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PubMed2006

An uncontrolled trial of cytisine (Tabex) for smoking cessation.

OBJECTIVES: Cytisine (Tabex) has been licensed in Eastern Europe as an aid to smoking cessation for 40 years. Cytisine is a partial agonist with high affinity binding to the alpha4beta2 nicotinic acetylcholine receptor believed to be central to the rewarding effect of nicotine. There is insufficient information on effectiveness to warrant licensing by modern standards. To assess whether full-scale controlled trials are warranted, this study sought to obtain an estimate of the 12-month continuous abstinence rates of smokers using cytisine with minimal behavioural support. DESIGN: An uncontrolled, open-label trial. SETTING: A smokers' clinic in an oncology centre in Warsaw, Poland. SUBJECTS: 436 consecutive attendees of the smokers' clinic of whom 191 were male. The mean dependence score (Fagerstrom Test for Nicotine Dependence) was 6.1. INTERVENTION: The standard regimen of Tabex (cytisine) was used, involving 25 days of treatment with minimal behavioural support. MAIN OUTCOME MEASURE: Self-reported continuous abstinence for 12 months; with abstinence verified by carbon monoxide at the final follow up (after 12 months). RESULTS: 60 participants (13.8% of the total sample) were abstinent for 12 months. Of the 315 subjects, who had taken the drug, 49 (15.5%) stopped cytisine because of adverse effects (mostly gastric disturbances and nausea), although they were not serious. The frequency of the minor adverse effects, primarily gastric disturbance, was similar to that observed in previous studies with the drug. CONCLUSIONS: The long-term abstinence rates were similar to those observed in smokers receiving nicotine replacement therapy. Full-scale randomised trials of cytisine (Tabex), conducted to the standards required by regulatory authorities, are warranted.

Adult↗
PubMed2004

Biodegradation of the nitramine explosives hexahydro-1,3,5-trinitro-1,3,5-triazine and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine in cold marine sediment under anaerobic and oligotrophic conditions.

The in situ degradation of the two nitramine explosives, hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), was evaluated using a mixture of RDX and HMX, incubated anaerobically at 10 degrees C with marine sediment from a previous military dumping site of unexploded ordnance (UXO) in Halifax Harbor, Nova Scotia, Canada. The RDX concentration (14.7 mg.L-1) in the aqueous phase was reduced by half in 4 days, while reduction of HMX concentration (1.2 mg.L-1) by half required 50 days. Supplementation with the carbon sources glucose, acetate, or citrate did not affect the removal rate of RDX but improved removal of HMX. Optimal mineralization of RDX and HMX was obtained in the presence of glucose. Using universally labeled (UL)-[14C]RDX, we obtained a carbon mass balance distributed as follows: CO2, 48%-58%; water soluble products, 27%-31%; acetonitrile extractable products, 2.0%-3.4%; and products covalently bound to the sediments and biomass, 8.9% (in the presence of glucose). The disappearance of RDX was accompanied by the formation of the mononitroso derivative hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) and formaldehyde (HCHO) that subsequently disappeared. In the case of HMX, mineralization reached only 13%-27% after 115 days of incubation in the presence or absence of the carbon sources. The disappearance of HMX was also accompanied by the formation of the mononitroso derivative. The total population of psychrotrophic anaerobes that grew at 10 degrees C was 2.6 x 10(3) colony-forming units.(g sediment dry mass)-1, and some psychrotrophic sediment isolates were capable of degrading RDX under conditions similar to those used for sediments. Based on the distribution of products, we suggest that the sediment microorganisms degrade RDX and HMX via an initial reduction to the corresponding mononitroso derivative, followed by denitration and ring cleavage.

Acetates↗
PubMed2003

Modulation of L-type Ca2+ channels in neonatal rat heart by a novel Ca2+ channel agonist.

L-type Ca2+ channels are essential in triggering the intracellular Ca2+ release and contraction in heart cells. In this study, we used patch clamp technique to compare the effect of two pure enantiomers of L-type Ca2+ channel agonists: (+)-CGP 48506 and the dihydropyridine (+)-SDZ-202 791 in cardiomyocytes from rats 2-5 days old. The predominant Ca2+ current activated by standard step pulses in these myocytes was L-type Ca2+ current. The dihydropyridine antagonist (+)-PN200-110 (5 microM) blocked over 90% of Ca2+ currents in most cells tested. CGP 48506 lead to a maximum of 200% increase in currents. The threshold concentration for the CGP effect was at 1 microM and the maximum was reached at 20 microM. SDZ-202 791 had effects in nanomolar concentrations and a maximum effect at about 2 microM. The maximal effect of (+)-SDZ-202 791 was a 400% increase in the amplitude of Ca2+ currents and was accompanied by a 10-15 mV leftward shift in the voltage dependence of activation. CGP 48506 increased the currents equally at all voltages tested. Both compounds slowed the deactivation of tail currents and lead to the appearance of slowly activating and slowly deactivating current components. However, SDZ-202 791 had larger effects on deactivation and CGP 48506 had larger effect on the rate of Ca2+ current activation. The effect of SDZ-202 791 was fully additive to that of CGP 48506 even after maximum concentrations of CGP. This observation suggests that the two Ca2+ channel agonists may act at two different sites on the L-type Ca2+ channel. We suggest that CGP 48506 would be a potential cardiotonic agent without the deleterious proarrhythmic effects attributable to the dihydropyridine agonists.

Animals↗
PubMed1988

Effects of a kappa-receptor agonist, U-50,488H, on the release of endogenous brain dopamine.

The potential interaction between kappa-opiate receptors and dopamine activity was examined in this study by monitoring the effect of U-50,488H on the release of endogenous dopamine from rat striatal slices in both the absence and presence of 10 microM nomifensine, a potent dopamine uptake inhibitor. Basal dopamine release was increased 10-fold in the presence of nomifensine, and the normally steady base line was observed to increase gradually under these conditions. U-50,488H, a potent kappa-agonist, enhanced the spontaneous release of dopamine, but only at relatively high concentrations (40.0 microM) and only in the absence of nomifensine. Likewise, nomifensine and U-50,488H (40.0 microM) each significantly inhibited the synaptosomal uptake of [3H]dopamine. As with basal release, nomifensine markedly enhanced the potassium-evoked release of dopamine, and this evoked release was significantly attenuated by U-50,488H (0.4 and 40.0 microM) in both the absence and presence of nomifensine. This opiate-mediated inhibition of evoked dopamine release was antagonized in a time-dependent manner by the putative kappa-antagonist, WIN 44,441-3, suggesting that striatal kappa-receptor activation modulates dopamine release.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

Endogenous opioids may mediate secondary damage after experimental brain injury.

Although endogenous opioids have been implicated in the pathophysiology of spinal cord injury and brain ischemia, the role of specific opioid peptides and opiate receptors in the pathophysiology of traumatic brain injury remains unexplored. This study examined regional changes in brain opioid immunoreactivity and cerebral blood flow (CBF) after fluid-percussion brain injury in the cat and compared the effect of an opiate antagonist (Win 44,441-3 [Win-(-)]) with its dextroisomer Win 44,441-2 [Win-(+)] (which is inactive at opiate receptors) in the treatment of brain injury. Dynorphin A immunoreactivity (Dyn A-IR) but not leucine-enkephalin-like immunoreactivity accumulated in injury regions after traumatic injury; Dyn-IR increases also occurred predominantly in those areas showing significant decreases in regional CBF. Administration of Win-(-) but not Win-(+) or saline at 15 min after injury significantly improved mean arterial pressure, electroencephalographic amplitude, and regional CBF and reduced the severity and incidence of hemorrhage. Win-(-) also significantly improved survival after brain injury. Taken together, these findings suggest that dynorphin, through actions at opiate receptors, may contribute to the pathophysiology of secondary brain injury after head trauma and indicate that selective opiate-receptor antagonists may be useful in treatment of traumatic brain injury.

Animals↗
PubMed1989

Opioid receptors and the initiation of migrating myoelectric complexes in dogs.

The role of endogenous opioids and opioid receptors in the control of migrating myoelectric complexes (MMCs) was studied in conscious dogs implanted with silver-silver chloride electrodes. In normal fasted dogs, MMC cycle times were 103 +/- 7 min in the duodenum. During naloxone infusion (1-2 mg/kg iv, then 0.2-1.0 mg.kg-1.h-1 iv) cycle times increased to 219 +/- 29 min (P less than 0.01). Naloxone (2 mg/kg iv, then 1 mg.kg-1.h-1 iv) had no effect on the response of the small intestine to bethanecol (5 mg sc) or to feeding. Pretreatment with naloxone (2 mg/kg iv) 5 min before the administration of motilin (400-500 micrograms/kg iv) did not block the initiation of MMCs by motilin. In separate experiments, animals were pretreated with the positive or negative isomer of the opioid receptor antagonist WIN-44,441 (0.2 mg/kg iv) 5 min before morphine administration. The negative isomer binds to opioid receptors whereas the positive isomer does not. The negative but not the positive isomer antagonized all effects of morphine on intestinal myoelectric activity. These studies suggest that endogenous opioids and opioid receptors may play a role in control of the initiation of MMCs and that motilin and exogenous opioids act via different mechanisms to initiate MMCs.

Animals↗
PubMed2000

Presynaptic nicotinic acetylcholine receptors in the myenteric plexus of guinea pig intestine.

Presynaptic nicotinic acetylcholine receptors (nAChRs) were studied in myenteric plexus preparations from guinea pig ileum using intracellular electrophysiological methods. Microapplication of nicotine (1 mM) caused a biphasic depolarization in all AH neurons (n = 30) and in 36 of 49 S neurons. Cytisine (1 mM) caused fast depolarizations in S neurons and no response in AH neurons. Mecamylamine (10 microM) blocked all responses caused by nicotine and cytisine. TTX (0.3 microM) blocked slow excitatory synaptic potentials in S and AH neurons but had no effect on fast depolarizations caused by nicotine. Nicotine-induced slow depolarizations were reduced by TTX in two of twelve AH neurons (79% inhibition) and four of nine S neurons (90+/-12% inhibition). Slow nicotine-induced depolarizations in the remaining neurons were TTX resistant. TTX-resistant slow depolarizations were inhibited after neurokinin receptor 3 desensitization caused by senktide (0.1 microM); senktide desensitization inhibited the slow nicotine-induced depolarization by 81+/-5% and 63+/-15% in AH and S neurons, respectively. A low-calcium and high-magnesium solution blocked nicotine-induced slow depolarizations in AH neurons. In conclusion, presynaptic nAChRs mediate the release of substance P and/or neurokinin A to cause slow depolarizations of myenteric neurons.

Alkaloids↗
PubMed1996

CGP-48506 increases contractility of ventricular myocytes and myofilaments by effects on actin-myosin reaction.

We measured the effects of the benzodiazocine derivative, CGP-48506 (5-methyl-6-phenyl-1,3,5,6-tetrahydro-3,6-methano-1, 5-benzodiazocine-2,4-dione), on contraction of intact myocytes and permeabilized fibers of rat ventricular muscle. CGP-48506 is unique in that it is able to sensitize cardiac myofilaments to Ca2+, but unlike all other agents in this class, it is not an inhibitor of type III phosphodiesterase. When added to isolated intact myocytes, CGP-48506 significantly increased the amplitude of cell shortening with little or no change in the Ca2+ transient, as determined by the fluorescence ratio of fura 2. The late phase of the relation between fura 2 ratio and cell length was shifted to the left in the presence of CGP-48506. CGP-48506 also induced a relatively small decrease in diastolic length. However, compared with the thiadiazinone EMD-57033, CGP-48506 had a much smaller effect on diastolic length at concentrations in which there was a bigger inotropic effect. When added to solutions bathing detergent-extracted (skinned) fiber bundles, CGP-48506 increased maximum force. CGP-48506 also increased submaximal force and shifted the pGa-force relation to the left. However, compared with EMD-57033, there was less of an effect of CGP-48506 on force at relatively high pCa values. CGP-48506 did not alter Ca2+ binding to myofilament troponin C. CGP-48506 was able to reverse inhibition of contraction induced by butanedione monoxime both in intact cells and in skinned fiber bundles. Our results indicate that CGP-48506, like EMD-57033, is a positive inotropic agent working through a direct effect downstream from troponin C. CGP-48506, however, appears to have a unique mechanism resulting in less effect on diastolic function.

Actin Cytoskeleton↗
PubMed1997

Relaxation effect of CGP-48506, EMD-57033, and dobutamine in ejecting and isovolumically beating rabbit hearts.

Because it is not known whether ejection influences the negative effect of the Ca(2+)-sensitizing drugs on ventricular relaxation, we extended our previous analysis of stress-dependent relaxation in isovolumic beats to encompass ejecting beats and evaluated the relationships between both the time of onset of relaxation and the rate of relaxation and wall stress in a broader analysis framework. Furthermore, because the sites of action of the Ca(2+)-sensitizing drugs CGP-48506 and EMD-57033 may be different, and thus CGP-48506 may have fewer adverse effects on resting muscle length or force, we compared these two drugs to test the hypothesis that CGP-48506 would have less effect than EMD-57033 on relaxation in the isolated buffer-perfused rabbit heart. This analysis of stress-dependent relaxation in both ejecting and isovolumic beats readily differentiates between the negative lusitropic effect of 2 x 10(-6) M EMD-57033, the negligible lusitropic effect of 6 x 10(-6) M CGP-48506, and the positive lusitropic effect of 1.25 x 10(-6) M dobutamine. Furthermore, comparison of the effect of the two Ca(2+)-sensitizing drugs in ejecting versus isovolumic contractions shows that CGP-48506 affects relaxation differently in ejecting contractions than it does in isovolumic contractions, whereas EMD-57033 affects relaxation similarly in both ejecting and isovolumic contractions.

Animals↗
PubMed1994

Nicotine and acetylcholine induce release of calcitonin gene-related peptide from rat trachea.

In the present study, we observed that nicotine, the nicotinic analogue cytisine, and acetylcholine (ACh) evoked a concentration-dependent (5 x 10(-6)-5 x 10(-5) M) release of calcitonin gene-related peptide (CGRP) from the rat trachea. After a prolonged exposure to capsaicin, nicotine-induced CGRP release was absent, suggesting that the release of CGRP by nicotine is derived from capsaicin-sensitive afferent terminals. Nicotine- and cytisine-induced release displayed a significant degree of tachyphylaxis after sequential exposures. The release of CGRP evoked by capsaicin was also reduced after nicotine and cytisine desensitization. This indicates that similar mechanisms may mediate the tachyphylactic effect of capsaicin and nicotine. Hexamethonium and mecamylamine blocked the effect of nicotine but not that of ACh, whereas atropine significantly attenuated the release of CGRP outflow induced by ACh. Physostigmine and neostigmine did not alter resting release of CGRP from rat trachea, although exogenous (10(-5) M) ACh-induced CGRP release was enhanced in the presence of neostigmine, suggesting minimal tonic cholinergic activity in this model. We conclude that activation of nicotinic and muscarinic receptors in the rat trachea can induce local release of CGRP. These observations indicate that cholinergically induced airway responses may be mediated in part by activation of the peripheral terminals of primary afferent sensory neurons and subsequent release of local neuropeptides.

Acetylcholine↗
PubMed2002

A non-alpha7 nicotinic acetylcholine receptor modulates excitatory input to hippocampal CA1 interneurons.

The nicotinic acetylcholine receptor (nAChR), particularly the alpha7 subtype, has received profound attention for its role in modifying excitatory postsynaptic currents (EPSCs) in hippocampal pyramidal neurons as well as in neurons from other brain regions. Here, we tested the possibility that an nAChR could affect EPSCs in the interneurons of rat hippocampal slices. Using whole-cell patch-clamp technique on CA1 stratum radiatum interneurons and U-tube application of agents, we show that nicotinic agonists enhance EPSC frequency in interneurons. Among the agents tested, cytisine and mecamylamine were the most effective agonist and antagonist, respectively, suggesting a role for alpha3beta4-containing nAChRs in the modulation of interneuron EPSCs. Ligands selective for the alpha7 nAChR had very little or no effect on interneuron EPSCs. Low concentrations of nicotine also enhanced EPSC frequency, implicating the involvement of non-alpha7 nAChRs in controlling interneuron excitability in smokers. We conclude that nAChR-dependent EPSC modulation in the hippocampus is both subtype- and neuron-specific and that a non-alpha7 nAChR, presumably alpha3beta4, controls glutamate transmission to CA1 interneurons.

Acetylcholine↗
PubMed2001

Dorsal root ganglion neurons express multiple nicotinic acetylcholine receptor subtypes.

Although nicotinic agonists can modulate sensory transmission, particularly nociceptive signaling, remarkably little is known about the functional expression of nicotinic acetylcholine receptors (nAChRs) on primary sensory neurons. We have utilized molecular and electrophysiological techniques to characterize the functional diversity of nAChR expression on mammalian dorsal root ganglion (DRG) neurons. RT-PCR analysis of subunit mRNA in DRG tissue revealed the presence of nAChR subunits alpha2-7 and beta2-beta4. Using whole cell patch-clamp recording and rapid application of nicotinic agonists, four pharmacologically distinct categories of nicotinic responses were identified in cultured DRG neurons. Capacitance measurements were used to divide neurons into populations of large and small cells, and the prevalence of nicotinic responses was compared between groups. Category I (alpha7-like) responses were seen in 77% of large neurons and 32% of small neurons and were antagonized by 10 nM methyllycaconitine citrate (MLA) or or 50 nM alpha-bungarotoxin (alpha-BTX). Category II (alpha3beta4-like) responses were seen in 16% of large neurons and 9% of small neurons and were antagonized by 20 microM mecamylamine but not 10 nM MLA or 1 microM DHbetaE. Category II responses had a higher sensitivity to cytisine than nicotine. Two other types of responses were identified in a much smaller percentage of neurons and were classified as either category III (alpha4beta2-like) or category IV (subtype unknown) responses. Both the alpha7-like and alpha3beta4-like responses could be desensitized by prolonged applications of the analgesic epibatidine.

Acetylcholine↗
PubMed2002

Nicotinic receptor gene cluster on rat chromosome 8 in nociceptive and blood pressure hyperresponsiveness.

Spontaneously hypertensive rats (SHR) exhibit enhanced pressor, heart rate, and nociceptive responses to spinal nicotinic agonists. This accompanies a paradoxical decrease in spinal nicotinic receptor number in SHR compared with normotensive rats. The congenic strain, SHR-Lx, with an introgressed chromosome 8 segment from the normotensive Brown-Norway-Lx strain (BN-Lx) exhibits reduced blood pressure. This segment contains a gene cluster for three nicotinic receptor subunits expressed in the nervous system. We examined the implication of this gene cluster in the enhanced responsiveness of the SHR. Pressor and nociceptive responses to spinal cytisine, a nicotinic agonist, were diminished in SHR-Lx. Moreover, with repeated administration, these responses desensitized faster in SHR-Lx and progenitor BN-Lx than in progenitor SHR/Ola. This implicates the gene cluster in both cardiovascular and nociceptive responses to spinal nicotinic agonists. Since diminished responsiveness to agonist stimulation is greater than the basal blood pressure differences between the strains and the introgressed rat chromosome maps to a quantitative trait locus in human hypertension, polymorphisms in the three nicotinic receptor genes become candidates for altered central control of blood pressure.

Alkaloids↗
PubMed1989

Third ventricular injection of alpha-bungarotoxin decreases pulsatile luteinizing hormone secretion in the ovariectomized rat.

The injection of purified alpha-bungarotoxin (alpha-BTX), an antagonist of the muscle nicotinic cholinergic receptors, into the third ventricle (3rd V) of ovariectomized rats decreased the frequency of pulses of luteinizing hormone (LH) but had no significant effect on the amplitude or nadir of LH secretion. Approximately 24 h after the 3rd V injection of alpha-BTX, the pulsatile secretion rate of LH was increased and thus the alpha-BTX effect was reversible. The 3rd V injection of the two nicotinic cholinergic agents, cytisine (10 micrograms) and dihydro-beta-erythroidine, also decreased the frequency of pulses of LH. Cytisine and dihydro-beta-erythroidine inhibited the binding of (125I)alpha-BTX to rat hypothalamic synaptosomes (P2B) and also to frozen coronal sections of the hypothalamus as studied by film autoradiography. Injection of a lower dose of cytisine (1 micrograms) had no effect on LH secretion, but when administered with alpha-BTX into the 3rd V, cytisine significantly reduced the alpha-BTX-induced decreased LH secretion. The injection of cytisine with (125I)alpha-BTX into the 3rd V also decreased in vivo labeling of the (125I)alpha-BTX-binding sites in the hypothalamus of ovariectomized rats. The results suggest that alpha-BTX can inhibit the pulsatile secretion of LH in ovariectomized rats and this inhibition may be mediated by specific subclass of a CNS (central nervous system) nicotinic acetylcholine receptor.

Alkaloids↗
PubMed1991

Endogenous opioid suppression of luteinizing hormone pulse frequency and amplitude in the ewe: hypothalamic sites of action.

Evidence suggests that endogenous opioid peptides (EOP) inhibit pulsatile luteinizing hormone (LH) secretion during both the luteal and follicular phases of the ovine estrous cycle. Further data from sheep and other species indicate that the hypothalamus is the primary site of action for this EOP inhibition. The purpose of the following experiments was to determine which areas of the hypothalamus are involved in the EOP inhibition of pulsatile LH secretion. Regularly cycling ewes (n = 10) were stereotaxically implanted with guide tubes into the preoptic area (POA) and medial basal hypothalamus (MBH). Implants containing the EOP antagonist WIN 44,441-3 (WIN) were placed into each of these areas. Blood samples were collected at 12-min intervals for 3 h before and during WIN administration in the luteal phase and for 4 h before and during WIN administration in the follicular phase of the estrous cycle. During the luteal phase, WIN implants in either area increased (p less than 0.01) LH pulse frequency (POA 1.4 +/- 0.3/3 h before vs. 3.1 +/- 0.4/3 h during; MBH 1.1 +/- 0.2/3 h before vs. 2.8 +/- 0.5/3 h during). There was no effect on LH pulse amplitude. In contrast, during the follicular phase, WIN implants selectively increased (p less than 0.01) LH pulse frequency when implanted in the POA (3.2 +/- 0.4/4 h before vs. 5.2 +/- 0.6/4 h during) while increasing (p less than 0.05) only LH pulse amplitude when placed in the MBH (0.7 +/- 0.2 ng/ml before vs. 1.4 +/- 0.3 ng/ml during).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Immunocytochemical localization of beta endorphin and gonadal steroid regulation of proopiomelanocortin messenger ribonucleic acid in the ewe.

In the ewe, estradiol and progesterone inhibit luteinizing hormone (LH) secretion during the breeding season. Endogenous opioid peptides (EOP) are also inhibitory to LH secretion, and both estrogen and progesterone have been reported to enhance EOP inhibition of LH release. Which EOP are involved in this inhibition is unclear. In this study, we concentrated on beta-endorphin because evidence for its ability to inhibit LH secretion exists in ewes. We first studied the distribution of beta-endorphin-immunoreactive neurons in 4 cycling ewes using immunocytochemistry. Cell bodies were found only within the medial basal hypothalamus (MBH) and were concentrated in arcuate nucleus and mammillary recess of the third ventricle, with a few in the median eminence. Extensive fiber tracts were seen in preoptic area (POA) and median eminence. We next tested the hypothesis that gonadal steroids increase the synthesis of EOP by measuring levels of mRNA for proopiomelanocortin (POMC), the precursor to beta-endorphin. Ovariectomized ewes were treated with no steroids (n = 7) or given subcutaneous Silastic implants containing either estradiol (n = 6) or progesterone (n = 6). After 4 days of treatment, EOP inhibition of LH secretion was measured by determining the LH response to WIN 44,441-3 (WIN), an EOP antagonist. LH pulse frequency and pulse amplitude were determined in blood samples collected at 12-min intervals for 3 h before and after intravenous administration of 12.5 mg WIN. WIN injection increased (p < 0.01) the LH pulse-frequency only in progesterone-treated and pulse amplitude only in estradiol-treated ewes. After blood sampling, the ewes were killed, and POA, MBH, and pituitary gland were removed. Total RNA was extracted from these tissues and dot blotted onto nitrocellulose membranes for hybridization with a DNA probe complementary to the POMC mRNA. The resulting autoradiographs were quantified densitometrically. Levels of POMC mRNA in the MBH were increased (p < 0.01) by both estradiol and progesterone as compared with the no steroid group. There was no detectable POMC mRNA in the POA. These results suggest that estrogen and progesterone enhance EOP inhibition of LH secretion by increasing POMC mRNA levels and thus synthesis of beta-endorphin.

Animals↗
PubMed1995

Nicotinic agonists administered into the fourth ventricle stimulate norepinephrine secretion in the hypothalamic paraventricular nucleus: an in vivo microdialysis study.

Nicotinic cholinergic agonists stimulate ACTH secretion by a central mechanism involving brainstem catecholamines. In vivo microdialysis studies were conducted to measure the release of norepinephrine (NE) in the hypothalamic paraventricular nucleus (PVN) in response to the administration of nicotine (Nic) or another nicotinic cholinergic (NAch) agonist, cytisine (Cyt), directly into the IVth ventricle. Alert, freely mobile rats, equipped 24 h previously with a chronic guide cannula in the IVth ventricle and microdialysis probe in the PVN, were injected with artificial cerebrospinal fluid (CSF, 500 nl/60 s), Nic (1-5 micrograms), or Cyt (1-25 micrograms) after three 20-min baseline samples had been taken. Analysis of the dialysates by HPLC with electrochemical detection demonstrated the dose-dependent secretion of PVN NE to Nic or Cyt with ED50s of approximately 1 or 6 micrograms, respectively; these were completely blocked by prior IVth ventricular injection of the NAch antagonist, mecamylamine (4 micrograms). In contrast, alpha-bungarotoxin, which antagonizes the action of NAch agonists by acting through the alpha 7 bungarotoxin-type NAchR, failed to reduce the NE response to Nic. Partial, but significant desensitization of NE secretion in response to a second injection of Nic (2.5 or 5 micrograms) 100 min after the first was seen, whereas NE responses to the second injection of Cyt (5 or 25 micrograms) were completely desensitized. However, cross-desensitization of each agonist to the other did not occur. This may reflect heterogeneity of the NAch receptor subtypes involved. The results of this study establish a correlation between the action of nicotine on brainstem norepinephrinergic regions and the resultant release of NE in the PVN, which would lead to the release of ACTH secretagogues.

Alkaloids↗