Nicotinic Cholinoceptors Research Articles

Investigation of the Roles of Non-neuronal Acetylcholine in Chronic Myeloid Leukemic Cells and their Erythroid or Megakaryocytic Differentiated Lines.

Many studies suggested that Acetylcholine (ACh) might serve as an autocrine/ paracrine growth factor in several types of tumors or tumor cell lines. High levels of Acetylcholinesterase (AChE) activity have been reported in primary brain tumors, ovarian, colon and lung tumors. The role of cholinergic signaling needs to be clarified in in leukemia. K562 cells were derived from a chronic myelogenous leukemia patient during blast crisis serving as pluripotent hematopoietic stem cells. K562 cells were incubated with various cholinergic agonists or antagonists to investigate the role of ACh in different differentiated cell lines. Our experiments showed that AChE activity was increased in response to ACh in undifferentiated K562 cells, but in the erythroid differentiated K562 cells a high concentration of ACh (1 mM) decreased the AChE activity. ACh failed to elevate the AChE activity in the megakaryocytic differentiated K562 cells. An AChE inhibitor, eserine, also suppressed the AChE activity in a concentration-dependent manner. Choline uptake inhibition by hemicholinium did increase the AChE activity but not in the erythroid differentiated K562 cell line. Likewise, megakaryocytic differentiated K562 cells also displayed a similar pattern. Vesamicole, a vesicular choline uptake inhibitor, produced similar results. Curare, a nicotinic antagonist, elevated the cell counts of the megakaryocytic differentiated cells. Our findings may suggest excess extracellular ACh will decrease the cell growth in undifferentiated and megakaryocytic differentiated K562 cell lines through nicotinic type cholinoceptors.

Inhibitory action of oxytocin on spontaneous contraction of rat distal colon by nitrergic mechanism: involvement of cyclic GMP and apamin-sensitive K+ channels.

The mechanisms underlying the inhibitory effects of oxytocin (OT) on colon tone are not totally understood. We explore the mechanisms of OT on spontaneous contractility in rat distal colon and identify the mediators involved in this action. In rat distal colon strips, mechanical activity was analysed and the production of nitric oxide (NO) in tissue loaded with the fluorochrome DAF-FM was visualized by confocal microscopy. OT receptor (OTR) expression was determined by Western blotting and immunofluorescence. In rat distal colon, OT produced a concentration-dependent reduction in the spontaneous contraction, which was abolished by the OTR antagonist atosiban, the neural blocker tetrodotoxin and the inhibitor of neuronal nitric oxide synthase (nNOS) NPLA. The inhibitory effects of OT were not affected by propranolol, atropine, the nicotinic cholinoceptor blocker hexamethonium, the vasoactive intestinal peptide receptor antagonist VIPHyb, the P2 purinoceptor antagonist PPADS, the adenosine A1 receptors antagonist DPCPX and the prostacyclin receptor antagonist Ro1138452. The soluble guanylyl cyclase (sGC) inhibitor ODQ and the small conductance Ca2+ -activated K+ (Ca K+ ) channels blocker apamin significantly reduced the relaxation induced by OT, nicotine, sodium nitroprusside and the sGC activator BAY 41-2272. The neural release of NO elicited by OT was prevented by NPLA, tetrodotoxin and atosiban. The presence of the OTR and its co-localization with nNOS was detected by immunohistochemistry and Western blotting experiments. These results demonstrate the NO release from enteric neurones induced by activation of OTR mediates distal colon relaxation. sGC and small conductance Ca K+ channels are involved in this relaxation.

Possible role for anisodamine in organophosphate poisoning.

In cases of organophosphate poisoning, patients are treated with a combination of antidotes. In addition to these poison-directed antidotes, patients may require extra oxygen and artificial ventilation; other modalities may also be needed due to the wide range of toxic effects. Anisodamine is a belladonna alkaloid, and like other drugs from this family is non subtype-selective muscarinic, and a nicotinic cholinoceptor antagonist, which has been employed in traditional Chinese medicine. As a muscarinic antagonist, it displays similar pharmacological effects to atropine and scopolamine. However, anisodamine is not only less potent than atropine and scopolamine but also less toxic. Current in vitro and animal model studies have demonstrated that anisodamine has protective effects in a variety of diseases. Organophosphate poisoning involves not only the central and peripheral nervous systems, but also the cardiac and respiratory systems, as well as activation of inflammatory processes and oxidative stress. Therefore, the anticholinergic and additional activities of anisodamine appear to be relevant and justify its consideration as an addition to the existing remedies. However, more research is needed, as at present data on the role of anisodamine in the management of organophosphate poisoning are limited. Here, we review the beneficial effects of anisodamine on processes relevant to organophosphate poisoning.

Nicotinic mechanisms in the treatment of psychotic disorders: a focus on the α7 nicotinic receptor.

Nicotine is heavily abused by persons with schizophrenia. Nicotine better enables people with schizophrenia to filter out extraneous auditory stimuli. Nicotine also improves prepulse inhibition when compared to placebo. Nicotine similarly increases the amplitude of patients' duration mismatch negativity. The 15q13-14 region of the genome coding for the α7 nicotinic receptor is linked to schizophrenia. Multiple single nucleotide polymorphisms have been identified in this 15q13-14 gene promoter region that are more frequently present in people with schizophrenia than in normal controls. Abnormalities in expression and regulation of central nicotinic cholinoceptors with decreased α7 binding in multiple brain regions are also present. Nicotine enhances cognition in schizophrenia. Alternative agents that activate the nicotinic receptor have been tested including 3-[2,4-dimethoxybenzylidene]anabaseine (DMXB-A). This compound improved attention, working memory, and negative symptoms in an add-on study in nonsmoking patients with schizophrenia. There are multiple other nicotinic agents, including positive allosteric modulators, in the preclinical stages of development. Finally, the effects of varenicline and clozapine and their relation to smoking cessation are discussed.

Facilitation of central imidazoline I1‐site/extracellular signal‐regulated kinase/p38 mitogen‐activated protein kinase signalling mediates the hypotensive effect of ethanol in rats with acute renal failure

This study investigated the role of central sympathetic activity and related mitogen-activated protein kinase (MAPK) signalling in the cardiovascular effects of ethanol in a model of acute renal failure (ARF). The effects of pharmacological interventions that inhibit peripheral or central sympathetic activity or MAPK on the cardiovascular actions of ethanol in rats with ARF induced by glycerol were evaluated. Glycerol (50%, 10 mL.kg(-1), i.m.) caused progressive increases and decreases in blood pressure (BP) and heart rate (HR) respectively. Subsequent i.v. ethanol (0.25 or 1 g.kg(-1)) elicited dose-related changes in BP (decreases) and HR (increases). These effects were replicated after intracisternal (i.c.) administration of ethanol. Blockade of nicotinic cholinoceptors (nAChR, hexamethonium, 20 mg.kg(-1)) or alpha(1)-adrenoceptors (prazosin, 1 mg.kg(-1)) attenuated cardiovascular effects of ethanol. Ethanol hypotension was also attenuated after the centrally acting sympatholytic drug moxonidine (selective I(1)-site agonist, 100 microg.kg(-1) i.v.), but not guanabenz (selective alpha(2)-receptor agonist, 30 microg.kg(-1), i.v.), suggesting involvement of central circuits of I(1) sites in ethanol-evoked hypotension. Selective blockade I(1) sites (efaroxan) but not alpha(2) (yohimbine) adrenoceptors abolished the hypotensive response to ethanol. Intracisternal administration of PD98059 or SB203580, inhibitors of extracellular signal-regulated kinase (ERK 1/2) and p38 MAPK, respectively, reduced the hypotensive action of moxonidine or ethanol. When used simultaneously, the two MAPK inhibitors produced additive attenuation of ethanol hypotension. Sympathoinhibitory pathways of central I(1)-sites and downstream ERK/p38 MAPK signalling were involved in the hypotensive action of ethanol in ARF.

Effect of nicotine on neuromuscular transmission in mouse motor synapses

Nicotine (10 nM) inhibits rhythmic activity of the neuromuscular synapse in mice. This effect was prevented by alpha-cobratoxin and apamin. Hence, the effects of nicotine are realized via presynaptic neuronal nicotinic cholinoceptors and Ca(2+)-activated potassium channels.

Effects of Salvia officinalis L. (sage) leaves on memory retention and its interaction with the cholinergic system in rats

Objective The leaves of sage ( Salvia officinalis L., Lamiaceae) are reported to have a wide range of biological activities, such as anti-bacterial, fungistatic, virustatic, astringent, eupeptic and anti-hydrotic effects. To determine the mnemogenic effect of sage leaves, we investigated the effects of ethanolic extract of sage leaves and its interaction with cholinergic system on memory retention of passive avoidance learning in rats. Methods Post-training intracerebroventricular (i.c.v) injections were carried out in all the experiments except ethanolic extract (i.p. intraperitoneally). Results Administration of ethanolic extract (50 mg/kg), pilocarpine (0.5 and 1 mg/rat), the muscarinic cholinoceptor agonist, and nicotine (0.1 and 1 μg/rat) increased, while mecamylamine (1, 5 μg/rat), the muscarinic cholinoceptor antagonist, and mecamylamine (0.01 and 0.1 μg/rat), the nicotine cholinoceptor antagonist decreased memory retention in rats. Activation of muscarinic cholinoceptors by pilocarpine potentiated the response of ethanolic extract. Also, pharmacological blockade of scopolamine attenuated potentiating effect of ethanolic extract. Activation of nicotinic cholinoceptor by nicotine potentiated the response of ethanolic extract. Blockade of nicotinic cholinoceptor by mecamylamine attenuated the response of ethanolic extract. Conclusion It is concluded that the ethanolic extract of salvia officinalis potentiated memory retention and also it has an interaction with muscarinic and nicotinic cholinergic systems that is involved in the memory retention process.

Carbachol induces burst firing of dopamine cells in the ventral tegmental area by promoting calcium entry through L‐type channels in the rat

Enhanced activity of the central dopamine system has been implicated in many psychiatric disorders including schizophrenia and addiction. Besides terminal mechanisms that boost dopamine levels at the synapse, the cell body of dopamine cells enhances terminal dopamine concentration through encoding action potentials in bursts. This paper presents evidence that burst firing of dopamine cells in the ventral tegmental area was under cholinergic control using nystatin-perforated patch clamp recording from slice preparations. The non-selective cholinergic agonist carbachol excited the majority of recorded neurones, an action that was not affected by blocking glutamate and GABA ionotropic receptors. Twenty per cent of dopamine cells responded to carbachol with robust bursting, an effect mediated by both muscarinic and nicotinic cholinoceptors postsynaptically. Burst firing induced as such was completely dependent on calcium entry as it could be blocked by cadmium and more specifically the L-type blocker nifedipine. In the presence of the sodium channel blocker tetrodotoxin, carbachol induced membrane potential oscillation that had similar kinetics and frequency as burst firing cycles and could also be blocked by cadmium and nifedipine. Direct activation of the L-type channel with Bay K8644 induced strong bursting which could be blocked by nifedipine but not by depleting internal calcium stores. These results indicate that carbachol increases calcium entry into the postsynaptic cell through L-type channels to generate calcium-dependent membrane potential oscillation and burst firing. This could establish the L-type channel as a target for modulating the function of the central dopamine system in disease conditions.

Role of Cholinergic Structures in Individual Resistance of Rat Circulatory System to Posthemorrhagic Hypoxia

Experiments employing ultrasound technique showed that nonselective blockade of central muscarinic cholinoceptors with amizyl significantly increases the number and lifespan of rats highly resistant to acute massive blood loss. This pretreatment increased individual resistance of the circulatory system to posthemorrhagic hypoxia (blood pressure and portal blood flow rate). Preliminary blockade of central nicotinic cholinoceptors and peripheral muscarinic cholinoceptors with cyclodol and methacin, respectively, had no effect on the percentage of rats highly and low resistant to acute blood loss. Preliminary blockade of peripheral muscarinic cholinoceptors with methacin prevented the decrease in the cardiac output in low resistant animals during the posthemorrhagic period.

Investigation of the mechanism of nicotine-induced relaxation on the sheep sphincter of Oddi

Possible mechanisms for nicotine-induced relaxation were investigated in the isolated sheep's sphincter of Oddi. Sheep's sphincter of Oddi rings were mounted in tissue bath with modified Krebs-Henseleit solution and aerated with 95% oxygen and 5% carbon dioxide. Tension was measured with isometric force transducers, and muscle relaxation was expressed as percent decrease of precontraction induced by carbachol. Nicotine (1 x 10(-5) to 3 x 10(-3) mol/L) produced concentration-dependent relaxation on sphincter of Oddi precontracted by carbachol (10(-6) mol/L). Nicotine-induced relaxation was 72.8 +/- 4.2% of precontraction with carbachol (10(-6) mol/L) (mean pD2 value, 3.76 +/- 0.05 mol/L). Nicotine-induced relaxation was not affected by N(w)-nitro L-arginine methyl ester (L-NAME) (3 x 10(-5) mol/L), methylene blue (10(-5) mol/L), indomethacin (10(-5) mol/L), hexamethonium (10(-5) mol/L), glibenclamide (10(-5) mol/L), 4-aminopyridine (10(-3) mol/L), tetraethylammonium (3 x 10(-4) mol/L), clotrimazole (10(-6) mol/L), 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) (10(-6) mol/L), and anthracene-9-carboxylate (9-AC) (10(-6) mol/L), but potentiated by bupivacain (10(-5) mol/L). A calcium-antagonizing effect of nicotine was not observed. The results suggest that nicotine-induced relaxation of the sheep's sphincter of Oddi is not mediated by the release of prostaglandins, nitric oxide (NO), or a related substance; by the activation of potassium channels or chloride channels; or by the stimulation of nicotinic cholinoceptors. Potentiation of the nicotine-induced relaxation by bupivacain indicates that blockade of sodium channels may play a role in this relaxation.

Investigation of the mechanism of nicotine induced relaxation in rabbit corpus cavernosum in vitro.

In order to determine whether nicotine acts on corporal smooth muscle, the mechanism of its effect on strips of rabbit corpus cavernosum was studied in vitro. Rabbit corpus cavernosum muscle strips were mounted in an organ bath with modified Krebs-Henseleit solution and aerated with 95% O(2) and 5% CO(2). Tension was measured with isometric force transducers, and muscle relaxation was expressed as the percent decrease of precontraction induced by phenylephrine. Nicotine produced concentration dependent relaxation when preparations were precontracted by phenylephrine (10(-5) M). The maximum nicotine-induced relaxation was 60.4 +/- 4.2% of the phenylephrine contraction and was not affected by indomethacin (10(-5) M), N(w)-nitro L-arginine methyl ester (3 x 10(-5) M), methylene blue (10(-5) M), glibenclamide (10(-5) M), clotrimazole (10(-6) M), tetraethylammonium (3 x 10(-4) M), or 4-aminopyridine (10(-3) M). Nicotine did not exhibit a calcium antagonizing effect. From these results, we conclude that nicotine-induced relaxation of the rabbit corpus cavernosum is not mediated by the release of nitric oxide, prostaglandins or a related substance, by the activation of potassium channels, or by the stimulation of nicotinic cholinoceptors. Further work is needed to determine the cellular mechanism(s) of the action by which nicotine acts on corporal smooth muscle.

Investigation of the mechanism of nicotine-induced relaxation in guinea pig gallbladder

Background. Muscular contraction of the gallbladder is the primary determinant of bile delivery into duedonum. Gallbladder filling and emptying are influenced by both inhibitory and excitatory stimuli, and NO plays a key role in normal relaxation. In this study, to determine whether nicotine acts on the gallbladder muscle, the mechanism of its effect on strips of guinea pig gallbladder was studied in vitro. Materials and methods. Guinea pig gallbladder muscle strips were mounted in organ bath with modified Krebs-Henseleit solution and aerated with Carbogen. Tension was measured with isometric force transducers, and muscle relaxation was expressed as percent decrease of precontraction induced by carbachol. Results. Nicotine produced concentration dependent relaxation when preparations were precontracted by carbachol (10 −6 M). Nicotine-induced relaxation was 51.6 ± 3.2% of phenylephrine contraction and was not affected by guanethidine (10 −5 M), propranolol (10 −6 M), hexamethonium (10 −4 M), indomethacin (10 −5 M), N w-nitro l-arginine methyl ester ( l-NAME) (3 × 10 −5 M), methylene blue (10 −5 M), glibenclamide (10 −5 M), clotrimazole (10 −6 M), tetraethylammonium (3 × 10 −4 M), or 4-aminopyridine (10 −3 M). Nicotine did not exhibit a calcium antagonizing effect. Conclusions. From these results, we concluded that nicotine-induced relaxation of the guinea pig gallbladder is not mediated by the release of noradrenaline, nitric oxide (NO), prostaglandins, or a related substance, or by the activation of potassium channels, or by the stimulation of nicotinic cholinoceptors. Further work is needed to determine the cellular mechanism(s) of action by which nicotine acts on gallbladder smooth muscle.

125I]Epibatidine-labelled nicotinic receptors in the extended striatum and cerebral cortex: lack of association with serotonergic afferents

In rat extended striatum, most nicotinic cholinoceptors are likely to be presynaptic. A previous report suggested that DA and 5-HT afferents each account for at least 30% of nicotinic binding sites in the striatum. To explore this question further, rats received unilateral infusions of the neurotoxins 5,7-dihydroxytryptamine, 6-hydroxydopamine or vehicle into the medial forebrain bundle, and were sacrificed 3 weeks later. Denervation was quantified by [ 125I]RTI-55 autoradiography, using separate assay conditions that revealed DA and 5-HT transporters (i.e. DAT and SERT). Nicotinic cholinoceptors were quantified by [ 125I]epibatidine autoradiography. Infusion of 6-hydroxydopamine depleted DAT but not SERT labelling in all striatal areas (i.e. caudate-putamen, nucleus accumbens core and shell, olfactory tubercle). The serotonergic neurotoxin 5,7-dihydroxytryptamine depleted SERT and, to a lesser extent, DAT labelling. Both neurotoxins reduced [ 125I]epibatidine binding in striatal areas. Multiple linear regression analysis showed that these reductions in [ 125I]epibatidine binding were entirely associated with loss of DAT rather than SERT. The DAT-associated proportion of total [ 125I]epibatidine binding was 36±2% (caudate-putamen), 28±3% (accumbens core), 27±4% (accumbens shell) and 44±5% (olfactory tubercle). Cortical [ 125I]epibatidine binding was unaltered by 5,7-dihydroxytryptamine lesions that reduced SERT labelling by 46 to 73%. In all brain areas, even small (3.4 to 8.8%) SERT-associated reductions in [ 125I]epibatidine binding would have been detected as statistically significant. In conclusion, we report the failure to detect nAChRs on 5-HT terminals in extended striatum or cerebral cortex, using a sensitive [ 125I]epibatidine autoradiographic assay.

Perioperative shivering: physiology and pharmacology.

IN homeothermic species, a thermoregulatory system coordinates defenses against cold and heat to maintain internal body temperature within a narrow range, thus optimizing normal physiologic and metabolic function. The combination of anesthetic-induced thermoregulatory impairment and exposure to a cool environment makes most unwarmed surgical patients hypothermic. Although shivering is but one consequence of perioperative hypothermia, and rarely the most serious, it occurs frequently (i.e., 40–60% after volatile anesthetics), and it remains poorly understood. While coldinduced thermoregulatory shivering remains an obvious etiology, the phenomenon has also been attributed to numerous other causes. Our first goal is to review the organization of the thermoregulatory system, and particularly the physiology of postanesthetic shivering. We then discuss the pharmacology of thermoregulation and review the putative mechanisms and sites of action of various antishivering drugs.

Effects of nicotine on regional cerebral glucose metabolism in awake resting tobacco smokers

Eleven healthy tobacco smoking adult male volunteers of mixed race were tobacco abstinent overnight for this study. In each subject, positron emission tomographic images of regional cerebral metabolism of glucose with [ 18F]fluorodeoxyglucose were obtained in two conditions in the morning on different days: about 3 min after approximately 1–2 mg of nasal nicotine spray and after an equivalent volume of an active placebo spray of oleoresin of pepper in a random counterbalanced design. A Siemens/CTI 931/08-12 scanner with the capability of 15 horizontal brain slices was used. The images were further converted into a standard uniform brain format in which the mean data of all 11 subjects were obtained. Images were analysed in stereotactic coordinates using pixel-wise t statistics and a smoothed Gaussian model. Peak plasma nicotine levels varied three-fold and the areas under the curve 0–30 min varied seven-fold among the individual subjects. Nicotine caused a small overall reduction in global cerebral metabolism of glucose but, when the data were normalized, several brain regions showed relative increases in activity. Cerebral structures specifically activated by nicotine (nicotine minus pepper, Z score >4.0) included: left inferior frontal gyrus, left posterior cingulate gyrus and right thalamus. The visual cortex, including the right and left cuneus and left lateral occipito-temporal gyrus fusiformis, also showed an increase in regional cerebral metabolism of glucose with Z scores >3.6. Structures with a decrease in regional cerebral metabolism of glucose (pepper minus nicotine) were the left insula and right inferior occipital gyrus, with Z scores >3.5. Especially important is the fact that the thalamus is activated by nicotine. This is consistent with the high density of nicotinic cholinoceptors in that brain region. However, not all brain regions affected by nicotine are known to have many nicotinic cholinoceptors. The results are discussed in relation to the cognitive effects of nicotine.

Endogenous calcitonin gene-related peptide (CGRP) mediates adrenergic-dependent vasodilation induced by nicotine in mesenteric resistance arteries of the rat.

1. The mechanisms underlying vasodilator effect of nicotine on mesenteric resistance blood vessels and the role of calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves were studied in the rat. 2. Mesenteric vascular beds isolated from Wistar rats were perfused with Krebs solution, and perfusion pressure was measured with a pressure transducer. 3. In preparations with intact endothelium and contracted by perfusion with Krebs solution containing methoxamine, perfusion of nicotine (1 - 100 microM) for 1 min caused a concentration-dependent vasodilator response without vasoconstriction. 4. The nicotine-induced vasodilation was markedly inhibited by hexamethonium (nicotinic cholinoceptor antagonist, 10 microM) and blocked by guanethidine (adrenergic neuron blocker, 5 microM). 5. Either denervation by cold storage (4 degrees C for 72 h) or adrenergic denervation by 6-hydroxydopamine (toxin for adrenergic neurons, 2 mM for 20 min incubation, twice) blocked the nicotine-induced vasodilation. 6. Neither endothelium removal with perfusion of sodium deoxycholate (1.80 mg ml(-1), for 30 s) nor treatment with N(omega)-nitro-L-arginine (nitric oxide synthase inhibitor, 100 microM), atropine (muscarinic cholinoceptor antagonist, 10 nM) or propranolol (beta-adrenoceptor antagonist, 100 nM) affected the nicotine-induced vasodilation. 7. In preparations without endothelium, treatment with capsaicin (depleting CGRP-containing sensory nerves, 1 microM) or human CGRP[8 - 37] (CGRP receptor antagonist, 0.5 microM) markedly inhibited the nicotine-induced vasodilation. 8. These results suggest that, in the mesenteric resistanc artery of the rat, nicotine induces vasodilation, which is independent of the function of the endothelium and is involved in activation of CGRPergic nerves. It is also suggested that nicotine stimulates presynaptic nicotinic cholinoceptors on adrenergic nerves to release adrenergic neurotransmitters, which then act on CGRPergic nerves to release endogenous CGRP from the nerve.

Effect of acute nicotine administration on striatal dopamine output and metabolism in rats kept at different ambient temperatures.

1. The effect of ambient temperature on the nicotine-induced (0.3, 0.5 or 0.8 mg kg(-1) s.c.) changes of the striatal concentrations of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) was studied in freely-moving rats by in vivo microdialysis. 2. At the ambient temperature of 30 - 33 degrees C, but not at 20 - 23 degrees C, nicotine doses of 0.5 (P<0. 01) and 0.8 mg kg(-1) (P<0.05) significantly increased the extracellular DA concentration. The nicotine doses of 0.5 and 0.8 mg kg(-1) increased the DA metabolite levels similarly at both ambient temperatures studied (P</=0.0001), but the dose of 0.3 mg kg(-1) only at 30 - 33 degrees C (DOPAC: P<0.05; HVA: P<0.01). 3. At 30 - 33 degrees C, dihydro-beta-erythroidine (DHbetaE 2.8 mg kg(-1) i.p.) blocked the nicotine-induced (0.5 or 0.8 mg kg(-1)) increases of extracellular DA concentration but only tended to antagonize the increases of DA metabolites. Mecamylamine (5.0 mg kg(-1) i.p.) blocked the increase of DA output induced by 0.5 mg kg(-1) but not that induced by 0.8 mg kg(-1) of nicotine and fully prevented the nicotine-induced elevations of DOPAC and HVA. 4. Elevation of ambient temperature did not affect the cerebral concentration of nicotine or the nicotine-induced elevation of serum corticosteroids. Also, the rectal temperatures of rats given nicotine at either ambient temperature did not significantly change. 5. Our results show that the nicotine-induced output of striatal DA is enhanced at high ambient temperature. Further, our findings suggest that the nicotinic cholinoceptors mediating the effects of nicotine on striatal DA release are different from those mediating nicotine's effects on DA metabolism.

Nicotinic receptors modulating somatodendritic and terminal dopamine release differ pharmacologically

Ascending dopaminergic and noradrenergic neurons possess somatodendritic and terminal nicotinic cholinoceptors in the rat. Each neuronal population expresses mRNA for several types of nicotinic cholinoceptor subunit, including α6 and β3. In superfused rat striatal synaptosomes, epibatidine evoked release of [ 3H]dopamine with similar efficacy to ACh, whereas nicotine and cytisine were weaker (70±6% and 58±6%, respectively). The four agonists were equi-efficacious in evoking [ 3H]noradrenaline release from hippocampal synaptosomes. Nicotine-evoked synaptosomal release was tetrodotoxin-insensitive. Somatodendritic nicotinic cholinoceptors on dopaminergic neurons were studied using a dendrosomal [ 3H]dopamine release assay and also in locomotor activity tests. In both assays, nicotine appeared more efficacious than epibatidine. Furthermore, with repeated nicotine exposure, the acute locomotor stimulant response to nicotine increased, whereas the epibatidine response became undetectable. In conclusion, somatodendritic nicotinic cholinoceptors located on dopaminergic neurons appear to differ pharmacologically from those on striatal dopaminergic terminals and hippocampal noradrenergic terminals.

The role of nicotinic and muscarinic acetylcholine receptors in attention.

This study tried to determine the relative roles of muscarinic and nicotinic cholinergic receptors in attentional processing. The effects of cholinoceptor agonists and antagonists, and of an anticholinesterase, were studied on performance of rats in a five-choice serial reaction time task. Scopolamine (0.1 mg/kg) and mecamylamine (5.0 mg/kg) produced deficits in accuracy and reaction time, respectively. This may suggest a differential role for the two types of cholinoceptors in information processing. Combinations of sub-threshold doses of scopolamine (0.01-0.03 mg/kg) and mecamylamine (0.5-1.6 mg/kg), which alone did not affect accuracy or reaction time, did not produce significant deficits in attention. However, the pattern of effects after combined treatment suggested that the differential deficits seen with these drugs alone remained. The anticholinesterase physostigmine (0.1 mg/kg) and the non-selective muscarinic agonist oxotremorine (0.03 mg/kg) induced severe behavioural disruption at doses that appeared to be relatively well tolerated in previous studies; this precluded the derivation of accuracy and response time data at these doses. At lower doses, neither physostigmine (0.05 mg/kg) nor oxotremorine (0.003 mg/kg) significantly affected any performance measure; this may reflect the ability of both drugs to indirectly or directly activate presynaptic muscarinic receptors that inhibit acetylcholine release, respectively. Both muscarinic and nicotinic cholinoceptors may be important in attention but they may serve different roles in information processing; this hypothesis could be tested using tasks that place different emphasis on different stages of information processing.

Intracellular regulation of neuronal nicotinic cholinoreceptors.

Experiments on isolated superior cervical ganglia from rats were used to study the effects of substances affecting intracellular second messengers on membrane currents evoked by iontophoretic application of acetylcholine (ACh currents) and on excitatory postsynaptic currents (EPSC) induced by single discharges of preganglionic nerve fibers. These studies showed that the adenylate cyclase activator forskolin, the phosphodiesterase inhibitor isobutylmethylxanthine (IMBX), and the protein kinase C activator phorbol ester decreased the amplitude of the ACh current. Neither IMBX nor phorbol ester had any effect on the amplitude or decay time constant of EPSC, while forskolin increased the amplitude of EPSC without altering its decay time constant. Thapsigargin, which liberates intracellular calcium, not only decreased the amplitude of the ACh current, but also decreased EPSC amplitude without affecting its decay time constant. These results suggest that intracellular signaling via protein kinases A and C may affect neuronal nicotinic cholinoceptors (nAChR) only by altering receptor desensitization and not affecting receptor sensitivity to transmitters released from nerves or the kinetics of receptor ion channels. At the same time, neuronal nAChR are influenced by intracellular calcium, which decreases their ability to be activated by exogenous (perhaps acting via desensitization) and nerve-released acetylcholine without affecting the kinetics of ion channel function.