Pharmacological characterization of nicotine-induced acetylcholine release in the rat hippocampus in vivo: evidence for a permissive dopamine synapse.
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In this study, the mechanism of nicotine-induced hippocampal acetylcholine (ACh) release in awake, freely moving rats was examined using in vivo microdialysis. Systemic administration of nicotine (0.4 mg kg(-1), s.c.) increased the levels of ACh in hippocampal dialysates. The nicotine-induced hippocampal ACh release was sensitive to the pretreatment of neuronal nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine (3.0 mg kg(-1), s.c.) and dihydro-beta-erythrodine (DHbetaE; 4.0 mg kg(-1), s.c.) as well as systemic administration of the dopamine (DA) D1 receptor antagonist SCH-23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzaz epine; 0.3 mg kg(-1), s.c.). Local perfusion of mecamylamine (100 microM), DHbetaE (100 microM) or SCH-23390 (10 microM) through microdialysis probe did not increase basal hippocampal ACh release. Hippocampal ACh release elicited by systemic administration of nicotine (0.4 mg kg(-1), s.c.) was antagonized by local perfusion of SCH-23390 (10 microM), but not by MEC (100 microM) or DHbetaE (100 microM). Direct perfusion of nicotine (1 mM, but not 0.1 mM) increased hippocampal ACh levels; however, this effect was relatively insensitive to blockade by co-perfusion of either mecamylamine (100 microM) or SCH-23390 (10 microM). These results suggest that nicotine-induced hippocampal ACh release occurs by two distinct mechanisms: (1) activation of nAChRs outside the hippocampus leading to DA release and subsequent ACh release involving a permissive DA synapse, and (2) direct action of nicotine within the hippocampus leading to ACh release via non-DA-ergic mechanism. (+info)
Dose-dependent up-regulation of rat pulmonary, renal, and hepatic cytochrome P-450 (CYP) 1A expression by nicotine feeding.
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In a previous study in which a single 2.5 mg/kg (15.4 micromol/kg) s. c. dose of nicotine effected a transient, lung-specific induction of cytochrome P-450 (CYP) 1A1 in the rat, a dose-response study and assessment of the lung specificity of the induction was limited by toxicity of the acute parenteral nicotine exposure. In the present study, we examined the dose-CYP1A1/2 induction response relationship and the tissue specificity of the induction by orally administered nicotine, which lacks the toxicity of the parenterally administered drug. Nicotine, administered in a nutritionally balanced liquid diet, at a level of 20 (low), 60 (medium), or 200 (high) mg/kg of diet, induced CYP1A1 in the lung and kidney in a dose-dependent manner and in the liver at the high nicotine dose only, whereas CYP1A2 was induced in the liver dose-dependently and in the kidney at the high nicotine dose only. The high nicotine dose up-regulated mRNA level in the three tissues examined, but with the lung being the most responsive to the up-regulation. Induction of the CYP1A1-preferential activity ethoxyresorufin O-deethylase by the low, medium, and high nicotine diets was 1.9-, 4.9-, and 21.6-fold, respectively, in the lung, 1.4-, 1.7-, and 15.9-fold, respectively, in the kidney, and 1.7-, 2.9-, and 5.1-fold, respectively, in the liver. Similarly, albeit to lower extents, the dietary alkaloid induced the CYP1A2-preferential activity methoxyresorufin O-demethylase in all three tissues dose-dependently. Plasma nicotine concentration correlated neither with the dietary nor intake dose of the alkaloid nor with tissue levels of CYP1A, especially with the high-dose diet. Plasma nicotine levels at which CYP1A induction was maximal were comparable to those reported in smokers, suggesting that nicotine may induce CYP1A1 in humans. (+info)
One GABA and two acetylcholine receptors function at the C. elegans neuromuscular junction.
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We describe an electrophysiological preparation of the neuromuscular junction of the nematode C. elegans, which adds to its considerable genetic and genomic resources. Mutant analysis, pharmacology and patch-clamp recording showed that the body wall muscles of wild-type animals expressed a GABA receptor and two acetylcholine receptors. The muscle GABA response was abolished in animals lacking the GABA receptor gene unc-49. One acetylcholine receptor was activated by the nematocide levamisole. This response was eliminated in mutants lacking either the unc-38 or unc-29 genes, which encode alpha and non-alpha acetylcholine receptor subunits, respectively. The second, previously undescribed, acetylcholine receptor was activated by nicotine, desensitized rapidly and was selectively blocked by dihydro-beta-erythroidine, thus explaining the residual motility of unc-38 and unc-29 mutants. By recording spontaneous endogenous currents and selectively eliminating each of these receptors, we demonstrated that all three receptor types function at neuromuscular synapses. (+info)
Prenatal effects of maternal smoking on daughters' smoking: nicotine or testosterone exposure?
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OBJECTIVES: The purpose of this study was to specify the effect of prenatal fetal exposure to maternal cotinine and testosterone on daughters' smoking in adolescence and adulthood. METHODS: Longitudinal causal models were estimated among 240 White mother-daughter pairs from the Child Health and Development Study. Mothers and daughters were reinterviewed when daughters were aged 15 to 17 years, and daughters were interviewed at 27 to 30 years of age. Blood samples were obtained from both parents during pregnancy and from adult daughters. RESULTS: Testosterone and smoking were positively correlated among mothers during their pregnancy and among adult daughters. Maternal prenatal cotinine had no direct effect on daughters' smoking; self-reported smoking in pregnancy did have a direct effect. Smoking among daughters during adolescence was determined by maternal prenatal testosterone and self-reported maternal smoking during pregnancy and postnatally. Smoking among adult daughters reflected chronic smoking since adolescence and the continuing effect of postnatal maternal smoking. Prenatal maternal testosterone affected adult daughters' testosterone. CONCLUSIONS: Estimates of the impact of prenatal maternal smoking depend on the measure of smoking. Prenatal testosterone exposure is a previously unrecognized risk factor for smoking among female offspring. (+info)
Oral irritant properties of piperine and nicotine: psychophysical evidence for asymmetrical desensitization effects.
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Using a bipolar rating scale, human subjects rated the intensity of irritation sensation evoked by repeated application of piperine (75 p.p.m.) or nicotine (0.12%) to one side of the dorsal surface of the tongue. The intensity of irritation elicited by repeated application of piperine significantly increased, while irritation elicited by repeated nicotine significantly decreased. We additionally tested if nicotine or piperine desensitized the tongue. After either piperine or nicotine was repeatedly applied to one side of the tongue, a 5 or 10 min rest period ensued, followed by re-application of piperine or nicotine to both sides of the tongue. Subjects were asked to choose which side of the tongue gave rise to a stronger irritation in a two-alternative forced choice (2-AFC) paradigm. In addition, they gave separate ratings of the intensity of irritation on the two sides of the tongue. When piperine was applied bilaterally after unilateral pretreatment with piperine and a 10 min rest period, subjects consistently chose the non-pretreated side to yield stronger irritation and assigned significantly higher ratings to that side, indicative of piperine self-desensitization. A similar self-desensitization effect was found when bilateral application of nicotine followed unilateral treatment with nicotine and a 5 min rest period. Unilateral treatment with piperine also reduced nicotine-evoked irritation on the pretreated side (cross-desensitization), but treatment with nicotine did not affect piperine-evoked irritation. This asymmetrical cross-desensitization pattern is similar to that observed between capsaicin and nicotine and constitutes an additional similarity between piperine and capsaicin. (+info)
Injection of nicotine into the superior colliculus facilitates occurrence of express saccades in monkeys.
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To clarify the role of cholinergic inputs to the intermediate layer of the superior colliculus (SC), we examined the effect of microinjection of nicotine into the SC on visually guided saccades in macaque monkeys. After injection of 0.4-2 microl of 1-100 mM nicotine into the SC, frequency of extremely short latency saccades (express saccades; reaction time = 70-120 ms) dramatically increased, for the saccades the direction and amplitude of which were represented at the location of the injection site on the collicular map. However, no marked change was observed for the relationship between the peak velocities and the amplitudes of saccades. These results suggested that activation of nicotinic acetylcholine receptors in the SC can facilitate initiation but causes no major change in dynamics of visually guided saccades. (+info)
Inactivation gating determines nicotine blockade of human HERG channels.
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We have previously found that nicotine blocked multiple K+ currents, including the rapid component of delayed rectifier K+ currents (IKr), by interacting directly with the channels. To shed some light on the mechanisms of interaction between nicotine and channels, we performed detailed analysis on the human ether-a-go-go-related gene (HERG) channels, which are believed to be equivalent to the native I(Kr) when expressed in Xenopus oocytes. Nicotine suppressed the HERG channels in a concentration-dependent manner with greater potency with voltage protocols, which favor channel inactivation. Nicotine caused dramatic shifts of the voltage-dependent inactivation curve to more negative potentials and accelerated the inactivation process. Conversely, maneuvers that weakened the channel inactivation gating considerably relieved the blockade. Elevating the extracellular K+ concentration from 5 to 20 mM increased the nicotine concentration (by approximately 100-fold) needed to achieve the same degree of inhibition. Moreover, nicotine lost its ability to block the HERG channels when a single mutation was introduced to a residue located after transmembrane domain 6 (S631A) to remove the rapid channel inactivation. Our data suggest that the inactivation gating determines nicotine blockade of the HERG channels. (+info)
Antinociceptive and pharmacological effects of metanicotine, a selective nicotinic agonist.
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Metanicotine [N-methyl-4-(3-pyridinyl)-3-butene-1-amine], a novel neuronal nicotinic agonist, was found to bind with high affinity (K(i) = 24 nM) to rat brain [(3)H]nicotine binding sites and it generalized to nicotine in a dose-dependent manner in the drug discrimination procedure. Metanicotine produced significant antinociceptive effects in mice and rats subjected to either acute thermal (tail-flick), mechanical (paw-pressure), chemical (para-phenylquinone), persistent (Formalin), and chronic (arthritis) pain stimuli. Metanicotine was about 5-fold less potent than nicotine in the tail-flick test after s.c administration, but slightly more potent after central administration. Its duration of action was longer than that of nicotine. Nicotinic antagonists, mecamylamine and dihydro-beta-erythroidine, blocked metanicotine-induced antinociception in the different pain models. However, the antinociceptive effect was not affected by pretreatment with either naloxone or by atropine, confirming that metanicotine exerts its antinociceptive effect via nicotinic rather than either opioid or muscarinic mechanisms. In contrast to nicotine, antinociceptive effects of metanicotine were observed at doses that had virtually no effect on spontaneous activity and body temperature in mice. These data indicate that metanicotine is a centrally acting neuronal nicotinic agonist with preferential antinociceptive effects in animals. Thus, metanicotine and related nicotinic agonists may have great potential for development as a new class of analgesics. (+info)