Effects of nicotine on neocortical electrical activity in rats

The present study investigates the effects of acute and repeated nicotine i.p. treatment on cortical EEG activity. Nicotine at 0.3 and 0.9 mg/kg, but not at 0.1 mg/kg, decreased high voltage spindles (HVSs). Nicotine at 2.7 mg/kg suppressed HVSs completely. Mecamylamine, a nicotinic cholinergic antagonist, increased HVSs at 5 and 7.5 mg/kg. Nicotine blocked the HVS induction induced by mecamylamine. Mecamylamine at 1.25 mg/kg antagonized the HVS suppressing action of nicotine at 0.3 mg/kg. The muscarinic cholinergic antagonist, scopolamine (0.2 mg/kg), increased the 1 to 20 Hz amplitude sum value, and this increase was blocked to some extent by the highest dose of nicotine (2.7 mg/kg). However, nicotine did not block the effect of a higher scopolamine (2.0 mg/kg) dose on the sum amplitude values. Mecamylamine at 2.5 and 7.5 mg/kg blocked the effect of nicotine at 2.7 mg/kg on the EEG sum amplitude values in scopolamine (0.2 mg/kg)-treated rats. The peripherally acting nicotinic and muscarinic cholinergic antagonists, hexamethonium and scopolamine methylbromide, had no effect on spectral EEG and HVS values. In quisqualic acid nucleus basalis-lesioned rats, a frontal cortical choline acetyltransferase depletion (-72%) and slowing of the EEG was observed. Nicotine could not restore EEG activity in nucleus basalis-lesioned rats. After repeated (10 days, three injections/day) administration of nicotine, no tolerance to the effects of either nicotine (0.9 mg/kg) on spontaneously occurring HVSs or nicotine (2.7 mg/kg) on the EEG change induced by scopolamine was observed. The present results show that nicotinic receptor stimulation desynchronizes neocortical EEG activity in normal animals, but this action disappears in basal forebrain-lesioned animals. Therefore, it is likely that the effects of nicotine in reversing EEG and behavioral abnormalities observed in Alzheimer's disease may be limited if the basal forebrain cell loss is extensive.     

Suppression of neocortical high-voltage spindles by nicotinic acetylcholine and 5-HT2 receptor stimulation

To investigate the roles of the nicotinic acetylcholine receptor and the serotonin (5-hydroxytryptamine; 5-HT) subtype 2 receptor in the modulation of rat thalamocortical oscillations, the effects of systemic (s.c.) administration of nicotine, a nicotinic acetylcholine receptor agonist, and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2 receptor agonist, on neocortical high-voltage spindle activity occurring during quiet waking-immobility behavior in aged (28 months of age) and adult (7 months of age) rats were studied. Nicotine 0.1 and 0.3 mg/kg alleviated the age-related increase of neocortical high-voltage spindles, whereas in adult rats only nicotine 0.3 mg/kg was effective. DOI 0.3, 1.0 and 2.0 mg/kg suppressed high-voltage spindles in both aged and adult rats. In aged rats, a combination of subthreshold doses of nicotine (0.03 mg/kg) and DOI (0.1 mg/kg) decreased neocortical high-voltage spindles, whereas in adult rats two different subthreshold dose combinations (nicotine 0.03 or 0.1 mg/kg+DOI 0.1 mg/kg) had no effect. p-Chlorophenylalanine (400 mg/kg/day i.p. for 3 consecutive days) treatment decreased brain serotonin concentration (> 80% reduction), but did not affect high-voltage spindles. However, in both aged and adult rats, p-chlorophenylalanine treatment blocked the decrease in high-voltage spindle activity produced by DOI 0.3 mg/kg, though not the decrease produced by higher doses of DOI (1.0 and 2.0 mg/kg). It is important that, in adult rats, p-chlorophenylalanine treatment was able to abolish the decrease in high-voltage spindle activity seen after a relatively high dose of nicotine (0.3 mg/kg). The results suggest that nicotinic acetylcholine and 5-HT2 receptors may act in concert to suppress neocortical high-voltage spindling in rats, and that intact brain serotonergic systems may be important for some of the therapeutic effects of nicotine.     

Role of renal interstitial pressure on chronic control of arterial blood pressure

We examined the modulatory effect of serotonergic activities on haloperidol-induced up-regulation of dopamine D2 receptors in rat striatum. Chronic treatment with haloperidol (0.1, 0.5 mg/kg, i.p., 3 weeks) increased the number of dopamine D2 receptors, while no increase was observed with atypical antipsychotic drugs clozapine (10 mg/kg) and ORG 5222 (0.25 mg/kg). Chronic treatment with MK 212, a serotonin (5-HT)2A/2C receptor agonist (2.5 mg/kg), or with citalopram, a 5-HT reuptake inhibitor (10 mg/kg), potentiated the haloperidol (0.1 mg/kg)-induced up-regulation of dopamine D2 receptor, while that with (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a 5-HT1A receptor agonist (0.1 mg/kg), had no influence on the dopamine D2 receptor up-regulation. Co-administration of ritanserin (1 mg/kg), a 5-HT2A/2C receptor antagonist, with a low dose of haloperidol (0.1 mg/kg), but not with a high dose of the agent (0.5 mg/kg), attenuated the dopamine D2 receptor up-regulation. Drug occupation of 5-HT2A and dopamine D2 receptors in vivo examined with use of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was 69.8% and 45.1%, respectively, after the acute administration of haloperidol (0.1 mg/kg) plus ritanserin (1 mg/kg). This profile that 5-HT2A receptors were highly occupied compared with dopamine D2 receptors was similar to that of clozapine or ORG 5222. These results suggest that potent 5-HT2A receptor antagonism versus weak dopamine D2 receptor blockade may be involved in the absence of up-regulation of dopamine D2 receptors after chronic treatment with clozapine or ORG 5222.     

Role of rpoS in the regulation of glutathione oxidoreductase (gor) in Escherichia coli

Caffeine (10-40 mg/kg, p.o.) enhanced locomotor activity (LA). Administration of GABA antagonist, bicuculline (0.5-1.0 mg/kg, i.p.), potentiated this caffeine-induced increase of LA, as well as LA of control rats. Treatment with the GABA agonist, muscimol (0.25-1 mg/kg, i.p.) or dopaminergic antagonist, haloperidol (0.25-1 mg/kg, i.p.) or muscarinic receptor blocker, atropine (3.75-5 mg/kg, i.p.), or inhibitor of acetylcholine esterase physostigmine (0.05-0.30 mg/kg, i.p.) or nicotine (0.5-1.5 mg/kg, i.p.) an nicotinic receptor agonist all decreased the LA of both caffeine-treated and control rats. Haloperidol-induced reduction in caffeine-induced increase in LA was found to be withdrawn with higher dose of caffeine. The dopamine agonist L-Dopa (75-150 mg/kg, p.o.) along with carbidopa (10 mg/kg, p.o.) increased the LA in control rats and potentiated the LA of caffeine treated rats. The haloperidol attenuated the bicuculline-induced increase in LA and atropine or physostigmine attenuated the bicuculline or L-Dopa + carbidopa-induced increase in LA in both caffeine treated and control rats when those drugs were administered concomitantly with bicuculline or L-Dopa+carbidopa. These results suggest that (a) the GABAergic system has direct role in the regulation of LA, and (b) caffeine potentiates LA by antagonism of the adenosine receptor and activation of the dopaminergic system which, in turn, reduces GABAergic activity through the reduction of cholinergic system.     

Ozone-induced loss of neuronal M2 muscarinic receptor function is prevented by cyclophosphamide

We tested the hypothesis that inflammatory cells mediate the loss of neuronal M2 muscarinic receptors in the lung after ozone exposure. Pathogen-free guinea pigs treated with cyclophosphamide (30 mg.kg-1.day-1 i.p. for 7 days) before exposure to ozone were compared with untreated ozone-exposed animals. This dose of cyclophosphamide significantly reduced leukocytes in peripheral blood and bronchoalveolar lavage fluid. Twenty-four hours after ozone, muscarinic receptor function was tested in anesthetized animals. In air-exposed guinea pigs, vagally induced bronchoconstriction was attenuated by the muscarinic agonist pilocarpine (0.1-100 micrograms/kg i.v.) and potentiated by the selective M2 antagonist gallamine (0.1-10 mg/kg i.v.), indicating that the neuronal M2 muscarinic receptors were functioning. These responses were significantly reduced after ozone, indicating loss of neuronal M2 muscarinic receptor function. However, in those animals treated with cyclophosphamide, M2 muscarinic receptor function was not altered by ozone. These data suggest that ozone-induced loss of neuronal muscarinic receptor function is mediated via inflammatory cells and that the link between ozone-induced hyperresponsiveness and inflammation may be the neuronal M2 muscarinic receptor.     

Midline cervical cleft

The effect of m-chlorophenylbiguanide, a selective 5-HT3 receptor agonist, on gastric antral motility was investigated in conscious dogs with a force transducer implanted chronically. m-Chlorophenylbiguanide (0.1-1 mg/kg i.v.) dose dependently enhanced antral motility in the fasted state, and the amplitude of m-chlorophenylbiguanide (1 mg/kg i.v.)-induced antral contractions reached the level of natural phase III contractions. In contrast, m-chlorophenylbiguanide reduced the amplitude of antral contractions in the fed state. A selective 5-HT3 receptor antagonist, ramosetron (0.0003-0.03 mg/kg i.v.), inhibited both effects of m-chlorophenylbiguanide. m-Chlorophenylbiguanide (1 mg/kg i.v.)-induced contractions were inhibited by atropine (0.03 or 0.1 mg/kg i.v.). These results indicate that pharmacological activation of 5-HT3 receptors has opposite effects on canine gastric antral motility in the fasted and in the fed state, being stimulatory and inhibitory, respectively. The stimulatory effect seems to be mediated mainly via the release of acetylcholine.     

Myocardial bridging in a survivor of sudden cardiac near-death: role of intracoronary doppler flow measurements and angiography during dobutamine stress in the clinical evaluation

Studies were carried out using DBA/2 mice on the relationship between the behavioral effects of antagonists of different types of 5-HT receptors and the level of activity of alpha 2-adrenoceptors. The 5-HT1c receptor antagonists mianserin (2 mg/kg) and cyproheptadine (2 mg/kg) and the 5-HT2 receptor antagonist ketanserin (3 mg/kg) had no effect on movement activity, while the 5-HT3 and 5-HT4 receptor antagonists zacopride (1 mg/kg) and ICS 205-930 (1 mg/kg) reduced movement behavior in intact animals. On a background of treatment with the alpha 2-adrenoceptor blocker yohimbine (0.5 mg/kg), mianserin, cyproheptadine, and ketanserin inhibited movement activity and significantly reduced the sensitivity of animals to audiogenic convulsions. These data indicate that administration of alpha 2-adrenoceptor antagonists increases the efficiency with which serotonin receptors regulate behavior.     

Discriminative stimulus properties of the atypical neuroleptic clozapine in rats: tests with subtype selective receptor ligands

The interoceptive stimulus induced by clozapine (5 mg/kg, i.p.) has been characterized in an operant drug discrimination procedure in the rat using a wide range of receptor subtype-selective agonists and antagonists. Only the muscarinic receptor antagonist scopolamine generalized fully to clozapine (>80%). Partial generalization (defined here as 40% maximal generalization) was seen with the D1 receptor antagonist SCH 23390 (43% maximal generalization), the alpha1-adrenoceptor antagonist prazosin (67%) and the alpha2-adrenoceptor antagonist methoxyidazoxan (42%). All other specific agents tested induced <25% maximal generalization, including the alpha2-adrenoceptor antagonist yohimbine (24%), the histamine H1 receptor antagonist mepyramine (21%), the D2 antagonist typical neuroleptic haloperidol (23%), the D4 receptor antagonist L-745,870 (14%), the 5-hydroxytryptamine-1A (5-HT1A) receptor agonist S-14506 (8%), the 5-HT2A receptor antagonists ketanserin (0%) and M100907 (12%), the 5-HT2B/2C receptor antagonists SB 200646A (8%) and SDZ SER 082 (6%), and the 5-HT3 receptor antagonist ondansetron (0%). The clozapine discriminative stimulus was not blocked by the dopamine D1 receptor antagonist SCH 23390, or by the 5-HT1A receptor antagonist WAY 100635, when given concomitantly with clozapine. Although the results suggest that muscarinic antagonism plays a major role in the clozapine cue, the results have to be considered in the light of the full generalization to clozapine seen with various antipsychotic agents which have very low affinity for muscarinic receptors, including zotepine, quetiapine, JL13 and PNU 96415 (a finding replicated in rats from the same breeding colony as those which generalized to scopolamine). Thus, generalization to clozapine for antipsychotics with multiple affinities but with low muscarinic affinity is probably mediated by additive or perhaps supra-additive actions at other receptors, although extensive studies with various combinations of drug mixtures are required to validate this hypothesis.     

GR 127935 and (+)-WAY 100135 do not affect TFMPP-induced inhibition of 5-HT synthesis in the midbrain and hippocampus of Wistar-Kyoto rats

Wistar-Kyoto (WKY) rats display high emotivity (e.g. anxiety), compared to Wistar rats. The key role of serotonin (5-HT)1B/1D autoreceptors in 5-HT neurotransmission, and its consequences on emotivity, led us to measure the effects of the nonselective 5-HT1B/1D) receptor agonist m-trifluoromethyl-phenylpiperazine (TFMPP) on central tryptophan hydroxylase activity in male WKY and Wistar rats. In addition to strain-dependent differences in central 5-HT synthesis (WKY > Wistar), acute administration of TFMPP (1.5 and 3 mg/kg) decreased the amplitude of m-hydroxy-benzylhydrazine-elicited accumulation of hippocampal, striatal and cortical 5-hydroxytryptophan (5-HTP) in both strains. In midbrain, however, TFMPP decreased 5-HTP accumulation (but not tryptophan levels) in WKY rats only, whereas the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.2 mg/kg) decreased midbrain 5-HTP levels to a similar extent in both strains. Pretreatment of WKY rats with the selective 5-HT1B/1D receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1, 2,4-oxadiozol-3-yl)-biphenyl-4-carboxamide (GR 127935, 1.5 and 3 mg/kg) slightly increased midbrain tryptophan hydroxylase activity but did not affect the negative effect of TFMPP on 5-HTP formation. Pretreatment with the 5-HT1A receptor antagonist (+)-N-tert-butyl-3-(4-[2-methoxyphenyl]piperazin-1-yl)-2-phenylpro panamide ((+)-WAY 100135; 3 mg/kg), which decreased the inhibitory effect of 8-OH-DPAT on midbrain 5-HTP levels by 50%, did not alter that of TFMPP. Lastly, neither reserpine (5 mg/kg), ketanserin (1 mg/kg) mianserin (2 mg/kg) nor idazoxan (1 mg/kg) pretreatments affected TFMPP-induced inhibition of midbrain 5-HTP formation, ruling out a role for monoamine release, 5-HT2 receptors and alpha2-adrenoceptors. Our data show that TFMPP, an agonist often used to stimulate 5-HT1B/1D receptors, may inhibit central 5-HT synthesis through nonserotonergic mechanisms.     

Rapid increase in cytosolic calcium ion concentration mediated by acetylcholine receptors in cultured retinal neurons and Müller cells

PURPOSE: This study was conducted to detect the presence of muscarinic or nicotinic receptors in cultured retinal neurons and Müller cells. METHODS: Pure Müller cell cultures and cocultures of retinal neurons and Müller cells were used; the former, obtained from adult rabbit retinas, and the latter, retinal neurons from neonatal rats, were cocultured with Müller cells. Intracellular calcium ion concentration ([Ca2+]i) following the administration of acetylcholine, a cholinesterase inhibitor (trichlorfon), nicotine or muscarinic agonist with or without a receptor antagonist was monitored using the calcium ion indicator, fura-2. RESULTS: Acetylcholine and trichlorfon induced rapid increase in [Ca2+]i in half of either cell type. Trichlorfon induced positive response in coculture but not in the pure Müller cell cultures. This positive response was blocked only partially in the presence of atropine. Approximately 30-40% of neurons responded to nicotine at 5 microM, which was significantly blocked by alpha-bungarotoxin at 50 nM. No response to nicotine could be detected in Müller cells. Approximately 50% of neurons responded to muscarine at 50 microM, but 500 microM was required for the formation of calcium transients in 50% of Müller cells. The muscarine inducement of rapid increase in [Ca2+]i was blocked by atropine. The agonist of M1 (a muscarinic receptor subtype), McN-A-343, at 0.5 microM induced the most significant and rapid increase in [Ca2+]i both in neurons and Müller cells. McN-A-343 administration at 0.05 microM induced positive response in half the neurons, but only in approximately 10% of Müller cells. Such positive response was not observed following preincubation with the M1 antagonist, pirenzepine, at 50 microM. CONCLUSIONS: Cocultured retinal neurons enhance the release of acetylcholine following anticholinesterase administration, and approximately half the neurons were found to possess muscarinic and nicotinic receptors. However, Müller cells appeared to possess only the less sensitive muscarinic receptor. Muscarinic receptor subtypes on either type of cell contained at least M1.     

In vivo electrophysiological characterization of 5-HT receptors in the guinea pig head of caudate nucleus and orbitofrontal cortex

The aim of the present study was to characterize in vivo the 5-HT receptor subtypes which mediate the effect of microiontophoretic applied 5-HT in the guinea pig head of caudate nucleus and orbitofrontal cortex. 5-HT and the preferential 5-HT2A receptor agonist DOI and the preferential 5-HT2C receptor agonist mCPP, suppressed the quisqualate (QUIS)-induced activation of neurons in both structures. The inhibitory effect of DOI and mCPP was not prevented by acute intravenous administration of the 5-HT1/2 receptor antagonist metergoline (2 mg/kg) and the 5-HT2A/2C receptor antagonist ritanserin (2 mg/kg) in the two regions nor by the selective 5-HT2A receptor antagonist MDL100907 (1 mg/kg) in the head of caudate nucleus. However, the inhibitory effect of DOI, but not that of mCPP, was antagonized by a 4-day treatment with metergoline and ritanserin (2 mg/kg/day; using minipumps implanted subcutaneously) in head of caudate nucleus, but not in orbitofrontal cortex. Microiontophoretic ejection of the 5-HT1A/7 receptor agonist 8-OH-DPAT and of the 5-HT1A receptor antagonist WAY100635 both suppressed the spontaneous and QUIS-activated firing activity of orbitofrontal cortex neurons. At current which did not affect the basal discharge activity of the neuron recorded, microiontophoretic application of WAY100635 and BMY7378 failed to prevent the inhibitory effect of 8-OH-DPAT. The inhibitory effect of gepirone, which is a 5-HT1A receptor agonist but devoid of affinity for 5-HT7 receptors, was also not antagonized by WAY100635. Altogether, these results suggest the presence of atypical 5-HT1A receptors in the orbitofrontal cortex. The present results also indicate that the suppressant effect of DOI may be mediated by 5-HT2A receptors in head of caudate nucleus and atypical 5-HT2 receptors in orbitofrontal cortex.     

Electrophysiological characterization of 5-HT receptors on rat petrosal neurons in dissociated cell culture

The petrosal ganglion supplies chemoafferent pathways via the glossopharyngeal (IXth) nerve to peripheral targets which release various neurotransmitters including serotonin (5-HT). Here, we combined rapid 5-HT application with patch clamp, whole-cell recording to investigate whether 5-HT receptors are expressed on isolated petrosal neurons (PN), cultured from 7-12 day-old rat pups. In responsive cells, the dominant effect of 5-HT was a rapid depolarization associated with a conductance increase in approximately 43% of the neurons (53/123); however, in a minority population ( approximately 6%; 8/123), 5-HT caused membrane depolarization associated with a conductance decrease. In the former group, 5-HT produced a transient inward current (I5-HT) in neurons voltage-clamped near the resting potential ( approximately -60 mV); the effect was mimicked by the 5-HT3 receptor-specific agonist, 2-methyl-5-HT, suggesting it was mediated by 5-HT3 receptors. Further, I5-HT was selectively inhibited by the 5-HT3 receptor-specific antagonist MDL72222 (1-10 microM), but was unaffected by either 5-HT1/5-HT2 receptor antagonist, spiperone, or by 5-HT2 receptor-specific antagonist, ketanserin (50-100 microM). I5-HT displayed moderate inward rectification and had a mean reversal potential (+/-S.E.M.) of -4.3+/-6.6 mV (n=6). Application of 5-HT (dose range: 0.1-100 microM) produced a dose-response curve that was fitted by the Hill equation with EC50= approximately 3.4 microM and Hill coefficient= approximately 1.6 (n=8). The activation phase of I5-HT (10 microM 5-HT at -60 mV) was well fitted by a single exponential with mean (+/-S.E.M.) time constant of 45+/-30 ms (n=6). The desensitization phase of I5-HT was best fitted by a single exponential with mean (+/-S.E.M.) time constant of 660+/-167 ms (n=6). Fluctuation analysis yielded an apparent mean single-channel conductance (+/-S.E.M) of 2.7+/-1.5 pS (n=4) at -60 mV. In the minority ( approximately 6%) population of neurons which responded to 5-HT with a conductance decrease, the depolarization was blocked by the 5-HT2 receptor antagonist, ketanserin (50 microM). Taken together, these results suggest that 5-HT3 receptors are the major subtype expressed by rat petrosal neurons, and therefore are candidates for facilitating chemoafferent excitation in response to 5-HT released from peripheral targets.     

5-HT autoreceptors in the regulation of 5-HT release from guinea pig raphe nucleus and hypothalamus

5-HT autoreceptors involved in the regulation of 5-HT release in the guinea pig dorsal raphe nucleus have been studied in comparison with those in the hypothalamus. In vitro release was measured in slices of raphe and hypothalamus prelabelled with [3H]5-HT, superfused with Krebs solution and depolarized electrically. The non-selective 5-HT receptor agonist, 5-carboxamidotryptamine (5-CT) (0.1-10 nM for raphe: 1-100 nM for hypothalamus) and antagonist, methiothepin (10-1000nM), decreased and increased, respectively, the release of [3H]5-HT evoked by electrical stimulation in either of these regions when given alone. The selective 5-HT1B/D receptor antagonist, GR127935 (100-1000 nM), and the 5-HT1D receptor antagonist, ketanserin (300-1000 nM), had no significant effect on this release in either of these regions. Methiothepin and GR127935 (100-1000 nM) shifted to the right the concentration-effect curve of 5-CT in both the raphe and the hypothalamus. At 300 nM, ketanserin shifted to the right the concentration-effect curve of 5-CT in the raphe but did not modify the 5-CT curve in the hypothalamus. In microdialysis experiments ketanserin, applied locally at 10 microM, increased the extracellular levels of 5-HT in the dorsal raphe nucleus of the freely moving guinea pig, whereas 5-HT levels were unchanged in the hypothalamus. Ketanserin at 1 microM did not affect the decrease in 5-HT output induced by the selective 5-HT1B/D receptor agonist, naratriptan (used at 10 microM in raphe and 0.1 microM in hypothalamus), in the raphe or the hypothalamus. In the raphe, WAY100635, a 5-HT1A receptor antagonist, at 1 microM, did not prevent naratriptan (10 microM) from reducing the extracellular levels of 5-HT. These results suggest that, in the conditions used in this study, the release of 5-HT in the dorsal raphe nucleus is possibly modulated in part by 5-HT1B receptors but essentially the control is through 5-HT receptors whose subtype is still to be determined. In the hypothalamus, however, it is clear that only 5-HT1B receptors are involved in the modulation of 5-HT neurotransmission.     

Laryngeal electromyography is a cost-effective clinically useful tool in the evaluation of vocal fold function

Primary cultures of human bronchial epithelial cells (HBE-cells) were established to measure granulocyte-macrophage colony stimulating factor (GM-CSF) release. HBE-cells showed a basal GM-CSF release (82+/-20 ng/well/24 h; 30 donors), which was increased by interleukin-1 beta(IL-1beta, 1 ng/ml) by 270%. This effect was blocked by 1 microM dactinomycin or 10 microM cycloheximide, i.e. the stimulatory effect of IL-1beta depended on de-novo synthesis. Histamine (100 microM) and acetylcholine ( 100 nM) stimulated GM-CSF release more than two-fold above the baseline. Nicotine (1 microM) increased GM-CSF release to a similar extent, and this effect was prevented by 30 microM (+)-tubocurarine. The stimulatory effect was attenuated or even lost with high agonist concentrations (10 microM acetylcholine; 100 microM nicotine) suggesting receptor desensitization. The muscarinic receptor agonist oxotremorine did not affect GM-CSF release. Serotonin, substance P and calcitonin-gene related peptide had no effect on GM-CSF release. In conclusion, acetylcholine can trigger GM-CSF release from human airway epithelial cells via stimulation of nicotinic receptors.     

Pollen tube localization implies a role in pollen-pistil interactions for the tomato receptor-like protein kinases LePRK1 and LePRK2

An impulsive cognitive style may affect behaviour in several different ways, including rapid decision making, intolerance of the delay of reward and a tendency to terminate chains of responses prematurely. It has been proposed to measure the last of these in rats using fixed consecutive number (FCN) schedules. The present study uses a modified version of the FCN procedure in which responding was paced by retracting the response lever for short periods between presses. In this way, the experimenter can control the maximum rate of responding. The procedure was made up of two components. In both, the schedule requirement was FCN 8, but in the Fast component lever presses were spaced by a minimum of 2.5 s and in the Slow component by a minimum of 5 s. Alterations in impulsivity were inferred from changes in the mean chain length and the distribution of chain lengths. The 5-HT1A agonist, 8-OH-DPAT (0.03-0.3 mg/kg), increased chain lengths within a narrow dose range, whereas the 5-HT1A antagonist, WAY 100 635 (0.03-0.3 mg/kg), reduced chain lengths. The 5-HT2 agonist, DOI (0.1-1.0 mg/kg), markedly reduced chain lengths, whereas the 5-HT2 antagonist, ritanserin (0.03-0.3 mg/kg), had no effect. The 5-HT1A/1b agonist, RU 24969 (0.03-0.3 mg/kg), reduced chain lengths. The 5-HT releaser, p-chloramphetamine (0.1-1.0 mg/kg), had a weak, biphasic effect, slightly reducing the number of short chains at the lowest dose tested and slightly increasing this number at the highest dose. Other drugs tested, citalopram (1.0-10.0 mg/kg), metergoline (0.3-3.0 mg/kg) and MDL-72222 (0.1-3.0 mg/kg), had no significant effects. These results suggest that stimulation of 5-HT1A receptors reduces impulsivity, whereas stimulation of 5-HT2 receptors increases it. These data are in agreement with previous results using the DRL-72 schedule, and indicate that there is no simple role for serotonin in the control of impulsivity.     

Serotonin Type 3 Receptors Modulate the Aggression-Stimulating Effects of Adolescent Cocaine Exposure in Syrian Hamsters (Mesocricetus auratus).

Repeated cocaine (0.5 mg/kg) exposure throughout adolescence stimulates offensive aggression in hamsters. These studies examined whether the cocaine-induced aggressive response was regulated by serotonin Type 3 (5-HT?) receptor activity and correlated with altered 5-HT? receptor expression. Cocaine-treated Syrian hamsters (Mesocricetus auratus) were tested for aggression after the administration of either the 5-HT? antagonist 3-tropanylindole-3-carboxylate methiodide (tropisetron; 0.01-1.20 mg/kg) or the 5-HT? agonist l-(m-chlorophenyl)-biguanide hydrochloride (mCPBG; 5.0-15.0 mg/kg), alone or in combination. Tropisetron alone dose dependently reduced cocaine-induced aggression, with a significant reduction at 0.3 mg/kg, whereas mCPBG was ineffective. mCPBG administered prior to tropisetron required a higher dose (1.2 mg/kg) of antagonist to block aggression, indicating a selective 5-HT? effect. Cocaine-treated hamsters showed altered 5-HT? immunoreactivity in several brain areas implicated in aggression control. These data support a role for 5-HT? receptors in adolescent cocaine-induced aggression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pharmacological consequences of nicotinergic plus serotonergic manipulations

The present study investigates the effects of concurrent manipulations of nicotinic cholinergic receptors (nicotinic cholinergic agonist: nicotine 0.03, 0.1, 0.3 mg/kg, nicotinic cholinergic antagonist: mecamylamine 7.5 mg/kg) and serotonin neurons (p-chlorophenylalanine (PCPA), 400/kg mg on each of 3 days) on spatial navigation (water maze, WM) and passive avoidance (PA) performance. Nicotine did not affect PA performance but at the highest dose slightly impaired WM performance. PCPA did not affect WM navigation or PA performance in saline or nicotine-treated rats. Nicotine restored WM and PA performance defect in mecamylamine pretreated rats. PCPA aggravated the WM defect and decreased the WM performance-improving effect of nicotine in mecamylamine pretreated rats. PCPA did not aggravate the PA performance defect of mecamylamine but completely blocked the PA performance-improving effect of nicotine in mecamylamine pretreated rats. These results suggest that serotonergic and nicotinergic cholinergic systems jointly modulate performance in WM and PA tests.     

Full and partial 5-HT1A receptor agonists disrupt learning and performance in rats

As a means of characterizing the role of 5-hydroxytryptamine (5-HT1A) receptors in learning, a full 5-HT1A receptor agonist, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), was administered both alone and in combination with two partial agonists (buspirone and 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN-190)) and a 5-HT1A receptor antagonist (p-MPPI) to rats responding under a multiple schedule of repeated acquisition and performance of response sequences. In addition, the effects of another 5-HT1A receptor agonist, (LY228729), were also studied under this same procedure. When administered alone, both 8-OH-DPAT (0.1-3. 2 mg/kg) and LY228729 (0.32-3.2 mg/kg) dose dependently decreased overall response rate and increased the percentage of errors in the acquisition and performance components. At the doses of each drug tested, both buspirone (0.32 or 1 mg/kg) and NAN-190 (1 or 3.2 mg/kg) also decreased overall response rate and increased the percentage of errors. However, the effects of these drugs differed across behavioral components and dependent measures. The effects of buspirone and NAN-190 on rate and accuracy were also different when they were administered in combination with 8-OH-DPAT. In contrast, p-MPPI (3.2 or 10 mg/kg) had little or no effect when administered alone and antagonized the effects of 8-OH-DPAT; shifting the dose-effect curves for both response rate and the percentage of errors in both components to the right. Taken together, these results indicate that complex behaviors in rats are sensitive to disruption by drugs with both full and partial 5-HT1A receptor agonist properties, and that the effects of partial 5-HT1A receptor agonists on learning may be different depending on their efficacy at pre- and postsynaptic 5-HT1A receptors.     

Muscarinic acetylcholine receptors in Torpedo electric organ: effect of guanine nucleotides

The effect of guanine nucleotides on the binding properties of presynaptic muscarinic receptors has been studied in a membrane preparation from the electric organ of Torpedo marmorata by measuring the competitive displacement of the radiolabelled antagonist, [3H]quinuclidinyl benzilate, by nonradioactive muscarinic ligands. The binding of the antagonists, atropine, scopolamine and pirenzepine was to a single class of sites [slope factors (pseudo Hill coefficients) close to 1] and was unaffected by 0.1 mM GTP. The binding of the N-methylated antagonists, N-methylatropine and N-methyl-scopolamine was more complex (slope factors less than 1) but also insensitive (N-methylatropine) to 0.1 mM GTP. Agonist binding was complex and could be resolved into two binding sites with relatively high and low affinities. The proportion of high-affinity sites varied with the nature of the agonist (15-80%). Agonist binding was depressed by 0.1 mM GTP, and the order of sensitivity was oxotremorine-M greater than carbamoylcholine greater than muscarine greater than acetylcholine greater than arecoline greater than oxotremorine. The binding of pilocarpine, a partial agonist, was unaffected by GTP. With carbamoylcholine as a test ligand the GTP effect on agonist binding was half-maximal at 12 microM. GDP and guanylylimidodiphosphate produced comparable inhibition of carbamoylcholine binding, but GMP and cyclic GMP were ineffective, as were various adenine nucleotides. Analysis of agonist binding in terms of a two-site model indicates that the predominant effect of guanine nucleotides is to reduce the number of sites of higher affinity.     

Effects of oxyhemoglobin on vasoconstriction in response to 5-hydroxytryptamine in isolated, perfused canine basilar arteries

OBJECTIVE: Oxyhemoglobin (OxyHb) is thought to be a critical trigger in the pathogenesis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. We investigated whether extraluminally applied OxyHb influenced vascular responses to intraluminally applied vasoactive agents in isolated, perfused, canine basilar arteries. METHODS: The steel cannula insertion method was used to examine vascular responses to intraluminally applied 5-hydroxytryptamine (5-HT) receptor agonists, i.e., 5-HT, 5-carboxamidotryptamine (selective for 5-HT1 receptors), and alpha-methyl-5-hydroxytryptamine (selective for 5-HT2 receptors), potassium chloride, and acetylcholine, before and after extraluminal treatment with OxyHb. RESULTS: Extraluminal application of 2.5 x 10(-5) mol/L OxyHb immediately induced a transient elevation of the basal perfusion pressure, which gradually decreased and then stabilized at a level slightly higher than the control level. Each 5-HT agonist induced dose-dependent vasoconstriction. The potencies of the agonists were not very different, but the efficacies varied, i.e., alpha-methyl-5-hydroxytryptamine > 5-HT > 5-carboxamidotryptamine. Each response was strongly inhibited by ketanserin (a selective 5-HT2 receptor antagonist), indicating that each agonist induces vasoconstriction mediated by 5-HT2 receptors. The vasoconstriction in response to each 5-HT receptor agonist was consistently potentiated by treatment with OxyHb (2.5 x 10(-5) mol/L). 5-HT receptor agonist-induced constrictions after OxyHb treatment were much more markedly inhibited by ketanserin, compared with those before OxyHb treatment. Acetylcholine-induced constrictions were enhanced by OxyHb, but KCl-induced constrictions were significantly decreased by OxyHb. CONCLUSION: It is suggested that OxyHb enhancement of constrictions in response to 5-HT receptor agonists may be mediated by increased sensitivity of 5-HT2 receptors, in addition to actions in the endothelium, in canine basilar arteries. This potentiated vasoconstrictor mechanism may be partially implicated in cerebral vasospasm after subarachnoid hemorrhage.