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E J Wagner

Publications and source records attributed to E J Wagner.

At least 19 recordsLinked to original sources
PubMed2001

Estrogen biphasically modifies hypothalamic GABAergic function concomitantly with negative and positive control of luteinizing hormone release.

The principal role of estrogen is its control of the female ovulatory cycle via negative and positive feedback on gonadotropin secretion. However, a detailed, cohesive picture of how the steroid specifically regulates the excitability of hypothalamic neurons involved in the central control of gonadotropin secretion is still emerging. Here, we used an ovariectomized female guinea pig model to test the hypothesis that estrogen acts on GABAergic neurons in the preoptic area (POA) to elicit a biphasic profile of luteinizing hormone (LH) secretion. Intracellular electrophysiological recordings revealed that estradiol benzoate (EB; 25 microgram, s.c.) decreased the hyperpolarizing response of GABAergic neurons to the GABA(B) receptor agonist baclofen 24 hr after treatment. This effect of GABA(B) receptor stimulation in unidentified POA neurons was still depressed 42 hr after EB administration. By the use of a ribonuclease protection assay, however, EB reduced glutamic acid decarboxylase mRNA expression 42 hr but not 24 hr after its administration. Thus, estrogen attenuated the autoinhibition of GABAergic POA neurons during the initial LH suppressive (i.e., negative feedback) phase and subsequently reduced GABAergic function during the LH surge (i.e., positive feedback). These studies demonstrate that the effects of estrogen on hypothalamic GABAergic neurons coincide with the inhibitory and stimulatory actions, respectively, of the steroid on LH secretion. Furthermore, the data provide novel insights into the mechanism by which estrogen regulates hypothalamic GABAergic neurons, which are critical for the biphasic modulation of LH release observed over the course of the female ovulatory cycle.

Action Potentials↗
PubMed2001

The noradrenergic inhibition of an apamin-sensitive, small-conductance Ca2+-activated K+ channel in hypothalamic gamma-aminobutyric acid neurons: pharmacology, estrogen sensitivity, and relevance to the control of the reproductive axis.

The present study sought to determine whether small-conductance, Ca2+-activated K+ currents underlie the afterhyperpolarization (AHP) in neurons of the preoptic area (POA), a brain region important in controlling reproduction. We used an ovariectomized, female guinea pig model to test two hypotheses: 1) the current associated with the AHP (I(AHP)) regulates the firing rate of POA neurons and 2) amine neurotransmitters modulate it in a gonadal steroid-sensitive manner. Intracellular recordings followed by combined histofluorescence/in situ hybridization for glutamic acid decarboxylase, 65-kDa isomer, revealed that POA neurons, including gamma-aminobutyric acid (GABA)ergic neurons, exhibited an AHP and spike frequency adaptation. The corresponding I(AHP) was sensitive to antagonism by CdCl2 (200 microM), apamin (0.3-1 microM), and dequalinium (3 microM). The beta-adrenergic receptor agonist isoproterenol inhibited the I(AHP) in a dose-dependent, timolol-sensitive fashion. In addition, the alpha1-adrenergic receptor agonist methoxamine dose dependently inhibited the I(AHP) in a prazosin-sensitive manner and increased neuronal firing rate. Twenty-four-hour pretreatment with estradiol benzoate (EB; 25 microg, s.c.) markedly potentiated the inhibitory effect of methoxamine on the I(AHP), whereas that for isoproterenol was unaffected. Similarly, bath application of 17beta-estradiol (100 nM; 15-20 min) mimicked the effect of EB on the methoxamine-induced inhibition of the I(AHP). Thus, POA GABAergic neurons express an apamin-sensitive channel that mediates, at least in part, the I(AHP), and tempers the excitability of these cells. Furthermore, these studies demonstrate that estrogen enhances the alpha1-adrenergic receptor-mediated inhibition of this current.

Animals↗
PubMed2000

The role of intrinsic and agonist-activated conductances in determining the firing patterns of preoptic area neurons in the guinea pig.

Whole-cell and intracellular recordings were made in coronal hypothalamic slices prepared from ovariectomized female guinea pigs. 62% of preoptic area (POA) neurons fired action potentials in a bursting manner, and exhibited a significantly greater afterhyperpolarization (AHP) than did non-bursting POA neurons. The majority (70%) of POA neurons (n=76) displayed a time-dependent inward rectification (I(h)) that was blocked by CsCl (3 mM) or by ZD 7288 (30 microM). In addition, 51% of the cells expressed a low-threshold spike (LTS) associated with a transient inward current (I(T)) that was blocked by NiCl(2) (200 microM). A smaller percentage of POA neurons (29%) expressed a transient outward, A-type K(+) current that was antagonized by a high concentration of 4-aminopyridine (3 mM). Moreover, POA neurons responded to bath application of the mu-opioid receptor agonist DAMGO (93%) or the GABA(B) receptor agonist baclofen (83%) with a membrane hyperpolarization or an outward current. These responses were accompanied by a decrease in input resistance or an increase in conductance, respectively, and were attenuated by BaCl(2) (100 microM). In addition, the reversal potential for these responses closely approximated the Nernst equilibrium potential for K(+). These results suggest that POA neurons endogenously express to varying degrees an AHP, an I(h), an I(T) and an A-type K(+) current. The vast majority of these neurons also are inhibited upon mu-opioid or GABA(B) receptor stimulation via the activation of an inwardly-rectifying K(+) conductance. Such intrinsic and transmitter-activated conductances likely serve as important determinants of the firing patterns of POA neurons.

4-Aminopyridine↗
PubMed2000

Regional oral absorption, hepatic first-pass effect, and non-linear disposition of salmon calcitonin in beagle dogs.

The dose-dependent disposition, first pass hepatic elimination, and absorption pharmacokinetics (PK) of salmon calcitonin (sCT) were investigated in a canine Intestinal Vascular Access Port (IVAP) model. The PK of sCT were determined after intravenous (IV), subcutaneous (SC), portal venous (PV), and oral (PO) administration of sCT. Regional oral absorption of unformulated sCT was also evaluated by direct administration into the duodenum (ID), ileum (IL), and colon (IC) by means of surgically implanted, chronic catheters. Plasma samples were collected and analyzed by radioimmunoassay (RIA). Salmon calcitonin PK were evaluated using 2-compartmental and model independent methods. Intravenous sCT PK were non-linear over the dose range studied. High dose groups (100-1000 microg) demonstrated higher total plasma clearance (CL) and V(dss) than the low dose groups (1-25 microg). However, the MRT did not change for doses ranging from 10 to 1000 microg. After SC administration, the absorption of sCT was rapid with bioavailability (BA) varying from 21.4 to 52.9%. However, the BA of sCT was low after ID, IL, and IC administration (0.039, 0.064, and 0.021%, respectively). The role of hepatic first-pass elimination was negligible. The results of these studies demonstrate that the elimination of sCT is rapid but does not occur in the liver. Enhanced sCT clearance at higher doses was indicated by increasing V(dss) values, and it is hypothesized that increased renal blood flow and/or saturated plasma protein binding may contribute to the non-linear behavior. The IVAP canine model was found to have utility for probing the absorption and disposition PK of sCT. The combination of high oral bioavailability variability and non-linear disposition of sCT may produce highly variable therapeutic effects. The practical impact of the non-linear disposition of sCT remains to be determined. Based on the current results it appears that the rate-limiting step to the successful oral administration of sCT is its delivery into the portal vein since hepatic metabolism was negligible.

Administration, Oral↗
PubMed2000

An intronic splicing silencer causes skipping of the IIIb exon of fibroblast growth factor receptor 2 through involvement of polypyrimidine tract binding protein.

Alternative splicing of fibroblast growth factor receptor 2 (FGF-R2) transcripts involves the mutually exclusive usage of exons IIIb and IIIc to produce two different receptor isoforms. Appropriate splicing of exon IIIb in rat prostate cancer DT3 cells requires a previously described cis element (ISAR, for "intronic splicing activator and repressor") which represses the splicing of exon IIIc and activates the splicing of exon IIIb. This element is nonfunctional in rat prostate AT3 cells, which repress exon IIIb inclusion and splice to exon IIIc. We have now identified an intronic element upstream of exon IIIb that causes repression of exon IIIb splicing. Deletion of this element abrogates the requirement for ISAR in order for exon IIIb to be spliced in DT3 cells and causes inappropriate inclusion of exon IIIb in AT3 cells. This element consists of two intronic splicing silencer (ISS) sequences, ISS1 and ISS2. The ISS1 sequence is pyrimidine rich, and in vitro cross-linking studies demonstrate binding of polypyrimidine tract binding protein (PTB) to this element. Competition studies demonstrate that mutations within ISS1 that abolish PTB binding in vitro alleviate splicing repression in vivo. Cotransfection of a PTB-1 expression vector with a minigene containing exon IIIb and the intronic splicing silencer element demonstrate PTB-mediated repression of exon IIIb splicing. Furthermore, all described PTB isoforms were equally capable of mediating this effect. Our results support a model of splicing regulation in which exon IIIc splicing does not represent a default splicing pathway but rather one in which active repression of exon IIIb splicing occurs in both cells and in which DT3 cells are able to overcome this repression in order to splice exon IIIb.

Adenocarcinoma↗
PubMed1999

A powerful GABA(B) receptor-mediated inhibition of GABAergic neurons in arcuate nucleus.

We combined histofluorescence with in situ hybridization to identify GABAergic neurons in the arcuate nucleus (ARC) following electrophysiological recording, using GAD65 as a marker. Intracellular recordings 91 were made in hypothalamic slices prepared from ovariectomized guinea pigs. Over 90% of ARC neurons tested with the GABA(B) receptor agonist baclofen responded with a membrane hyperpolarization or an outward current. The hyperpolarization was dose dependent, and the GABA(B) receptor antagonist CGP 35,348 produced a rightward shift in the agonist dose-response curve. Agonist potency was lower, and the efficacy greater, in GAD-positive neurons. The use of this novel technique for identifying GABAergic neurons thus reveals differences in the pharmacodynamics of GABA(B) receptor activation between GABAergic and non-GABAergic ARC neurons.

Animals↗
PubMed1999

Biopharmaceutical approaches for developing and assessing oral peptide delivery strategies and systems: in vitro permeability and in vivo oral absorption of salmon calcitonin (sCT).

PURPOSE: To evaluate a biopharmaceutical approach for selecting formulation additives and establishing the performance specifications of an oral peptide delivery system using sCT as a model peptide. METHODS: The effect of formulation additives on sCT effective permeability and transepithelial electrical resistance (TEER) was evaluated in side-by-side diffusion chambers using rat intestinal segments. Baseline regional oral absorption of sCT was evaluated in an Intestinal and Vascular Access Port (IVAP) dog model by administration directly into the duodenum, ileum, and colon by means of surgically implanted, chronic catheters. The effect of varying the input rate and volume of the administered solution on the extent of sCT absorption was also evaluated. Citric acid (CA) was utilized in all studies to cause a transient reduction in local pH. In vitro samples and plasma samples were analyzed by radioimmunoassay (RIA). Two oral delivery systems were prepared based on the results of the in vitro and IVAP studies, and evaluated in normal dogs. RESULTS: Maximal permeability enhancement of sCT was observed using taurodeoxycholate (TDC) or lauroyl carnitine (LC) in vitro. Ileal absorption of sCT was higher than in other regions of the intestine. Low volume and bolus input of solution formulations was selected as the optimal condition for the IVAP studies since larger volumes or slower input rates resulted in significantly lower sCT bioavailability (BA). Much lower BA of sCT was observed when CA was not used in the formulation. The absolute oral bioavailability (mean+/-SD) in dogs for the control (sCT + CA) and two proprietary sCT delivery systems was 0.30%+/-0.05%, 1.10+/-0.18%, and 1.31+/-0.56%, respectively. CONCLUSIONS: These studies demonstrate the utility of in vitro evaluation and controlled in vivo studies for developing oral peptide delivery strategies. Formulation additives were selected, the optimal intestinal region for delivery identified, and the optimal release kinetics of additives and actives from the delivery system were characterized. These methods were successfully used for devising delivery strategies and fabricating and evaluating oral sCT delivery systems in animals. Based on these studies, sCT delivery systems have been fabricated and tested in humans with favorable results.

Administration, Oral↗
PubMed1998

A powerful GABA(B) receptor-mediated inhibition of GABAergic neurons in the arcuate nucleus.

We combined histofluorescence with in situ hybridization to identify GABAergic neurons in the arcuate nucleus (ARC) following electrophysiological recordings, using GAD65 as a marker. Intracellular recordings were made in hypothalamic slices prepared from ovariectomized guinea pigs. Over 90% of ARC neurons tested with the GABA(B) receptor agonist baclofen responded with a membrane hyperpolarization or an outward current. The hyperpolarization was dose-dependent, and the GABA(B) receptor antagonist CGP 35,348 produced a rightward shift in the agonist dose-response curve. Agonist potency was lower, and the efficacy greater, in GAD-positive neurons. The use of this novel technique for identifying GABAergic neurons thus reveals differences in the pharmacodynamics of GABA(B) receptor activation GABAergic and non-GABAergic ARC neurons.

Animals↗
PubMed1998

The peptide orphanin FQ inhibits beta-endorphin neurons and neurosecretory cells in the hypothalamic arcuate nucleus by activating an inwardly-rectifying K+ conductance.

Orphanin FQ (OFQ) is a novel heptadecapeptide whose structure resembles that of dynorphin A1-17. Its receptor shares appreciable homology with mu-, delta- and kappa-opioid receptors, and is highly expressed in the hypothalamus. The present study examined the effects of OFQ on neurons within the arcuate nucleus (ARC) of the mediobasal hypothalamus, using intracellular recordings from coronal slices. In current clamp, OFQ produced a hyperpolarization of ARC neurons, including those immunopositive for beta-endorphin, tyrosine hydroxylase and gonadotropin-releasing hormone. This hyperpolarization was dose-dependent, insensitive to antagonism by naloxone and was associated with a decrease in input resistance. In voltage clamp, OFQ produced an outward current associated with an increase in conductance. Varying the extracellular K+ concentration shifted the reversal potential for the OFQ response to the degree predicted by the Nernst equation. Furthermore, barium chloride markedly attenuated both the OFQ-induced hyperpolarization and decrease in input resistance. Administration of maximally effective concentrations of OFQ, followed by coadministration of maximal concentrations of either OFQ and the mu-opioid receptor agonist DAMGO or OFQ and the GABAB receptor agonist baclofen produced additive hyperpolarizations and outward currents. If DAMGO was applied first, followed by the coadministration of DAMGO and OFQ, then the responses were occluded. Taken together, these results indicate that OFQ inhibits beta-endorphin neurons, as well as A12 dopamine and GnRH neurosecretory cells, within the ARC by activating a subset of inwardly-rectifying K+ channels. This suggests that OFQ is not only an antiopioid peptide, but that it also modulates the hypothalamo-pituitary axis and, ultimately, reproductive behavior.

Animals↗
PubMed1998

Protein kinase A maintains cellular tolerance to mu opioid receptor agonists in hypothalamic neurosecretory cells with chronic morphine treatment: convergence on a common pathway with estrogen in modulating mu opioid receptor/effector coupling.

The present study examined protein kinase A (PKA) and protein kinase C (PKC) involvement in the maintenance of cellular tolerance to mu opioid receptor agonists resulting from chronic opiate exposure in neurosecretory cells of the hypothalamic arcuate nucleus (ARC). The possibility that the diminution of mu opioid receptor/effector coupling produced by acute 17beta-estradiol or chronic opiate exposures is mediated by a common kinase pathway also was investigated. Intracellular recordings were made in hypothalamic slices prepared from ovariectomized female guinea pigs. The mu opioid receptor agonist D-Ala2, N-Me-Phe4, Gly-ol5-enkephalin (DAMGO) produced dose-dependent hyperpolarizations of ARC neurons. Chronic morphine treatment for 4 days reduced DAMGO potency 2.5-fold with no change in the maximal response. This effect was mimicked by a 20-min bath application of the PKA activator cAMP, Sp-isomer, or the PKC activator phorbol-12,13-dibutyrate. A 30-min bath application of the broad-spectrum protein kinase inhibitor staurosporine completely abolished the reduced DAMGO potency seen in morphine-tolerant neurosecretory cells, including those immunopositive for gonadotropin-releasing hormone. The effect of staurosporine was mimicked by the PKA inhibitor cAMP, Rp-isomer, but not by the PKC inhibitor calphostin C. Finally, a 20-min bath application of 17beta-estradiol did not further reduce DAMGO potency in morphine-tolerant ARC neurons. Therefore, increased PKA activity maintains cellular tolerance to mu opioid receptor agonists in ARC neurosecretory cells caused by chronic morphine treatment. Furthermore, acute 17beta-estradiol and chronic opiate treatments attenuate mu opioid receptor-mediated responses via a common PKA pathway.

Analgesics, Opioid↗
PubMed1997

Tolerance to mu-opioid receptor agonists but not cross-tolerance to gamma-aminobutyric acid(B) receptor agonists in arcuate A12 dopamine neurons with chronic morphine treatment.

The present study examined the potential for cross-tolerance development between mu-opioid and gamma-aminobutyric acidB receptor agonists, in hypothalamic arcuate neurons, resulting from chronic morphine treatment. Intracellular recordings were made in hypothalamic slices prepared from ovariectomized female guinea pigs. The mu-opioid receptor agonist D-Ala2,N-Me-Phe4,Gly-ol5-enkephalin and the gamma-aminobutyric acidB receptor agonist baclofen produced dose-dependent membrane hyperpolarizations of arcuate neurons. The reversal potential for both agonist-induced hyperpolarizations was near -95 mV, indicative of the activation of an underlying K+ conductance. Coadministration of maximally effective concentrations of D-Ala2,N-Me-Phe4,Gly-ol5-enkephalin and baclofen produced a response that was not additive, indicating a convergence onto a common K+ channel. In arcuate neurons, including a subset that was immunopositive for tyrosine hydroxylase, chronic morphine treatment for 4 to 7 days produced a 3.2-fold reduction in the potency, with no change in the efficacy, of D-Ala2,N-Me-Phe4,Gly-ol5-enkephalin. In contrast, it affected neither the potency nor the efficacy of baclofen. Therefore, chronic morphine exposure does not produce cross-tolerance between mu-opioid and gamma-aminobutyric acidB receptor agonists in A12 dopamine neurons, suggesting that convergence upon a common effector is not a sufficient criterion for the development of cross-tolerance between receptor systems.

Animals↗
PubMed1996

Downregulation of mu-opioid receptor mRNA in the mediobasal hypothalamus of the female guinea pig following morphine treatment.

Ribonuclease protection assays were performed on the basal hypothalamus (BH), the preoptic area (POA) and the thalamus (THAL) from female guinea pigs that were ovariectomized and implanted with morphine (n = 8) or placebo (n = 8) pellets for 1 week. An antisense [32P]rUTP labeled riboprobe, representing a 280 bp fragment of the guinea pig mu-opioid receptor gene (spanning putative TM II through eight residues of TM IV), protected a single RNA band of 280 bp. In contrast to the rat, the guinea pig THAL expressed less mu-opioid receptor mRNA than both POA and BH. Morphine treatment caused a significant decrease (15.6 +/- 5.8%) in mu-opioid receptor mRNA expression in the BH, while POA and THAL were not different from placebo controls. Therefore, in conjunction with our previous findings of a downregulation of mu-opioid receptors, mu-opioid receptor mRNA is downregulated in the mediobasal hypothalamus of female guinea pigs following chronic morphine treatment.

Analgesics, Opioid↗
PubMed1996

Equilibrium vapor pressure of mercury from dental amalgam in vitro.

OBJECTIVES: The purpose of this study was to acquire reliable quantitative data on mercury vapor pressure above the surface of dental amalgam samples in both the as-formed and the abraded state. METHODS: The equilibrium vapor pressure of mercury from dental amalgam was obtained using residual gas analysis in conjunction with a quartz crystal microbalance. The measurements were performed under ultrahigh-vacuum conditions. RESULTS: Using the residual gas analyzer, the average mercury vapor pressures measured from the as-formed and abraded dental amalgam surfaces were 8 x 10(-7) and 1.7 x 10(-4) Pa, respectively. The corresponding vapor densities are: 6 x 10(-2) micrograms/m3 and 14 micrograms/m3. The average mercury vapor pressures measured from the as-formed and abraded dental amalgam surfaces using the quartz crystal microbalance were: 2.4 x 10(-6) and 1.0 x 10(-4) Pa, respectively. The corresponding vapor densities are: 0.2 microgram/m3 and 8 micrograms/m3. SIGNIFICANCE: This project provides a measurement of the equilibrium vapor pressure of mercury from as-formed and abraded amalgam surfaces. By definition, the equilibrium vapor pressure provides the maximum density of mercury which can be present in the environment above the amalgam. The vapor density of mercury within the oral cavity must be less than this value due to the dynamic nature of the system.

Chemical Phenomena↗
PubMed1996

Estrogen rapidly attenuates a GABAB response in hypothalamic neurons.

GABA is a predominant neurotransmitter in the hypothalamus and an important regulator of hypothalamic function. To elucidate the cellular basis for GABAergic action in this region, we used intracellular recordings from identified hypothalamic neurons. Ninety-three percent of the mediobasal hypothalamic neurons responded to GABAB receptor stimulation, and the presence of bicuculline-sensitive synaptic potentials indicated a tonic, GABAA receptor-mediated input. Stimulation of GABAB receptors hyperpolarized these cells by activating an inwardly rectifying potassium conductance. We characterized GABAB responses by generating concentration-response curves to the GABAB agonist baclofen. There was heterogeneity in the responses to baclofen, with one third of the cells having low baclofen potency (EC50 = 5.0 microM). Two thirds of the neurons had a 4-fold higher potency (EC50 = 1.2 microM), larger somas and a more lateral distribution. Previous work has shown that hypothalamic GABAB and mu-opioid receptors open the same K+ channels and that the response to mu-opioid agonists is rapidly attenuated by 17 beta-estradiol (E2). In order to test the hypothesis that the coupling of GABAB receptors to K+ channels is also altered, baclofen concentration-response curves were generated before and after an E2 challenge (100 nM, 20 min). Consistent with our hypothesis, the potency of baclofen was decreased nearly 4-fold in a subset of the cells that had a high potency response to baclofen. Furthermore, decreased baclofen potency only occurred in those cells in which E2 also altered the mu-opioid responses. Therefore, our findings suggest that a discrete subpopulation of hypothalamic neurons is sensitive to estrogen actions to alter inhibitory transmission. We propose that the alteration of GABAB and mu-opioid input is consistent with estrogen's rapid inhibition of the reproductive axis.

Animals↗
PubMed1994

Neurochemical evidence that AMPA receptor-mediated tonic inhibition of hypothalamic dopaminergic neurons occurs via activation of inhibitory interneurons.

Blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors with 6-nitro-7-sulfamoyl-benzo-[f]quinoxaline-2,3(1H,4H)-dione (NBQX) activates tuberoinfundibular (TIDA) and periventricular-hypophysial dopaminergic (PHDA) neurons suggesting that these neurons are tonically inhibited by endogenous excitatory amino acid neurotransmitters acting at AMPA receptors. The purpose of the present study was to identify prospective inhibitory neurotransmitters mediating this effect by examining the ability of gamma-aminobutyric acid (GABA)A and kappa-opioid receptor agonists to reverse the stimulatory effects of NBQX on the activity of these neurons (estimated from concentrations of 3,4-dihydroxyphenylacetic acid [DOPAC] in the median eminence and intermediate lobe of the pituitary). The GABAA receptor agonist isoguvacine prevented the NBQX-induced increase in DOPAC concentrations in the median eminence but not in the intermediate lobe. The kappa-opioid receptor agonist U-50,488 had no effect in the median eminence, but attenuated the NBQX-induced increase of DOPAC concentrations in the intermediate lobe. These results suggest that excitatory amino acid neurotransmitters activate AMPA receptors and increase release of GABA, which by acting at GABAA receptors tonically inhibits TIDA neurons. On the other hand, AMPA receptor-mediated tonic inhibition of PHDA neurons occurs, at least in part, by a mechanism involving endogenous kappa-opioids.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

GABAergic regulation of tuberoinfundibular dopaminergic neurons in the male rat.

The purpose of the present study was to examine the effects of gamma-aminobutyric acid (GABA)A and GABAB receptor blockade and activation on the activity of tuberoinfundibular dopaminergic (TIDA) neurons in male rats. The activity of TIDA neurons was estimated by measuring the concentration of the primary dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence. Administration of the GABAA receptor antagonist SR 95531 increased DOPAC concentrations in the median eminence, and decreased plasma concentrations of prolactin, in a dose- and time-related manner. Administration of the GABAA receptor agonist isoguvacine had no effect per se on DOPAC concentrations in the median eminence, but produced a delayed decrease in plasma prolactin concentrations. Isoguvacine pre-treatment prevented the increase in DOPAC concentrations in the median eminence produced by SR 95531. In contrast, administration of the GABAB receptor agonist baclofen decreased DOPAC concentrations in the median eminence, and increased plasma prolactin concentrations in a dose-dependent manner. Administration of the GABAB receptor antagonist 2-hydroxysaclofen had no effect on TIDA neurons per se, but blocked baclofen-induced decreases in DOPAC concentrations in the median eminence and increases in plasma prolactin concentrations. These results indicate that while activation of GABAB receptors inhibits TIDA neurons, these neurons are tonically inhibited by endogenous GABA acting at GABAA but not GABAB receptors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Non-NMDA receptor-mediated regulation of hypothalamic dopaminergic neurons in the rat.

The purpose of the present study was to examine the effects of non-NMDA receptor blockade and activation on the activity of tuberoinfundibular dopaminergic (TIDA), periventricular-hypophysial dopaminergic (PHDA) and, for comparison, nigrostriatal dopaminergic (NSDA) neurons in male and female rats. The activity of TIDA, PHDA and NSDA neurons was estimated by measuring the concentration of the primary dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence, intermediate lobe of the posterior pituitary and striatum, respectively. Systemic administration of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-selective antagonist 6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3(1H,4H)-dione (NBQX) increased DOPAC concentrations in the median eminence and intermediate lobe, and decreased plasma concentrations of prolactin and alpha-MSH, in a dose- and time-related manner. In contrast, NBQX had no effect on DOPAC concentrations in the striatum, suggesting that non-NMDA receptors are not involved in the tonic regulation of NSDA neurons. The increase in DOPAC concentrations in the median eminence and intermediate lobe, and the decrease in plasma concentrations of prolactin and alpha-MSH, produced by NBQX were prevented by AMPA but not by kainic acid. Taken together, the results demonstrate that endogenous excitatory amino acid neurotransmitters, acting at AMPA receptors, tonically inhibit both TIDA and PHDA neurons, and thereby increase the secretion of prolactin and alpha-MSH in male and female rats.

3,4-Dihydroxyphenylacetic Acid↗