Dopaminergic Inhibition Research Articles

α2‐Adrenoceptors are not involved in the regulation of striatal glutamate release: Comparison to dopaminergic inhibition

Striatal slices from the rat were loaded with [3H]glutamate ([3H]Glu) and superfused in order to measure release of radioactivity at rest and during potassium-evoked depolarization. Addition of KCl (22-40 mmol/liter) to the perfusion fluid enhanced the release of tritium in a concentration-dependent manner, and this release was abolished by omission of CaCl2. High-performance liquid chromatography (HPLC) separation coupled with radiochemical detection revealed that 23% and 41% of the tritium efflux detected in the perfusion fluid under resting conditions and during potassium stimulation, respectively, was due to [3H]Glu. At the end of the superfusion about 63% of residual tritium content in the tissue was [3H]Glu. Tritium efflux in response to KCl excess was significantly higher from striatum dissected from 6-hydroxydopamine-pretreated rats. Apomorphine decreased the KCl-evoked release of [3H]Glu, and haloperidol exerted the opposite effect. Yohimbine, which antagonized the decrease of dopa accumulation elicited by apomorphine in NSD-1015 and gamma-butyrolactone-pretreated rat caudate nucleus, also reversed the apomorphine inhibition of the release of [3H]Glu evoked by depolarization. The selective alpha 2-adrenoceptor antagonist CH-38083, however, did not modify the apomorphine inhibition of [3H]Glu release or dopa accumulation, and the alpha 2-adrenoceptor agonist xylazine did not alter tritium efflux from striatum preloaded with [3H]Glu. These findings suggest that release of glutamate (Glu) from the corticostriatal pathway is under tonic control of dopamine released from nigrostriatal neurons, and alpha 2-adrenoceptors are not involved in the regulation of glutamatergic transmission in the rat striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine receptor and adrenoceptor agonists inhibit prolactin release from MMQ cells

MMQ cells, a prolactin-secreting cell line possessing dopamine receptors, were exposed to the calcium channel activator maitotoxin and dopamine or adrenoceptor agonists or antagonists. Dopamine (500 nM) or the dopamine agonists lisuride (50 nM), terguride (50 nM), and N-0437 (50 nM) decreased maitotoxin-stimulated prolactin release from perifused MMQ cells. In this system, sulpiride (100 nM), a dopamine D 2 antagonist, reversed the prolactin inhibition produced by lisuride (20 nM). In static incubations of MMQ cells, lisuride (10–500 nM) inhibited maitotoxin-stimulated prolactin release in a concentration-dependent manner; this inhibition was attenuated in a concentration-related manner by sulpiride (100–500 nM). In addition, sulpiride reversed dopamine (50–500 nM), lisuride (10–500 nM), and terguride (50–500 nM) inhibition of forskolin-stimulated cAMP generation. The α 2-adrenergic agonist clonidine inhibited maitotoxin-stimulated prolactin release from perifused MMQ cells; this inhibition was abolished by idazoxan, an α 2-adrenergic antagonist. In contrast, serotonin or the serotonin antagonist methysergide had no effect on prolactin release from MMQ cells. These data indicate that activation of dopamine D 2 receptors and α 2-adrenoceptors by classically defined pharmacological agents inhibits prolactin release and cellular cAMP levels in MMQ cells. Therefore, MMQ cells may provide a valuable model for the development of pharmacological agents and assist in the identification of the mechanisms involved in the dopaminergic inhibition of prolactin release.

Differential Effect of Aging on Serum Levels of Prolactin and -Melanotropin in Rats

Prolactin (PRL) and alpha-melanocyte-stimulating hormone (alpha-MSH) are the only two pituitary hormones whose basal secretion is under tonic dopaminergic inhibition exerted by the hypothalamus. In the female rat, continuous exposure to estrogens is believed to depress hypothalamic dopaminergic activity and lead to the appearance of PRL-secreting pituitary adenomas during aging. Since there is no information about the impact of aging on circulating alpha-MSH levels, it was of interest to assess and compare the serum levels of PRL and alpha-MSH in male and female rats of different ages. Young (3-4 months) and old (24-25 months) male and female Sprague-Dawley rats as well as senescent (33-35 months) females were killed by decapitation between 10 AM and 1 PM, and pituitaries were immediately removed and dissected. Hormones were measured in unextracted trunk serum by radioimmunoassay. Serum PRL levels were (mean +/- SE), 18.4 +/- 2.0, 26.8 +/- 3.8, 19.8 +/- 2.5, 43.0 +/- 7.5, and 193.5 +/- 47.6 ng/ml for young and old males, and young, old, and senescent females, respectively. Serum alpha-MSH levels were 243.2 +/- 15.2, 252.9 +/- 24.8, 320.0 +/- 31.3, 234.7 +/- 19.1, and 374.0 +/- 29.7 pg/ml for young and old males, and young, old and senescent females, respectively. Anterior pituitary and neurointermediate lobe weights increased significantly with age in both sexes, although the change was particularly conspicuous in the females. We conclude that aging does not have a major impact on circulating alpha-MSH levels in rats and that melanotrophs probably have a greater ability than prolactotrophs to withstand age-associated alterations in central regulatory mechanisms.

Dopaminergic inhibition of glycoprotein hormone α-subunit in normal subjects

The pituitary glycoprotein hormones thyrotropin (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) consist of two noncovalently linked subunits, α and β. In addition to producing intact hormone, the pituitary releases free α-subunit, which is stimulated by gonadotropin-releasing hormone (GnRH) and thyrotropin-releasing hormone (TRH). However, little is known about the dopaminergic regulation of free α-subunit in vivo. The effect of dopamine (DA), metoclopramide (MTC), and the specific DA D-1 receptor agonist, fenoldopam, on circulating α-subunit levels was studied in normal men and women. Normal women received 4-hour infusions of either glucose (n = 6) or DA at rates of 0.04 (n = 6), 0.4 (n = 6), and 4.0 μg/kg · min (n = 6). After 3 hours, 10 mg MTC was administered intravenously (IV). The high dose of DA significantly lowered α-subunit levels ( P < .05). No response to MTC was observed in any of the groups. Six women received glucose or DA infusion (4.0 μg/kg · min) for 18 hours. DA significantly reduced basal α-subunit levels compared with control infusion ( P < .05). MTC administration after 17 hours induced a significant increase in α-subunit levels on the day of DA infusion compared with control ( P < .05). In a third study, nine normal males received fenoldopam (0.5 μg/kg · min) or placebo infusions for 4 hours. Fenoldopam did not affect basal α-subunit levels, but the α-subunit response to a GnRH TRH bolus was significantly increased during fenoldopam compared with control ( P < .05). The results suggest that α-subunit release may be modulated by the dopaminergic system in vivo. This dopaminergic effect on α-subunit secretion resembles dopaminergic modulation of LH, rather than TSH secretion.

Dopaminergic inhibition of dopamine-containing neurons in the ventral tegmental area: Enhancement by D-1 receptor activation of D-2 receptor-mediated inhibition

Dopaminergic inhibition of dopamine-containing neurons in the ventral tegmental area: Enhancement by D-1 receptor activation of D-2 receptor-mediated inhibition

Acceleration of Luteinizing Hormone Pulse Frequency in Functional Hypothalamic Amenorrhea by Dopaminergic Blockade*

A constellation of neuroendocrine secretory aberrations, including reduced LH pulse frequency and PRL concentrations, has been documented in women with functional hypothalamic amenorrhea (FHA). As pituitary function was preserved, these aberrations were attributed to an alteration in hypothalamic neuromodulation. To investigate the participation of the dopaminergic system in the genesis of the reduced LH pulse frequency and suppressed PRL levels in FHA, we studied six women with FHA and six cyclic women in the early follicular phase by obtaining blood samples at 15-min intervals for 48 h during sequential 24-h infusions of saline and a dopamine receptor blocker, metoclopramide (MCP). A hypothalamic vs. pituitary site of action was inferred from the pulsatility characteristics. MCP consistently elicited an increase in the LH pulse frequency in the women with FHA [7.3 +/- 1.2 (+/- SE) to 10.5 +/- 1.3 pulses/24 h; P less than 0.005]. In contrast, the eumenorrheic women did not show a significant change in LH pulse frequency in response to MCP (15.2 +/- 1.0 to 14.3 +/- 0.9 pulses/24 h). While the PRL concentrations were significantly lower in the FHA group during the infusion of saline (P less than 0.001) and MCP (P less than 0.005), the relative increases in PRL during MCP were similar in both groups. The acceleration of LH pulse frequency by blockade of dopamine receptors implies that there is increased hypothalamic dopaminergic inhibition of GnRH pulse frequency in women with FHA.

Dopaminergic Regulation of Aldosterone Secretion: Assessment in Different Subtypes of Primary Aldosteronism and in Essential Hypertension

The inhibitory effect of dopamine on aldosterone secretion was investigated in patients with different types of primary aldosteronism, six with idiopathic hyperaldosteronism (IHA) and four with dexamethasone-suppressible hyperaldosteronism (DSH), and in 10 patients with essential hypertension. The effects of 10 mg metoclopramide given intravenously, 10 mg bromocriptine given orally and 100 micrograms adrenocorticotrophic hormone given intravenously on plasma aldosterone and renin activities were investigated in all patients. Metoclopramide induced a rise in plasma aldosterone activity only in patients with IHA and not in those with DSH and essential hypertension. After bromocriptine plasma aldosterone concentrations decreased in patients with IHA only, and after adrenocorticotrophic hormone plasma aldosterone concentrations increased in patients with DSH only. Plasma renin activity was unaffected in all cases. These results provide evidence of increased endogenous dopaminergic inhibition of aldosterone secretion in IHA and of a blunted aldosterone response in both DSH and essential hypertension.

Functional Lactotroph Heterogeneity in Lactating Rats and in vitro Modification by 17Beta‐Estradiol

Abstract Lactotrophs from lactating rats were separated by unit gravity sedimentation on a continuous density gradient of bovine serum albumin and were identified in two populations located in the light fractions (fractions 3-5) and in the heavy fractions (fractions 7-9) of the gradient. After 7 days in vitro, the effects on prolactin release of thyrotropin-releasing hormone (TRH) and dopamine before and after pretreatment with 17beta-estradiol were studied by a continuous perifusion system and reverse hemolytic plaque assay. Light fraction lactotrophs spontaneously released large quantities of prolactin (22 ng/ml/2 min/10(6) cells) and this basal release was markedly elevated (51 ng/ml/2 min/10(6) cells) by pretreatment with 17beta-estradiol (10(-8) M, 48 h), while the amount of intracellular prolactin remained stable. Mean hemolytic plaque area was increased in the same manner by 17beta-estradiol pretreatment but the number of cells and the percentage of plaque-forming cells were not changed. Perifusion of dopamine-containing medium (10(-7) M) almost completely blocked basal prolactin release from light fraction cells and this inhibition was markedly reduced by 17beta-estradiol pretreatment. TRH-containing medium (10(-7) M) weakly stimulated basal prolactin release (about 190% from basal) and this response was significantly enhanced (to about 300% of basal release) by 17beta-estradiol pretreatment. Both dopaminergic inhibition and TRH-stimulatory effects were dose-dependent and their half maximal effect values were not changed by 17beta-estradiol pretreatment. Secretion of prolactin evaluated at the single cell level by the reverse hemolytic plaque assay corroborated the results obtained from perifusion experiments. Lactotrophs from heavy fractions released small amounts of prolactin (12 ng/ml/2 min/10(6) cells) and neither this basal release nor the amount of intracellular prolactin were markedly modified by 17beta-estradiol pretreatment. As opposed to the light fraction cells, lactotrophs found in heavy fractions were very sensitive to TRH (10(-7) M) stimulation with maximal stimulation reaching ten times basal release, but were less sensitive to dopamine (10(-7) M), with an inhibition of only 40% basal prolactin liberation. Pretreatment of heavy fraction lactotrophs with 17beta-estradiol induced similar effects to those observed after pretreatment of light fraction cells: the stimulation by TRH was increased (from 11 times to 16 times) whereas the inhibition by dopamine was diminished (from 35% to 60%), but cell number and the percentage of prolactin-secreting cells remained unchanged. From the above results, we suggest that: 1) lactotrophs in the lactating rat pituitary can be divided into two major subpopulations with regard to cellular size and density, prolactin production and responsiveness to TRH and dopamine; 2) 17beta-estradiol pretreatment increases basal prolactin release from light fraction cells but does not affect basal prolactin release from heavy fraction cells in this way; 3) pretreatment with 17beta-estradiol enhances TRH stimulation and reduces dopaminergic inhibition of prolactin release from lactotrophs.

In the rat medial nucleus accumbens, hippocampal and catecholaminergic terminals converge on spiny neurons and are in apposition to each other

The nucleus accumbens septi (Acb) represents an interface between limbic and motor systems and a site for modulation of these integrative functions by ascending catecholaminergic, principally dopaminergic, axons. This modulatory regulation is most likely attributed to pre- or postsynaptic associations between limbic telencephalic and brainstem afferents. In the present investigation, we examined the ultrastructure and synaptic associations of hippocampal afferents, as well as their relation to catecholaminergic terminals, in the medial Acb of adult rats. Hippocampal afferents were identified by anterograde transport of wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) injected in the ventral subiculum, and by anterograde degeneration seen 2–3 days following lesion of the fimbria. Specific comparisons between these methods were made (1) to determine whether similar populations of terminals were labeled and (2) to assess the feasibility of combining degeneration with immunoperoxidase labeling for the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH). Hippocampal afferents labeled with HRP were finely myelinated or unmyelinated and gave rise to small terminals (mean diameter 0.58 μm) containing mostly clear, round vesicles. Of the HRP-labeled terminals which made recognizable junctions, 85% (104/122) formed asymmetric synapses with the heads of dendritic spines. The remainder either formed asymmetric axodendritic synapses or symmetric junctions. Degenerating terminals were significantly smaller (mean diameter 0.35 μm) than terminals labeled with HRP. However, these also formed principally asymmetric axospinous synapses (89/102, 87%). Whether identified by HRP transport or anterograde degeneration, the hippocampal afferents comprised approximately 10% of all terminals and 30% of all asymmetric axospinous synapses in the medial Acb. In contrast to hippocampal afferents, TH-labeled terminals formed primarily symmetric contacts with dendritic shafts and the heads and necks of spines. Quantitative analysis of sections containing both anterograde degeneration and TH-immunoreactivity showed that 25% (26/104) of associations formed by degenerating hippocampal terminals involved convergent inputs with TH-labeled terminals on the same postsynaptic structure. These included dual input either to the same spine head or to different parts of the same dendrite. In addition, the plasma membranes of hippocampal and TH-labeled terminals were often directly apposed to each other (10/58, 17% of axo-axonal associations formed by degenerating terminals), without recognizable synaptic specializations. These results provide ultrastructural evidence consistent with (1) hippocampal excitation (asymmetric junctions) and dopaminergic inhibition (symmetric junctions) of certain common spiny neurons, (2) modulatory interactions between these afferents at the postsynaptic level, and (3) presynaptic modulation between transmitters in two physiologically diverse pathways to the medial Acb.

Neuroendocrine measures of dopaminergic function in chronic cocaine users

Plasma prolactin (PRL) and growth hormone (GH) levels are determined, in part, by the effects of dopamine (DA) at pituitary and hypothalamic DA receptors, respectively. To determine if chronic cocaine abuse alters dopaminergic activity, basal PRL and GH concentrations were measured in 16 male patients meeting DSM-III-R criteria for cocaine dependence (8 cocaine users and 8 cocaine + alcohol users) and 8 normal controls. In addition, the functional responsivity of DA receptors was assessed in the same group of patients by measuring the change in plasma PRL and GH concentration following the administration of the direct-acting DA agonist, apomorphine (0.01 mg/kg, s.c.) or saline. No difference in basal plasma PRL and GH levels or plasma PRL and GH responses to apomorphine administration was found between the entire group of cocaine patients and normal controls. However, three of the cocaine patients had basal plasma PRL levels that were more than 2.5 SD greater than that of the normal controls, suggesting that some interference of dopaminergic inhibition of PRL secretion might be present in at least some cocaine users. Although baseline plasma PRL levels were elevated in a subgroup of cocaine users, these data do not support the hypothesis that chronic cocaine abuse produces consistent abnormalities in dopaminergic function at the pituitary or hypothalamus.

Interaction between presynaptic dopaminergic inhibition and nicotinergic facilitation of acetylcholine release in the striatum

Interaction between presynaptic dopaminergic inhibition and nicotinergic facilitation of acetylcholine release in the striatum

Dopamine and Nonmodulating Hypertension

Sodium loading reduces aldosterone responses to angiotensin II (AII) when compared to the sodium restricted state. Recent investigations suggest that dopamine inhibits the aldosterone secretion and may contribute to the alteration in aldosterone response to AII with sodium intake, since administration of the dopamine antagonist, metoclopramide, enhances the aldosterone responses to AII on a high but not a low salt diet. Nonmodulating hypertension is characterized, in part, by a decreased aldosterone response to AII, raising the possibility that an increased dopaminergic inhibition of aldosterone secretion underlies the adrenal defect in nonmodulating hypertension. To assess this possibility, 69 patients with hypertension were characterized in relationship to their modulation status on a low sodium intake. Dopamine levels were significantly higher (P less than .05) in nonmodulators. To assess the physiologic relevance of these findings, the aldosterone response to AII infusion was assessed before and during administration of the dopamine antagonist, metoclopramide, in 13 patients. The adrenal response to AII did not change after metoclopramide in either hypertensive subgroup. Thus, it is unlikely that the adrenal defect is due to the increase in dopamine levels observed in nonmodulators. In the next study, the impact of dietary sodium intake on urinary dopamine levels was compared in normotensive and hypertensive subjects characterized as modulators and nonmodulators. Both modulators and normotensive subjects demonstrated an increase in urinary dopamine excretion in response to a high sodium intake--a feature that was not observed in the nonmodulators. Thus, the sodium retaining tendency of nonmodulators may reflect, at least in part, a reduction in intrarenal dopamine production in response to a sodium load.

EFFECT OF DOPAMINE AND A DOPAMINE D‐1 RECEPTOR AGONIST ON PULSATILE THYROTROPHIN SECRETION IN NORMAL WOMEN

The inhibitory effect of a pharmacological dose of dopamine and the specific dopamine D-1 receptor agonist fenoldopam on basal and pulsatile TSH secretion was investigated in normal women. The TSH response to fenoldopam and subsequent releasing hormone administration was also studied. Six women received placebo or dopamine infusion (4.0 micrograms/kg min) for 17 h. After 9 h, blood samples were collected every 10 min between 0800 and 1600 h for measurement of TSH. Eight women received 8-h (0900-1700 h) infusions of either fenoldopam (0.5 micrograms/kg min) or placebo. After 7 h of infusion 10 micrograms TRH, 5 micrograms GnRH and 25 micrograms CRF was given i.v. Blood samples were collected every 10 min. Dopamine infusion as well as fenoldopam infusion significantly reduced both mean basal TSH secretion and TSH pulse frequency compared with corresponding control infusions (P less than 0.05). However, while the effect on TSH pulsatility was comparable (P greater than 0.05), the percentage decrease in basal TSH levels after 16 h of dopamine infusion was 51 +/- 16% (mean +/- SD) and after 7 h of fenoldopam infusion 19 +/- 12% (P less than 0.05). Neither of the drugs affected TSH pulse amplitude and fenoldopam did not influence TRH-stimulated TSH release (P greater than 0.05). The results suggest that dopamine D-1 receptors are involved in modulation of TSH pulsatility probably at the hypothalamic level. It is argued that dopaminergic inhibition of basal TSH secretion and TSH pulsatility is predominantly regulated through dopamine D-2 receptors at the pituitary level, and through D-1 receptors at the hypothalamic level, respectively.

A high concentration of dopamine preferentially permitted release of newly synthesized prolactin

We used continuous labelling ([ 3H]leucine) of cultured adenohypophysial cells to investigate the relationship between the storage and release of newly synthesized and stored prolactin in response to dopamine (1 μmol/1) and thyrotropin-releasing hormone (TRH) (0.1 μmol/1) challenge. Newly synthesized prolactin was identified by the tritium radiation activity incorporated in prolactin. A maximal dose of dopamine (1 μmol/1) could not completely block prolactin release from a primary culture of lactotrophs. During 3 h of continuous labelling under maximal dopaminergic inhibition, newly synthesized prolactin was released which was of a significantly higher specific activity than control groups. In contrast, TRH stimulation produced results consistent with previous observations of the release of predominantly old, stored hormone. However, the absolute amount of the newly synthesized prolactin was increased by the TRH administration, and the increased release of the newly synthesized prolactin could be accounted for by increased levels of synthesis. Our results are consistent with the concept of the existence of a regulated route and a dopamine-insensitive constitutive route of prolactin release which predominantly encompasses newly synthesized hormone. However, the possibility that cellular heterogeneity or that non-dopaminergic prolactin-release inhibiting factor(s) (PIF) is responsible for this observed release cannot be ruled out.

Use of a pituitary cell dispersion method and primary culture system for the studies of gonadotropin-releasing hormone action in the goldfish, Carassius auratus II. Extracellular calcium dependence and dopaminergic inhibition of gonadotropin responses

Primary static cultures of dispersed goldfish pituitary cells obtained by controlled trypsinization released gonadotropin (GTH) in response to 2-hr stimulations of 0.1 n M to 1 μ M [Trp 7, Leu 8]-gonadotropin-releasing hormone (sGnRH), [ d-Arg 6, Pro 9- N-ethylamide]-sGnRH (sGnRHa), and [His 5, Trp 7, Tyr 8]-GnRH (cGnRH-II) in a dose-dependent manner. Coincubation with 10 to 1000 n M of a dopamine agonist, apomorphine, dose dependently reduced the GTH response to increasing concentrations of sGnRH. Apomorphine at 1 μ M completely abolished the dose-dependent GTH response to sGnRHa and cGnRH-II, but only partially inhibited the GTH-releasing action of high concentrations of sGnRH. Addition of calcium ionophores, 1 to 100 μ M A23187 and 10 to 100 μ M ionomycin, significantly increased GTH release. The ED 50s of the GTH response to A23187 and ionomycin were 0.88 ± 0.15 and 13.67 ± 2.76 μ M, respectively. Incubation with Ca 2+-deficient media, (media prepared without the addition of Ca 2+ salts) did not significantly affect basal GTH release, but severely decreased the hormone response to increasing concentrations of sGnRH, A23187, and ionomycin. These results confirm the direct inhibitory dopaminergic influence on GTH release in goldfish and further suggest that extracellular Ca 2+ plays a role in mediating GnRH action on gonadotropes in fish.

Coupling of a cloned rat dopamine-D2 receptor to inhibition of adenylyl cyclase and prolactin secretion.

We have previously described a cDNA which encodes a binding site with the pharmacology of the D2-dopamine receptor (Bunzow, J. R., VanTol, H. H. M., Grandy, D. K., Albert, P., Salon, J., Christie, M., Machida, C., Neve, K. A., and Civelli, O. (1988) Nature 336, 783-787). We demonstrate here that this protein is a functional receptor, i.e. it couples to G-proteins to inhibit cAMP generation and hormone secretion. The cDNA was expressed in GH4C1 cells, a rat somatomammotrophic cell strain which lacks dopamine receptors. Stable transfectants were isolated and one clone, GH4ZR7, which had the highest levels of D2-dopamine receptor mRNA on Northern blot, was studied in detail. Binding of D2-dopamine antagonist [3H]spiperone to membranes isolated from GH4ZR7 cells was saturable, with KD = 96 pM, and Bmax = 2300 fmol/mg protein. Addition of GTP/NaCl increased the IC50 value for dopamine competition for [3H]spiperone binding by 2-fold, indicating that the D2-dopamine receptor interacts with one or more G-proteins. To assess the function of the dopamine-binding site, acute biological actions of dopamine were characterized in GH4ZR7 cells. Dopamine, at concentrations found in vivo, decreased resting intra- and extracellular cAMP levels (EC50 = 8 +/- 2 nM) by 50-70% and blocked completely vasoactive intestinal peptide (VIP) induced enhancement of cAMP levels (EC50 = 6 +/- 1 nM). Antagonism of dopamine-induced inhibition of VIP-enhanced cAMP levels by spiperone, (+)-butaclamol, (-)-sulpiride, and SCH23390 occurred at concentrations expected from KI values for these antagonists at the D2-receptor and was stereoselective. Dopamine (as well as several D2-selective agonists) inhibited forskolin-stimulated adenylate cyclase activity by 45 +/- 6%, with EC50 of 500-800 nM in GH4ZR7 membranes. Dopaminergic inhibition of cellular cAMP levels and of adenylyl cyclase activity in membrane preparations was abolished by pretreatment with pertussis toxin (50 ng/ml, 16 h). Dopamine (200 nM) abolished VIP- and thyrotropin-releasing hormone-induced acute prolactin release. These data show conclusively that the cDNA clone encodes a functional dopamine-D2 receptor which couples to G-proteins to inhibit adenylyl cyclase and both cAMP-dependent and cAMP-independent hormone secretion.

A presumptive role for GABA in the stimulatory effects of desgly 10, [D-AlA 6]-LHRH-ethylamide and pimozide on the gonadotropin release in carp

To investigate the effect of endogenous γ-aminobutyric acid (GABA) on the blood maturating gonadotropin (GtH) levels, or to study its interaction with pimozide (dopamine antagonist) and a luteinizing hormone- releasing hormone analog (LHRH-a), sexually mature male and female carps were treated with drugs that may either inhibit GABA biosynthesis or GABA degradation. In females the irreversible inhibitor of GABA- transaminase, γ-vinyl GABA (GVG), which was to increase the endogenous GABA-ergic tone, had no influence on GtH release. On the other hand, the increased GtH response to the combination of pimozide (PIM) and LHRH-a was clearly enhanced by the administration of 3-mercaptopropionic acid (MPA), an inhibitor of the rate limiting enzyme of GABA-biosynthesis. In males the GABA-ergic compound, valproic acid (DPA) decreased LHRH-a stimulated GtH levels. In male carps that received PIM to diminish the dopaminergic inhibition of GtH release, the spermiating response to LHRH-a was increased by administration of MPA. These data suggest that GABA interacts with the action of dopamine and the gonadotropin releasing hormone (GnRH) on the release of GtH.

Septal dopaminergic–cholinergic interactions during stress

AbstractTo find out whether or not modification of the dopaminergic tone affects the stress response of the septo‐hippocampal cholinergic system, rats were treated with DA‐2 receptor agonist or antagonist. The findings indicate that after treatment with the DA antagonist sulpiride, when the septo‐hippocampal cholinergic system is released from tonic dopaminergic inhibition, it becomes activated to a certain level and cannot be further activated in response to acute stress. Enhancement of the dopaminergic tone, by treatment with the DA agonist apomorphine, may suppress the activation of the cholinergic system in response to acute stress. Thus, when stressful conditions are encountered, the initial transient activation of the septo‐hippocampal cholinergic system, which subsides within minutes, may be temporally related to a slower stress‐induced activation of the mesoseptal dopaminergic system. These results imply that septo‐hippocampal cholinergic activity represents an active pathway for major dopaminergic neuronal signals of stress.

Cocaine effects on pulsatile secretion of anterior pituitary, gonadal, and adrenal hormones.

Pulse frequency analysis of LH, PRL, testosterone, and cortisol was carried out with the Cluster Analysis Program in eight male cocaine abusers and eight aged-matched normal men. Four of the eight cocaine abusers had hyperprolactinemia (range, 22.08-44.65 micrograms/L). Cocaine users as a group had significantly higher mean peak height (P less than 0.02) than control subjects. Cocaine users with hyperprolactinemia had higher mean peak height than control subjects or cocaine users with normal PRL levels (P less than 0.01). Cocaine users with hyperprolactinemia also had higher mean amplitude increments than control subjects (P less than 0.02). Cocaine users with hyperprolactinemia had a higher mean valley than controls (P less than 0.01) and cocaine users with normal PRL levels (P less than 0.03). However, there were no significant differences in PRL peak frequency, peak duration, or interpulse intervals between cocaine users with or without hyperprolactinemia and control subjects. There were minimal differences between cocaine users and control subjects in pulse frequency analysis of LH parameters; the small differences in mean LH levels and average interpulse interval were not in the abnormal range and were probably not biologically significant. No differences between cocaine users and controls were detected for pulse frequency analysis of testosterone or cortisol. Cocaine-induced hyperprolactinemia may contribute to disorders of sexual and reproductive function in men who abuse the drug, and recent reports that PRL modulates immune function suggest that cocaine-induced derangements of PRL secretion may also contribute to cocaine-related comorbidity in infectious disease. Since cocaine users with hyperprolactinemia had a higher mean valley as well as a higher peak pulse PRL height than control subjects, but did not have greater PRL pulse frequencies, we conclude that hyperprolactinemia in these men may be due to a cocaine-induced derangement of dopaminergic inhibition of basal PRL secretion.

Impaired Down-Regulation of Pituitary Dopamine Receptors by Estradiol in Aged Rats

Administration of 17 beta-estradiol to mature (6-12 months) rats results in a more than 50% reduction in pituitary dopamine receptor concentrations, without affecting binding affinity. In contrast, when the same manipulation is performed on senescent (24-25 months) rats, negligible change in receptor concentration occurs. These results suggest that age-related increases in estrogen-stimulated prolactin release are not due to decreased dopaminergic inhibition at the receptor level.