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Behavioural Pharmacology Oct 2021Despite the evidence that the muscarinic agonist arecoline is a drug of abuse throughout Southeast Asia, its stimulus characteristics have not been well studied. The...
Despite the evidence that the muscarinic agonist arecoline is a drug of abuse throughout Southeast Asia, its stimulus characteristics have not been well studied. The goal of this work was to understand more about the mediation of discriminative stimulus effects of arecoline. Arecoline (1.0 mg/kg s.c.) was trained as a discriminative stimulus in a group of eight rats. The ability of various cholinergic agonists and antagonists to mimic or antagonize the discriminative stimulus effects of arecoline and to modify its rate-suppressing effects was evaluated. A muscarinic antagonist, but neither of two nicotinic antagonists, was able to modify the discriminative stimulus effects of arecoline, suggesting a predominant muscarinic basis of arecoline's discriminative stimulus effects in this assay. However, both nicotine itself and two nicotine agonists with selective affinity for the α4β2* receptor (ispronicline and metanicotine) produced full arecoline-like discriminative stimulus effects in these rats. The discriminative stimulus effects of the selective nicotine agonists were blocked by both the general nicotine antagonist mecamylamine and by the selective α4β2* antagonist, dihydro-beta-erythroidine (DHβE). Surprisingly, only DHβE antagonized the rate-suppressing effects of the selective nicotine agonists. These data indicate a selective α4β2* nicotine receptor component to the behavioral effects of arecoline. Although the nicotinic aspects of arecoline's behavior effects could suggest that abuse of arecoline-containing material (e.g. betel nut chewing) is mediated through nicotinic rather than muscarinic actions, further research, specifically on the reinforcing effects of arecoline, is necessary before this conclusion can be supported.
Topics: Animals; Arecoline; Behavior, Animal; Dihydro-beta-Erythroidine; Discrimination Learning; Mecamylamine; Muscarinic Agonists; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Pyridines; Rats; Receptors, Nicotinic; Substance-Related Disorders
PubMed: 34417356
DOI: 10.1097/FBP.0000000000000652 -
PloS One 2018Nicotine evokes chorda tympani (CT) taste nerve responses and an aversive behavior in Trpm5 knockout (KO) mice. The agonists and antagonists of nicotinic acetylcholine...
Nicotine evokes chorda tympani (CT) taste nerve responses and an aversive behavior in Trpm5 knockout (KO) mice. The agonists and antagonists of nicotinic acetylcholine receptors (nAChRs) modulate neural and behavioral responses to nicotine in wildtype (WT) mice, Trpm5 KO mice and rats. This indicates that nicotine evokes bitter taste by activating a Trpm5-dependent pathway and a Trpm5-independent but nAChR-dependent pathway. Rat CT responses to ethanol are also partially inhibited by nAChR blockers, mecamylamine and dihydro-β-erythroidine. This indicates that a component of the bitter taste of ethanol is also nAChR-dependent. However, at present the expression and localization of nAChR subunits has not been investigated in detail in taste receptor cells (TRCs). To this end, in situ hybridization, immunohistochemistry and q-RT-PCR techniques were utilized to localize nAChR subunits in fungiform and circumvallate TRCs in WT mice, Trpm5-GFP transgenic mice, nAChR KO mice, and rats. The expression of mRNAs for α7, β2 and β4 nAChR subunits was observed in a subset of rat and WT mouse circumvallate and fungiform TRCs. Specific α3, α4, α7, β2, and β4 antibodies localized to a subset of WT mouse circumvallate and fungiform TRCs. In Trpm5-GFP mice α3, α4, α7, and β4 antibody binding was observed in a subset of Trpm5-positive circumvallate TRCs. Giving nicotine (100 μg/ml) in drinking water to WT mice for 3 weeks differentially increased the expression of α3, α4, α5, α6, α7, β2 and β4 mRNAs in circumvallate TRCs to varying degrees. Giving ethanol (5%) in drinking water to WT mice induced an increase in the expression of α5 and β4 mRNAs in circumvallate TRCs with a significant decrease in the expression of α3, α6 and β2 mRNAs. We conclude that nAChR subunits are expressed in Trpm5-positive TRCs and their expression levels are differentially altered by chronic oral exposure to nicotine and ethanol.
Topics: Animals; In Situ Hybridization; Mice; Mice, Inbred C57BL; Mice, Transgenic; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Nicotinic; TRPM Cation Channels; Taste Buds
PubMed: 29293602
DOI: 10.1371/journal.pone.0190465 -
The World Journal of Biological... Oct 2020Concurrent abuse of cocaine and nicotine is considered a public health problem. To date, no effective therapy has been known to reduce the reinforcing effects of...
Concurrent abuse of cocaine and nicotine is considered a public health problem. To date, no effective therapy has been known to reduce the reinforcing effects of concurrent use of cocaine and nicotine. Mirtazapine, an antagonist of the α-adrenoceptor and the 5-HT and the 5-HT receptors has proven effective in reducing the cocaine, nicotine and methamphetamine behavioural effects in humans and animals. Our study evaluated the effect of mirtazapine on enhancing locomotor activity during the induction and expression of locomotor sensitisation induced by a cocaine + nicotine mixture. Wistar rats were dosed with cocaine, nicotine or cocaine + nicotine combination. Mirtazapine (30 mg/kg, i.p.) was administered during the extinction phase. Mirtazapine decreased cocaine + nicotine-induced locomotor activity and induction and expression of locomotor sensitisation. In addition, we found that co-administration of mecamylamine and mirtazapine significantly enhanced the effect of mirtazapine on cocaine + nicotine-induced locomotor activity during induction and expression of behavioural sensitisation. Our results suggest that mirtazapine demonstrated efficacy in decreasing the psycho-stimulant effects of concurrent use of cocaine and nicotine.
Topics: Animals; Cocaine; Locomotion; Male; Mirtazapine; Nicotine; Rats; Rats, Wistar
PubMed: 31104538
DOI: 10.1080/15622975.2019.1620967 -
The Journal of Pain Jul 2019Sensory neuron nicotinic acetylcholine receptors (nAChRs) contribute to pain associated with tissue injury. However, there are marked differences between rats and mice...
Sensory neuron nicotinic acetylcholine receptors (nAChRs) contribute to pain associated with tissue injury. However, there are marked differences between rats and mice with respect to both the properties and distribution of nAChR currents in sensory neurons. Because both species are used to understand pain signaling in humans, we sought to determine whether the currents present in either species was reflective of those present in human sensory neurons. Neurons from the L4/L5 dorsal root ganglia were obtained from adult male and female organ donors. Nicotine evoked currents were detected in 40 of 47 neurons (85%). In contrast with the naïve mouse, in which almost all nAChR currents are transient, or the rat, in which both mouse-like transient and more slowly activating and inactivating currents are detected, all the currents in human DRG neurons were slow, but slower than those in the rat. Currents were blocked by the nAChR antagonists mecamylamine (30 µmol/L), but not by the TRPA1 selective antagonist HC-030031 (10 µmol/L). Single cell polymerase chain reaction analysis of nicotinic receptor subunit expression in human DRG neurons are consistent with functional data indicating that receptor expression is detected 85 ± 2.1% of neurons assessed (n = 48, from 4 donors). The most prevalent coexpression pattern was α3/β2 (95 ± 4% of neurons with subunits), but α7 subunits were detected in 70 ± 3.4% of neurons. These results suggest that there are not only species differences in the sensory neuron distribution of nAChR currents between rodent and human, but that the subunit composition of the channel underlying human nAChR currents may be different from those in the mouse or rat. PERSPECTIVE: The properties and distribution of nicotine evoked currents in human sensory neurons were markedly different from those previously observed in mice and rats. These observations add additional support to the suggestion that human sensory neurons may be an essential screening tool for those considering moving novel therapeutics targeting primary afferents into clinical trials.
Topics: Action Potentials; Animals; Female; Ganglia, Spinal; Humans; Male; Mice; Nicotine; Rats; Receptors, Nicotinic; Sensory Receptor Cells; Species Specificity
PubMed: 30659887
DOI: 10.1016/j.jpain.2019.01.005 -
Brain Research Bulletin Nov 2020Previous studies showed that mecamylamine a noncompetitive and nonspecific blocker of nicotinic acetylcholine receptors (nAChRs), stimulates the activity of the dorsal...
Previous studies showed that mecamylamine a noncompetitive and nonspecific blocker of nicotinic acetylcholine receptors (nAChRs), stimulates the activity of the dorsal raphe nucleus (DRN) serotonergic neurons and DRN serotonin (5-HT) release. In the present study, the mechanisms involved in these mecamylamine-induced effects were examined using electrophysiology and calcium-imaging studies, both performed in Wistar rat midbrain slices. Mecamylamine (0.5-9 μM), bath administered, increased the firing frequency of identified 5-HT DRN neurons by a maximum of 5% at 3 μM. This effect was accompanied by a 112 % increase in the frequency of spontaneous excitatory postsynaptic currents of 5-HT DRN neurons. It was blocked by the AMPA/kainate receptor blocker CNQX (10 μM) and by the specific α4β2 nAChRs blocker dihydro-β-erythroidine (100 nM) but was not affected by tetrodotoxin (TTX, 500 nM). Simultaneously, mecamylamine produced a 58 % decrease in the frequency of GABAergic spontaneous inhibitory postsynaptic currents, an effect that was not influenced by TTX. Calcium-imaging studies support the results obtained with the electrophysiological studies by showing that mecamylamine (3 μM) increases the activity of a cell population located in the midline of the DRN, which was sensitive to the inhibitory effects of 8-OH-DPAT, an agonist at 5-HT receptors. It is assumed that mecamylamine, in low concentrations, acts as an agonist of α4β2 nAChRs present on the glutamatergic DRN terminals, thus increasing intra-raphe glutamate release. This stimulatory effect is reinforced by the decrease in DRN GABA release, which is dependent on the mecamylamine-induced blockade of α7 nAChRs located on DRN GABAergic terminals. We hypothesize that at least a part of mecamylamine antidepressant effects described in animal models of depression are mediated by an increase in DRN 5-HT release.
Topics: Action Potentials; Animals; Calcium; Dorsal Raphe Nucleus; Ganglionic Blockers; Male; Mecamylamine; Patch-Clamp Techniques; Rats; Rats, Wistar; Serotonergic Neurons
PubMed: 32910991
DOI: 10.1016/j.brainresbull.2020.08.031 -
European Journal of Pharmaceutics and... Nov 2018The relevance of the rat single-pass intestinal perfusion model for investigating in vivo time-dependent effects of absorption-modifying excipients (AMEs) is not fully...
The relevance of the rat single-pass intestinal perfusion model for investigating in vivo time-dependent effects of absorption-modifying excipients (AMEs) is not fully established. Therefore, the dynamic effect and recovery of the intestinal mucosa was evaluated based on the lumen-to-blood flux (J) of six model compounds, and the blood-to-lumen clearance of Cr-EDTA (CL), during and after 15- and 60-min mucosal exposure of the AMEs, sodium dodecyl sulfate (SDS) and chitosan, in separate experiments. The contribution of enteric neurons on the effect of SDS and chitosan was also evaluated by luminal coadministration of the nicotinic receptor antagonist, mecamylamine. The increases in J and CL (maximum and total) during the perfusion experiments were dependent on exposure time (15 and 60 min), and the concentration of SDS, but not chitosan. The increases in J and CL following the 15-min intestinal exposure of both SDS and chitosan were greater than those reported from an in vivo rat intraintestinal bolus model. However, the effect in the bolus model could be predicted from the increase of J at the end of the 15-min exposure period, where a six-fold increase in J was required for a corresponding effect in the in vivo bolus model. This illustrates that a rapid and robust effect of the AME is crucial to increase the in vivo intestinal absorption rate before the yet unabsorbed drug in lumen has been transported distally in the intestine. Further, the recovery of the intestinal mucosa was complete following 15-min exposures of SDS and chitosan, but it only recovered 50% after the 60-min intestinal exposures. Our study also showed that the luminal exposure of AMEs affected the absorptive model drug transport more than the excretion of Cr-EDTA, as J for the drugs was more sensitive than CL at detecting dynamic mucosal AME effects, such as response rate and recovery. Finally, there appears to be no nicotinergic neural contribution to the absorption-enhancing effect of SDS and chitosan, as luminal administration of 0.1 mM mecamylamine had no effect.
Topics: Animals; Biological Transport; Chitosan; Excipients; Intestinal Absorption; Intestinal Mucosa; Intestine, Small; Male; Mecamylamine; Perfusion; Pharmaceutical Preparations; Rats; Rats, Wistar; Sodium Dodecyl Sulfate; Time Factors
PubMed: 30179738
DOI: 10.1016/j.ejpb.2018.09.001 -
Nicotine & Tobacco Research : Official... Nov 2021Smoking and the use of other nicotine-containing products is rewarding in humans. The self-administration of nicotine is also rewarding in male rats. However, it is...
INTRODUCTION
Smoking and the use of other nicotine-containing products is rewarding in humans. The self-administration of nicotine is also rewarding in male rats. However, it is unknown if there are sex differences in the reward-enhancing effects of nicotine self-administration and if the rewarding effects of nicotine change over time.
METHODS
Rats were prepared with catheters and intracranial self-stimulation (ICSS) electrodes to investigate the effects of nicotine and saline self-administration on reward function. A decrease in thresholds in the ICSS procedure reflects an enhancement of reward function. The ICSS parameters were determined before and after the self-administration sessions from days 1 to 10, and after the self-administration sessions from days 11 to 15.
RESULTS
During the first 10 days, there was no sex difference in nicotine intake, but during the last 5 days, the females took more nicotine than the males. During the first 10 days, nicotine self-administration did not lower the brain reward thresholds but decreased the response latencies. During the last 5 days, nicotine lowered the reward thresholds and decreased the response latencies. An analysis with the 5-day averages (days 1-5, 6-10, and 11-15) showed that the reward enhancing and stimulatory effects of nicotine increased over time. There were no sex differences in the reward-enhancing and stimulatory effects of nicotine. The nicotinic receptor antagonist mecamylamine diminished the reward-enhancing and stimulatory effects of nicotine.
CONCLUSION
These findings indicate that the rewarding effects of nicotine self-administration increase over time, and there are no sex differences in the reward-enhancing effects of nicotine self-administration in rats.
IMPLICATIONS
This study investigated the rewarding effect of nicotine and saline self-administration in male and female rats. The self-administration of nicotine, but not saline, enhanced brain reward function and had stimulatory effects. The rewarding effects of nicotine increased over time in the males and the females. Despite that the females had a higher level of nicotine intake than the males, the reward-enhancing effects of nicotine self-administration were the same. These findings suggest that in new tobacco and e-cigarette users, nicotine's rewarding effects might increase quickly, and a higher level of nicotine use in females might not translate into greater rewarding effects.
Topics: Animals; Electronic Nicotine Delivery Systems; Female; Male; Nicotine; Rats; Rats, Wistar; Reward; Self Stimulation
PubMed: 33987656
DOI: 10.1093/ntr/ntab097 -
CNS & Neurological Disorders Drug... 2015Major depressive disorder (MDD) is a serious mental illness that affects millions of people worldwide. There is now compelling evidence that the neuronal nicotinic... (Review)
Review
Major depressive disorder (MDD) is a serious mental illness that affects millions of people worldwide. There is now compelling evidence that the neuronal nicotinic acetylcholine receptors (nAChRs) play an important role in MDD and co-morbid alcohol or nicotine addiction. As a result, there has been growing interest for the treatment of MDD and co-morbid alcohol or nicotine use disorder by targeting nAChRs. Emerging evidence suggests that specific ligands that act at nAChRs significantly reduce depression-like behaviors in preclinical models that mimic MDD and co-morbid alcohol or nicotine use disorder. In this review, the pharmacological efficacy of nAChR ligands, such as mecamylamine, lobeline, cytisine, sazetidine-A, and others will be discussed. Overall, findings from preclinical and clinical studies included here suggest that the nAChR ligands may be of potential benefit in reducing MDD symptoms and that may aid in the prevention and treatment of MDD and co-morbid alcohol or nicotine use disorder.
Topics: Alcoholism; Animals; Brain; Cholinergic Agents; Depressive Disorder, Major; Disease Models, Animal; Humans; Receptors, Nicotinic; Tobacco Use Disorder
PubMed: 25921743
DOI: 10.2174/1871527314666150429112954 -
European Journal of Pharmacology Oct 2015In this study we aimed to test central administration of CDP-choline on serum ghrelin, leptin, glucose and corticosterone levels in rats. Intracerebroventricular...
In this study we aimed to test central administration of CDP-choline on serum ghrelin, leptin, glucose and corticosterone levels in rats. Intracerebroventricular (i.c.v.) 0.5, 1.0 and 2.0 µmol CDP-choline and saline were administered to male Wistar-Albino rats. For the measurement of serum leptin and ghrelin levels, blood samples were obtained baseline and at 5, 15, 30, 60 and 120 min following i.c.v. CDP-choline injection. Equimolar doses of i.c.v. choline (1.0 µmol) and cytidine (1.0 µmol) were administered and measurements were repeated throughout the second round of the experiment. Atropine (10 µg) and mecamylamine (50 µg) were injected intracerebroventricularly prior to CDP-choline and measurements repeated in the third round of the experiment. After 1 µmol CDP-choline injection, serum ghrelin levels were suppressed significantly at 60 min (P=0.025), whereas serum leptin levels were increased at 60 and 120 min (P=0.012 and P=0.017 respectively). CDP-choline injections also induced a dose- and time-dependent increase in serum glucose and corticosterone levels. The effect of choline on serum leptin and ghrelin levels was similar with CDP-choline while no effect was seen with cytidine. Suppression of serum ghrelin levels was eliminated through mecamylamine pretreatment while a rise in leptin was prevented by both atropine and mecamylamine pretreatments. In conclusion; centrally injected CDP-choline suppressed serum ghrelin levels while increasing serum leptin levels. The observed effects following receptor antagonist treatment suggest that nicotinic receptors play a role in suppression of serum ghrelin levels,whereas nicotinic and muscarinic receptors both play a part in the increase of serum leptin levels.
Topics: Animals; Atropine; Blood Glucose; Corticosterone; Cytidine Diphosphate Choline; Ghrelin; Injections; Leptin; Male; Mecamylamine; Muscarinic Antagonists; Nicotinic Antagonists; Rats, Wistar; Receptors, Muscarinic; Receptors, Nicotinic
PubMed: 26162700
DOI: 10.1016/j.ejphar.2015.07.014 -
Pharmacology, Biochemistry, and Behavior Jul 2021Electronic-cigarette's (ECIGs) popularity has grown over the last decade and changed the way individuals administer nicotine. Preclinical research is imperative for...
Electronic-cigarette's (ECIGs) popularity has grown over the last decade and changed the way individuals administer nicotine. Preclinical research is imperative for understanding the addictive properties and health-risks associated with ECIG use; however, there is not a standard dosing regimen used across research laboratories. The main objective was to determine how vapor puff durations, administration session length, and flavored e-liquid alter general and mood-disorder related behaviors while providing a foundation of vapor administration parameters. Adult male and female C57BL/6 mice were exposed to several nicotine-free unflavored vapor puff durations (1, 3, 6, or 10 s) and vapor administration session lengths (10 and 30 min) then measured on the following assays: locomotor activity (LMA), tail suspension test (TST), and light-dark test. The effects of mecamylamine and the time-course of vapor-induced depression of LMA also were assessed. Additionally, mice were exposed to flavored (strawberry and adventurers tobacco blend) vapor inhalation and measured on locomotor activity, tail suspension test, and light-dark test. Following both 10 and 30 min vapor administration session, there was a puff duration-dependent decrease in distance traveled, time in center, and rearing. The vapor-induced depression of LMA was not mediated by nicotine or nicotinic acetylcholine receptor (nAChR) activation and lasted 60-90 min. The 10 s puff duration produced an anxiogenic-like effect in the light-dark test by decreasing the time spent in the light side. Vapor inhalation did not significantly alter TST behavior. No significant effects of sex or flavor were found. The anxiogenic-like effects of nicotine-free vapor inhalation are concerning as many adolescents vape nicotine-free flavored e-liquid, and there is an association between ECIGs and mood disorders. Additionally, these studies demonstrate that vapor puff duration, but not vapor administration session length, is an important variable to consider during research design as it can become a confounding variable and alter baseline behaviors.
Topics: Administration, Inhalation; Adolescent; Animals; Anxiety; Behavior, Animal; E-Cigarette Vapor; Electronic Nicotine Delivery Systems; Female; Flavoring Agents; Humans; Locomotion; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Nicotine; Nicotinic Antagonists; Receptors, Nicotinic; Sex Factors; Time Factors; Vaping
PubMed: 34019915
DOI: 10.1016/j.pbb.2021.173207