of the MtTW 15 prolactin-secreting adenoma. Serum prolactin was elevated significantly by 3 weeks after adenoma inoculation and increased progressively thereafter. An additional ten Wister-Furth rats were inoculated with the MtTW 15 adenoma and an equal number of age-matched controls were used to evaluate the drinking response to several dipsogenic agents. The hyperprolactinaemic rats consumed twice as much water as did control rats over a 24 hr period. Administration of the beta-adrenergic agonist, isoprenaline (25 micrograms/kg, s.c.), resulted in a similar increase in water intake in both groups prior to an elevation in serum prolactin. However, as serum prolactin increased there was a corresponding significantly attenuated dipsogenic response to isoprenaline. Chronic hyperprolactinaemia did not alter the drinking response to angiotensin II (200 micrograms/kg, s.c.), to 24 hr of dehydration or to administration of hypertonic (1 M) saline. These results indicate that chronic hyperprolactinaemia selectively attenuates the dipsogenic response to beta-adrenergic stimulation and support an involvement of prolactin in modifying the responsiveness of the beta-adrenergic system.

Adenoma↗

PubMed1983

Effects of a sustained-release naloxone pellet on luteinizing hormone secretion in female rats.

Studies were undertaken to develop a naloxone implant capable of chronically blocking opioid receptors for several weeks in an effort to evaluate the effect of this prolonged narcotic antagonism on luteinizing hormone (LH) secretion in female rats. Antagonism of opiate receptors was achieved with a tablet formulation which contained 75 mg naloxone free base and a high content of the insoluble binding material, Mg stearate. Subcutaneous placement of this implant prevented morphine-induced analgesia for 2 weeks and antagonized the LH suppressory effects of morphine (15 or 30 mg/kg) administration. Thus, this naloxone delivery system is capable of chronically occupying the opioid receptors which mediate morphine's effects on analgesia and LH secretion. Despite this, the naloxone pellet only moderately enhanced the initial rate of increase in LH secretion following ovariectomy (day 1) and was ineffective in further augmenting LH secretion at 3 and 7 days after implantation. In rats which were ovariectomized and implanted immediately with estradiol-containing Silastic capsules, the naloxone pellet was ineffective in altering LH secretion 1, 3 or 7 days later. Thus, while chronic exposure to naloxone persistently antagonizes the pharmacologic actions of morphine, the naloxone pellet only transiently blocked the tonic inhibitory effect of endogenous opioid peptides. The mechanism by which the LH secretory effects of naloxone are lost following chronic exposure to the antagonist are at present unknown, but may involve the activation of compensatory mechanisms which are inhibitory to LH secretion.

Analgesics, Opioid↗

PubMed1983

Variable effects of testosterone on dopamine activity in several microdissected regions in the preoptic area and medial basal hypothalamus.

We have observed previously that systemic treatments or local implants of testosterone (T) suppress dopamine (DA) turnover in the preoptic area-anterior hypothalamus of male rats. In the present study, we sought to identify discrete regions innervated by the incertohypothalamic DA system and the tuberoinfundibular DA system which respond to T replacement. Adult male rats were orchidectomized and immediately treated with either empty (controls) or T-containing Silastic implants. After 14 days, animals from each group were treated with alpha-methylparatyrosine and killed 0, 45, and 90 min later for analysis of DA turnover in eight microdissected brain regions. The T implants produced an increase in serum T and 5 alpha-dihydrotestosterone and reduced serum LH to concentrations observed in intact male rats without affecting serum PRL levels. Serum levels of T within the physiological range caused a profound decrease in the DA turnover rate in the medical preoptic nuclei and anterior hypothalamic nuclei without influencing DA activity in the periventricular nuclei, the site of perikarya for these DA projections. In contrast, DA turnover in the median eminence was increased 3-fold by T treatment, while DA activity in the arcuate nuclei, the locus of cell bodies of the tuberoinfundibular DA system, was not affected. These studies reveal disparate effects of T on the terminal fields of the two DA systems. While augmentation in the median eminence DA activity may participate in the negative feedback effects of T on gonadotropin secretion, the T-induced suppression of DA turnover in the medial preoptic nuclei and anterior hypothalamic nuclei may well be involved in androgen-dependent aggression and copulatory behavior.

Animals↗

PubMed1983

Cysteamine depletes prolactin in young and old hyperprolactinemic rats.

Studies were undertaken to evaluate the effects of cysteamine on serum and anterior pituitary concentrations of prolactin in hyperprolactinemic female rats. Serum prolactin was elevated in young (4 to 5 months old) rats by implantation of 17 beta-estradiol while 26- to 28-month-old rats were in constant estrus and exhibited an age-related hyperprolactinemia. At 4 h after treatment with cysteamine (90 mg/kg body wt) serum and anterior pituitary prolactin concentrations were reduced in young animals by 98 and 85%, respectively. In old constant-estrous rats, cysteamine reduced serum prolactin by 92% and anterior pituitary prolactin by 82%. In young pseudopregnant rats, cysteamine induced a prompt resumption of estrous cycles. These studies indicate that cysteamine is an effective depletor of serum and pituitary prolactin in hyperprolactinemic rats.

Aging↗

PubMed1983

Modulation of endogenous opioid influence on luteinizing hormone secretion by progesterone and estrogen.

Studies were undertaken using the opiate receptor antagonist naloxone (NAL) to evaluate the relative influence of endogenous opioid peptides (EOP) on LH secretion in cycling and ovariectomized, steroid-treated adult rats. Intact animals received NAL (2 mg/kg, sc) or saline (control vehicle) at 0800 and 1400 h on estrus, 0800 h on diestrus day 1,2000 h on diestrus day 2, and before (at 0800, 1200, and 1400 h) and during the preovulatory LH surge (at 1600 and 1800 h) on proestrus. NAL stimulated LH release by 2- to 3-fold at all stages of the estrous cycle, including during the proestrous gonadotropin surge. Ovariectomized rats were treated with estradiol benzoate (EB; 7.5 micrograms/rat, sc) and 2 days later received NAL (2 mg/kg, sc) or saline at 1000, 1200, 1400, 1600, and 2000 h. NAL induced a relatively small (44-73%), but significant, increase in LH release before (1000, 1200, and 1400 h), during (1600 h), and after (2000 h) the afternoon LH rise. While progesterone (P) treatment (5 mg, sc, day 2 at 1000 h) of EB-primed ovariectomized rats augmented NAL-induced LH release before the LH surge (1200 h), it abolished the LH secretory response to NAL during the LH surge (1400, 1600, and 1800 h). The NAL-induced LH response returned after the LH surge at 2000 h. Likewise, administration of P on proestrus morning (0900 h) abolished the LH secretory response to NAL during the LH surge. These studies indicate that central opioid neurons participate in the tonic inhibition of LH secretion at all stages of the estrous cycle of the rat. The ability of exogenous P to advance and amplify the LH surge on proestrus and in EB-primed ovariectomized rats appears to result in part from a reduction in the EOP inhibitory influence on LH secretion and may indicate a role for EOP in mediating the stimulatory effects of endogenous steroids on LH secretion in the female rat.

Animals↗