Biomedical subjects

C L Bethea

Publications and source records attributed to C L Bethea.

At least 37 records · Page 2Linked to original sources

PubMed1997

Lack of ovarian steroid hormone regulation of norepinephrine transporter mRNA expression in the non-human primate locus coeruleus.

Decreases in ovarian steroids can negatively affect mood, and drugs which block the norepinephrine transporter (NET) or the serotonin transporter (SERT) alleviate depression. However, the respective contribution of the noradrenergic and serotonergic systems may vary depending upon the etiology of the depression. We previously demonstrated that E and P alter gene expression for tryptophan hydroxylase (TPH) and for the serotonin reuptake transporter (SERT) in raphe neurons of the rhesus monkey. In this study, we questioned whether the noradrenergic system contributes to depression related to the reproductive function in women, using a non-human primate model of the menstrual cycle. The effect of estrogen (E) or E plus progesterone (P) on the expression of the NET gene in the locus coeruleus (LC) was examined with in situ hybridization for NET mRNA. In addition, we questioned whether the neurons of the LC contain nuclear E or P receptors (ER/PR). Hence, immunocytochemistry for ER and PR were performed on adjacent sections. Treatment groups consisted of monkeys (n = 4 per treatment) which were ovariectomized/hysterectomized (spayed), E-treated (28 days) and E+P-treated (14 days E, +14 days E+P). Expression of mRNA for NET was unchanged at any level of the LC due to steroid treatment (p > .05). Neither ER nor PR were detected in the LC of any treatment group. Therefore, E and P in a treatment paradigm which mimics the menstrual cycle do not directly regulate NET mRNA expression in the non-human primate LC. In addition, the noradrenergic neurons of the primate LC lack nuclear receptors for ovarian steroids. These data suggest that the noradrenergic system may not contribute significantly to depression related to changes in ovarian hormones.

Animals↗

PubMed1997

RU 486 blocks and fluoxetine augments progesterone-induced prolactin secretion in monkeys.

Progesterone (P) stimulates prolactin secretion through an unknown neural mechanism in estrogen (E)-primed female monkeys. Serotonin also stimulates prolactin secretion and this laboratory demonstrated that E induces nuclear progestin receptors (PR) in serotonin neurons. Thus, PR in serotonin neurons could transduce the action of P on prolactin secretion. Studies were performed to determine (1) whether blocking nuclear PR would block P-induced prolactin secretion and conversely; (2) whether increasing serotonin concentrations in the synapse would augment P-induced prolactin secretion. In both studies, female monkeys were spayed, adapted to a vest and tether remote sampling system and catheterized prior to experiments. Monkeys received 2 E-filled silastic implants (3.0 cm) 1-3 weeks prior to study. P (20 mg) in corn oil was injected (s.c.) to transiently increase prolactin secretion. In both studies, each monkey served as its own control. To block nuclear PR and not membrane PR, RU 486 (2 mg/kg, i.m.) or ethanol (control) was administered with the P injection. Relative to the P injection, blood samples were taken twice daily from -30 to +24 h, then every 4 h from +36 to +48 h and once at +65 h. To increase serotonin in the synapse, the serotonin reuptake inhibitor, fluoxetine (5 mg/day, i.v.), was infused for 4 weeks. P was injected during the week of vehicle infusion and during the last week of fluoxetine infusion. Blood samples were obtained twice daily prior to and following P treatment. Prolactin, E, P and RU 486 concentrations were determined by RIA. RU 486 completely blocked the P-induced prolactin surge (n = 3). In addition, fluoxetine significantly increased prolactin secretion during the P-induced prolactin peak compared to equal time points during saline infusion (n = 5). These data indicate that P induces prolactin via a genomic mechanism and not through a membrane action. The data also support a pivotal role for serotonin in the neural regulation of P-induced prolactin secretion.

Animals↗

PubMed1996

Ovarian steroid regulation of tryptophan hydroxylase mRNA expression in rhesus macaques.

Progesterone (P) stimulates prolactin secretion through an unknown neural mechanism in estrogen (E)-primed female monkeys. Serotonin is a stimulatory neurotransmitter in prolactin regulation, and this laboratory has shown previously that E induces progestin receptors (PR) in serotonin neurons. Therefore, we questioned whether E and/or E+P increased serotonin neural function. The expression of mRNA for tryptophan hydroxylase (TPH) was examined in ovariectomized (spayed) control, E-treated (28 d), and E+P-treated monkeys (14 d E and 14 d E+P) using in situ hybridization and a 249 bp TPH cRNA probe generated with RT-PCR (n = 5 animals/group). Densitometric analysis of film autoradiographs revealed a ninefold increase in TPH mRNA in E-treated macaques compared to spayed animals (p < 0.05). With supplemental P treatment, TPH mRNA signal was increased fivefold over spayed animals (p < 0.05), but was not significantly different compared to E-treated animals. These results were verified by grain counts from photographic emulsion-coated slides. There were significantly higher single-cell levels of TPH mRNA in serotonergic neurons of the dorsal raphe in E- and E+P-treated groups (p < 0.05). These data indicate that E induces TPH gene expression in nonhuman primates and that the addition of P has little additive effect on TPH gene expression. Thus, the action of P on prolactin secretion is probably not mediated at the level of TPH gene transcription. However, because P increases raphe serotonin content in E-primed rodents, the possibility remains that P may have other actions on post-translational processing or enzyme activity.

Animals↗

PubMed1996

Immunohistochemical detection of progestin receptors in hypothalamic beta-endorphin and substance P neurons of steroid-treated monkeys.

Progesterone (P) acts in the central nervous system to increase prolactin secretion in estrogen (E)-primed female monkeys. beta-Endorphin (BE) and Substance P (SP) are two hypothalamic peptides which increase prolactin secretion when administered to rats and monkeys. Studies were performed to determine if P acts on these two potential prolactin-releasing systems. The presence of a nuclear steroid receptor defines the cell as a target for the cognate hormone. Therefore, the hypothalamic populations of BE and SP neurons were examined for the presence and regulation of nuclear progestin receptors (PR) in spayed, E-treated (28 days) and E + P-treated monkeys (14 days E + 14 days E + P). Hypothalamic blocks were prepared after perfusion fixation with 4% paraformaldehyde. Cryosectioning (10 mu m) was followed by double immunocytochemistry (ICC) for PR (black nuclear stain) and either BE or SP (brown cytoplasmic stain). Sections were processed for ICC at 100- or 200-mu m intervals through the hypothalamic block. Peptidergic neurons with and without PR were counted in each section. The E + P-treated monkeys exhibited a significant increase in serum prolactin. BE neurons were found only in the arcuate nucleus (ARC) and median eminence (ME). The colocalization of BE and PR equaled 2% in spayed controls, 21% in the E-treated group and 25% in the E + P-treated group. SP neurons were located in a dorsomedial hypothalamic (DMH) subpopulation which extended caudally under the mamillary nuclei and in a subpopulation located in the ARC and ME. Neither the DMH or submamillary SP neurons contained PR. The percent colocalization of SP and PR in the ARC/ME equaled 5, 26 and 10% in the spayed, E- and E + P-treated groups, respectively. The decrease in PR + SP colocalization with P treatment is probably due to a decrease in SP and not to a decrease in PR immunoreactivity. In summary, E treatment induced PR in BE and SP neurons. Addition of P to the E treatment did not alter the expression of PR in BE neurons, but PR colocalization decreased in SP neurons. Therefore, it is unlikely that SP neurons could transduce the action of P on prolactin secretion in primates, but BE neurons may play an intermediary role.

Animals↗

PubMed1996

Beta-endorphin, but not oxytocin, substance P or vasoactive-intestinal polypeptide, contributes to progesterone-induced prolactin secretion in monkeys.

Progesterone (P) stimulates prolactin secretion through a neural mechanism in estrogen (E)-primed female monkeys. Several peptides, including beta-endorphin (BE), oxytocin (OT), substance P (SP) and vasoactive intestinal polypeptide (VIP) are potential prolactin stimulatory factors and could mediate the effect of P. We hypothesized that the antagonism of a pivotal peptidergic neural system would block P-induced prolactin secretion and that the function of a pivotal peptidergic system would be altered by changes in gonadal steroid concentrations. Therefore it was of interest (1) to examine the effect of infusion of antagonists to these peptides on P-induced prolactin secretion, and (2) to determine BE, OT, SP and VIP levels in the hypothalamus of monkeys of various reproductive states. For the antagonist studies, female monkeys (n = 8) were spayed, adapted to a vest and tether remote sampling system and catheterized prior to antagonist challenges. E-primed monkeys received P injections 48 h prior to antagonist administration. Prolactin increased within 36-48 h of P injection. All antagonist challenges were administered in varying doses during the P-induced prolactin elevation and blood samples were collected every 10 min for prolactin determinations. The opiate antagonist, naloxone (n = 5), reduced serum prolactin in a dose-related manner with a mean IC50 of 1.5 +/- 0.6 micrograms/kg/min. The OT (n = 4), SP (n = 4) or VIP (n = 4) antagonists did not reduce serum prolactin in a dose-related manner. We previously reported that the hypothalamic content of OT is increased by ovarian hormones. To determine whether the hypothalamic content of BE, SP or VIP was related to gonadal status, the peptide levels in 4 hypothalamic regions of monkeys in various physiological states were measured. BE (ng/mg protein) in the medial basal hypothalamus (MBH) was significantly greater in adult females (17.7 +/- 6.9; n = 6) as compared to spayed females (0.6 +/- 0.2; n = 3) and juvenile females (1.8 +/- 1.1; n = 3). Hypothalamic content of SP in the preoptic area and mammillary bodies, but not the MBH, was significantly greater in gonadal intact females than spayed females. VIP content (pg/mg protein) was not significantly different between adult, spayed and juvenile females nor between adult and juvenile males in any hypothalamic area. Taken together these results support a pivotal role for BE in the neural regulation of P-induced prolactin secretion. The involvement of OT, SP, and VIP in a specific manner at the pituitary level is not indicated.

Animals↗

PubMed1996

Steroid regulation of estrogen and progestin receptor messenger ribonucleic acid in monkey hypothalamus and pituitary.

The regulation of estrogen and progestin receptor (ER and PR, respectively) messenger RNA (mRNA) and protein by their cognate hormones was examined in the hypothalamus and pituitary of steroid-treated monkeys. Rhesus macaques (Macaca mulatta) were ovariectomized, hysterectomized (spayed), and implanted with SILASTIC brand capsules containing 17 beta-estradiol (E) or progesterone (P). The spayed control group received empty capsules. The E-treated group received E-filled capsules for 28 days. The E + P-treated animals received an E-filled capsule for 28 days and then a P-filled capsule for the last 14 of the 28 days. Steroid regulation of ER and PR mRNA levels in the hypothalamus and pituitary was examined with in situ hybridization. In the hypothalamus, ER and PR immunodetectable proteins were also examined in nearby sections. In the pituitary, mRNA levels were compared to previous ER and PR protein analysis of identically treated animals. E treatment induced PR mRNA in the medial basal hypothalamus and pituitary. Supplemental P treatment had no effect on PR mRNA levels in the hypothalamus, but markedly reduced PR mRNA in the pituitary. There was excellent agreement with PR protein detection by immunocytochemistry. E treatment had no effect on ER mRNA in the hypothalamus or pituitary. Supplemental P treatment decreased ER mRNA in the ventromedial nucleus, but not in the arcuate nucleus or pituitary. There was agreement between ER mRNA and ER protein in these areas. In summary, there is cell-specific regulation of PR by P in the hypothalamus and pituitary, where P down-regulates PR in the pituitary without affecting ER. However, P has no significant effect on PR expression in the hypothalamus even though P decreases ER in the ventromedial nucleus. Although these observations suggest diverse cell-specific regulatory mechanisms, they are consistent with ER- and PR-mediated physiological events, such as PRL secretion and sexual behavior.

Animals↗

PubMed1995

Insulin-like growth factor I promotes leiomyoma cell growth in vitro.

OBJECTIVE: Our purpose was to determine whether insulin-like growth factors I and II preferentially stimulate uterine leiomyoma cells versus myometrial cells in monolayer culture. STUDY DESIGN: Leiomyomas and normal myometrium were obtained at hysterectomy from five premenopausal women. Specimens were enzymatically digested for use in primary monolayer cell cultures. By use of serum-free media, insulin-like growth factor I or II was added in 1, 10, and 100 ng/ml concentrations to both cell types with the patient serving as her own control. Cell number, prolactin production, and proliferative index values were measured on day 15 of cell culture. RESULTS: Significant increases in cell number were found in the leiomyoma cultures (p < 0.05) treated with 10 and 100 ng/ml insulin-like growth factors I but not with insulin-like growth factors II. Neither factor exerted a stimulatory effect on myometrial cells. CONCLUSION: Insulin-like growth factors I preferentially stimulates leiomyoma cells in monolayer culture. These results suggest an autocrine-paracrine role in vivo for this factor in conjunction with gonadal steroids in promoting leiomyoma growth.

Cell Count↗

PubMed1995

Effects of progesterone on prolactin, hypothalamic beta-endorphin, hypothalamic substance P, and midbrain serotonin in guinea pigs.

Unlike rats, but similar to primates, guinea pigs exhibit prolonged function of the corpus luteum and elevated progesterone secretion after ovulation. The gonadotropins, estrogen (E) and progesterone (P) have been examined throughout the guinea pig estrous cycle. However, neither prolactin secretion nor its regulation by steroid hormones has been characterized, perhaps due to the lack of a specific radioimmunoassay. beta-Endorphin (BE), substance P (SP), and serotonin (5-HT) increase prolactin secretion in rats and monkeys. BE and SP neurons in guinea pigs and 5-HT neurons in monkeys contain progestin receptors which could mediate neuroendocrine effects of steroid hormones. Therefore, the effects of E and P on prolactin, BE, SP, and 5-HT and its metabolite 5-HIAA were examined in guinea pigs which were ovariectomized, E treated (28 days), and E+P treated (14 days E+14 days E+P). The rat NB2 lymphoma cell line was used as a bioassay for serum prolactin. BE and SP levels were measured by radioimmunoassay in four hypothalamic areas: the preoptic region (POA), the mediobasal hypothalamus (MBH), the dorsomedial hypothalamus (DMH), and the mamillary bodies (MB). 5-HT and 5-HIAA were measured in the midbrain raphe area by high-pressure liquid chromatography. E alone had little effect on serum prolactin levels, but E+P significantly increased prolactin as compared with ovariectomized controls. The BE levels increased with E treatment and remained elevated with E+P treatment in MBH and POA. The BE content was stimulated in DMH and MB by E+P treatment and not with E alone. The SP content in MBH, DMH, and MB increased in E-treated guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Steroid regulation of tyrosine hydroxylase messenger ribonucleic acid in dopaminergic subpopulations of monkey hypothalamus.

PRL release in primates can be stimulated by progesterone (P) after estrogen (E) priming. Hypothalamic dopaminergic neurons are a primary inhibitory system of PRL secretion, which differentially express progestin receptors (PR) in a cell-specific manner. Thus, these neurons may be an important target of P for increasing PRL. To further this hypothesis, two studies were performed. First, verification of the subpopulations of dopaminergic neurons that express PR was obtained with a combination of immunocytochemistry for PR and in situ hybridization for tyrosine hydroxylase (TH). Second, the effects of E and E plus P on the expression of TH messenger RNA (mRNA) were examined with in situ hybridization and image analysis in five different subpopulations of dopaminergic neurons. In the first study, dual labeled neurons were found rostrally around the ventral portion of the third ventricle and in more caudal periventricular areas, including the dorsal arcuate nucleus. Little or no PR were observed in TH-positive neurons located in the lateral chiasmatic area, paraventricular nucleus, ventral arcuate nucleus, or the substantia nigra. These results are consistent with our previous observations using double immunocytochemistry. In the second study, there was no significant effect of E or E plus P on single cell levels of TH mRNA in dopaminergic neurons of the subventricular area, periventricular area, or paraventricular nucleus. However, E plus P treatment produced a significant decrease in TH mRNA in the ventral arcuate dopaminergic neurons. There was no effect of E or E plus P in the dorsal arcuate dopaminergic neurons. In conclusion, E plus P decreases the expression of TH mRNA in the ventral arcuate dopaminergic neurons, a subpopulation that rarely expresses PR. The decrease in TH mRNA in the ventral arcuate dopaminergic neurons after E and P treatment is consistent with a role for this subpopulation of tuberoinfundibular neurons in P-induced PRL secretion.

Animals↗

PubMed1994

Cloning of decidual prolactin from rhesus macaque.

Rhesus monkey (Macaca mulatta) decidual prolactin cDNA was cloned and sequenced. The first 210 bp of the monkey sequence is not contiguous to the human pituitary prolactin transcription initiation site. Reverse transcription-polymerase chain reaction (RT-PCR) and Southern analysis confirmed that this 5'-extended prolactin transcript is present in monkey decidua but not in pituitary. Isolation and sequencing of a partial genomic monkey prolactin clone verified the nucleotide changes found in the rhesus cDNA. Comparison of the rhesus decidual prolactin cDNA to the human pituitary cDNA revealed more than 97% homology between the two. These data indicate that monkey prolactin mRNA from the decidualized endometrium of pregnancy contains unique 5' sequence not present in pituitary prolactin mRNA, suggesting the use of an alternative start site. Thus it is likely that the decidua uses promoter and regulatory regions different from those reported for pituitary prolactin.

Animals↗

PubMed1994

Regulation of progestin receptors in raphe neurons of steroid-treated monkeys.

Progesterone increases prolactin secretion in estrogen-primed primates. This action is probably mediated through a neural mechanism since lactotropes do not have progestin receptors (PR). This laboratory recently reported localization of PR in serotonin neurons of female macaques. Since serotonin (5HT) is a putative prolactin stimulatory agent, it was of interest to examine the regulation of PR in this neural system. Spayed monkeys were treated with either (1) an empty silastic capsule; (2) an estrogen (E)-filled capsule for 28 days, or (3) an E-filled capsule for 28 days supplemented with a progesterone (P)-filled capsule for the last 14 of the 28 days. Pontine tissue blocks were obtained at autopsy and processed for immunocytochemistry. Adjacent sections (10 microns) throughout the extent of the raphe nuclei were immunostained for 5HT and PR. 5HT-positive and PR-positive cells were counted in the same area of the dorsal and ventral raphe of adjacent sections at 4 representative levels and the PR/5HT ratio was calculated. The number of 5HT-positive cells was not different in spayed, E- or E+P-treated groups. E-treatment significantly increased the number of PR-positive cells and the PR/5HT ratio in the dorsal and ventral raphe. Supplementary P treatment did not significantly decrease the PR/5HT ratio in these areas. This data suggests that E induces PR in the 5HT neuronal system and that the expression of PR is maintained in the presence of chronically elevated progestin. Thus, the expression of PR in the raphe is consistent with the manner in which P increases prolactin secretion in estrogen-primed primates.

Animals↗

PubMed1994

Search for progestin receptors (PR) in prolactin-releasing peptidergic neurons: oxytocin neurons lack PR, but respond to gonadal steroids in monkeys.

Progesterone (P) increases PRL secretion in estrogen (E)-primed primates, but not by a direct action on lactotropes. Oxytocin is one of several hypothalamic hormones that stimulate PRL secretion. This study was conducted to determine whether oxytocin neurons directly mediate the action of P on PRL secretion. Hypothalamic sections from steroid-manipulated macaques were double immunolabeled for oxytocin and progestin receptors (PR). In addition, serum levels of oxytocin were measured in steroid-treated macaques, and hypothalamic levels of oxytocin were measured in monkeys under various physiological conditions. E treatment (28 days) of spayed monkeys caused a significant increase in the number of PR-positive neurons in the preoptic area, ventromedial nucleus, arcuate nucleus, and median eminence. Addition of P to the E treatment for the last 14 of 28 days did not change the number of PR-positive neurons in these areas. The number of PR-positive neurons was low and was unchanged by steroid treatment in the supraoptic and rostral paraventricular nuclei. Oxytocin neurons rarely contained PR regardless of anatomical location, steroid treatment, or fixation protocol. Serum oxytocin levels increased with E treatment and increased further with supplemental P treatment. The rostral and medial basal hypothalamic content of oxytocin was significantly higher in macaques with mature gonads. In conclusion, oxytocin neurons do not express nuclear PR and probably do not transcriptionally respond to P. However, gonadal steroids apparently affect the production and release of oxytocin in vivo. Thus, it is possible that oxytocin neurons transduce the action of P on PRL secretion via stimulatory neurotransmission from another PR-containing neural system.

Analysis of Variance↗

PubMed1993

Repeated exposure to cocaine produces long-lasting deficits in the serotonergic stimulation of prolactin and renin, but not adrenocorticotropin secretion.

To determine whether cocaine-induced deficits in serotonergic function are long-lasting, the neuroendocrine responses to the serotonin (5-hydroxytryptamine, 5-HT) releaser, p-chloroamphetamine were evaluated 1-8 weeks subsequent to 7 days of cocaine exposure (15 mg/kg b.i.d.). In cocaine-pretreated rats, the p-chloroamphetamine-induced elevations of prolactin and renin secretion were significantly reduced for 8 and 4 weeks, respectively. In contrast, the p-chloroamphetamine-induced elevation of adrenocorticotropic hormone (ACTH) secretion was at control values 1 week after cocaine exposure. The data suggest that some cocaine-induced deficits in serotonergic function are long-lasting.

Adrenocorticotropic Hormone↗

PubMed1993

Progesterone receptor messenger ribonucleic acid and protein are overexpressed in human uterine leiomyomas.

OBJECTIVE: Our purpose was to identify molecular mechanisms underlying abnormal growth of uterine leiomyomas. STUDY DESIGN: Biopsy samples of tumor and adjacent "normal" myometrium from nine patients were analyzed for progesterone receptor gene expression and for proliferation-associated antigen Ki-67. RESULTS: Northern analysis indicated that progesterone receptor messenger ribonucleic acid levels were increased twofold to 15-fold in leiomyoma compared with adjacent myometrial biopsy tissue from all patients (n = 9), whereas beta-actin messenger ribonucleic acid was at similar levels in these samples. Quantitative immunoassay, immunohistochemistry studies, and Western blot analyses revealed increased amounts of progesterone receptor protein in the tumor tissue. Both the progesterone receptor A and B forms were expressed in the leiomyoma and adjacent myometrium. Corresponding to increased progesterone receptor gene expression, the proliferation-associated antigen Ki-67 was also significantly elevated in the leiomyoma tissue. CONCLUSION: These data provide the first evidence that progesterone receptor messenger ribonucleic acid is overexpressed in uterine leiomyomas, suggesting that amplified progesterone-mediated signaling is instrumental in the abnormal growth of these tumors.

Adult↗

PubMed1993

Colocalization of progestin receptors with serotonin in raphe neurons of macaque.

Progesterone stimulates prolactin secretion in estrogen-primed women and monkeys. We hypothesize that this effect is neurally mediated since pituitary lactotropes do not contain progestin receptors (PR). In rodents, progesterone enhances hypothalamic serotonin (5HT) content, and both progesterone and 5HT stimulate prolactin and LH secretion. However, it was not known whether progesterone acts directly on 5HT neurons or through other neurons. Using a double immunocytochemical procedure, we show that 5HT neurons in macaque contain PR and thus are a progestin target system. Midbrain tissue blocks were obtained from two female monkeys and immersion-fixed prior to freezing and sectioning. PR was detected with a monoclonal antibody against human PR (B39) bridged to horseradish peroxidase and developed in diaminobenzidine. PR immunoreactivity appeared as a brown reaction product which localized in the nuclei of individual neurons. 5HT was detected with an antiserum generated against a conjugate of 5HT and BSA bridged to alkaline phosphatase. 5HT immunoreactivity appeared as a blue reaction product in the cytoplasm and axons of the pontine raphe nucleus. Neurons containing both nuclear reaction product for PR and cytoplasmic reaction product for 5HT were observed in both the dorsal and ventral aspects of the midbrain raphe nucleus as well as the raphe magnus. In summary, progesterone can have a direct action on 5HT neuronal function and thereby influence those endocrine and affective systems under serotonergic control.

Animals↗

PubMed1993

Ibotenic acid lesions in the bed nucleus of the stria terminalis attenuate conditioned stress-induced increases in prolactin, ACTH and corticosterone.

The contribution of the bed nucleus of the stria terminalis (BST) to the expression of stress-induced increases in ACTH/corticosterone, prolactin and renin secretion was assessed. Neurons in the lateral part of the BST were destroyed with bilateral injections of the cell-selective neurotoxin ibotenic acid (1.5 micrograms in 0.1 microliter of solution per side). Two weeks later, the rats were stressed using an immobilization or conditioned stress paradigm. Rats with lesions in the lateral part of the BST showed attenuated ACTH and corticosterone responses to conditioned stress. Bilateral ablation of lateral BST significantly reduced the prolactin secretory response to conditioned stress. The same lesions had no effect upon plasma increases in renin that occur in response to conditioned stress. Also, destruction of neurons in the BST did not affect immobilization-induced increases in ACTH, corticosterone, prolactin or renin. Previous studies have demonstrated that ibotenic acid lesions in the central amygdala reduce corticosterone and renin response to conditioned stress. Thus, both the BST and central amygdala are important for the adrenocortical response to conditioned stress. Neurons in the central nucleus of the amygdala are part of the circuitry that mediates renin responses to conditioned stress. Neurons in the BST are important for the full expression of prolactin responses to conditioned stress. The neuronal circuitry and stressor specificity in the mediation of prolactin, renin and ACTH/corticosterone responses are discussed.

Adrenocorticotropic Hormone↗

PubMed1993

Neurons in the hypothalamic paraventricular nucleus mediate the serotonergic stimulation of prolactin secretion via 5-HT1c/2 receptors.

These studies examined the hypothalamic site and receptor subtype mediating the serotonergic (5-HT) control of PRL secretion in conscious male rats. Initially, we characterized the pharmacology of the 5-HT releaser and 5-HT agonists that increase PRL release. Subsequently, we performed lesion experiments to locate the 5-HT receptors involved in PRL secretion. p-Chloroamphetamine, a 5-HT releaser, is postulated to enter serotonergic nerve terminals through the 5-HT uptake mechanism, which can be inhibited by fluoxetine. p-Chloroamphetamine (8 mg/kg, ip) increased the plasma PRL concentration approximately 6-fold. The 5-HT uptake inhibitor fluoxetine almost completely prevented this increase, demonstrating that p-chloroamphetamine increases PRL release via a serotonergic mechanism. The 5-HT1C/5-HT2 agonist +(-)-1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCl (ip) produced a strong (30-fold) dose-dependent elevation of plasma PRL, which was virtually eliminated by 0.1 mg/kg (sc) ritanserin, a 5-HT1C/5-HT2 antagonist. +(-)-1-(2,5-Dimethoxy-4-iodophenyl)2-aminopropane HCl injected intracerebroventricularly (icv) in doses below those that were peripherally effective also produced a significant (8-fold) increase in PRL secretion that was again attenuated by icv pretreatment with ritanserin (2 micrograms/kg). RU 24969 (5-methoxy-3-[1,2,3,4-tetrahydro-4-pyridinyl]1H-indole) was reported to act as both a 5-HT releaser and a direct postsynaptic 5-HT agonist. To test whether RU 24969 releases 5-HT to increase PRL secretion, we depleted 5-HT stores with the 5-HT synthesis inhibitor p-chlorophenylalanine. The ability of RU 24969 (0.5, 1, 5, and 10 mg/kg, ip) to elevate PRL secretion was not inhibited by pretreatment with p-chlorophenylalanine, suggesting that RU 24969 stimulates PRL secretion only through activation of postsynaptic 5-HT receptors. To test whether RU 24969 acts centrally, it was injected either icv, through chronic icv cannulae, or peripherally (ip). RU 24969 injected icv significantly stimulated PRL secretion (11-fold) at doses 500-fold lower than the peripherally effective doses (10 micrograms/kg vs. 5 mg/kg), suggesting a role for central 5-HT receptors in the regulation of PRL secretion. In addition, rats pretreated with the 5-HT1C/5-HT2 antagonist LY53857 (icv) significantly inhibited the PRL response if RU 24969 was injected ip, but not icv. The results of these experiments suggest that 5-HT1C or 5-HT2 receptors in the brain participate in the serotonergic stimulation of PRL secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Amphetamines↗

PubMed1992

Effect of cocaine injections on the neuroendocrine response to the serotonin agonist MK-212.

This study was undertaken to examine whether several of the hormones that can be released by activation of serotonin receptors will be affected by long-term cocaine administration. Male rats received cocaine injections (15 mg/kg, IP) twice daily for 7 days. Forty-two hr after the last cocaine injection, the rats were challenged with increasing doses (0, 1, 5, 10 mg/kg, IP) of the 5-HT1/5-HT2 agonist MK-212 (6-chloro-2-[1-piper-azinyl]-pyrazine). The following observations were made: (1) cocaine reduced the rate of body weight gain; (2) cocaine inhibited the stimulatory effect of MK-212 on plasma vasopressin, oxytocin, and prolactin concentrations and on plasma renin activity and concentration; (3) cocaine did not inhibit the stimulatory effect of MK-212 on plasma ACTH or corticosterone concentrations. The data indicate that a wide-spectrum 5-HT (serotonin) agonist such as MK-212 can reveal differential neuroendocrine responses. This effect could be related to cocaine-induced changes in the different 5-HT receptor subtypes that regulate the secretion of these hormones.

Adrenocorticotropic Hormone↗