-
Alcoholism, Clinical and Experimental... Jan 2016Ethanol (EtOH) and nicotine abuse are 2 leading causes of preventable mortality in the world, but little is known about the pharmacological mechanisms mediating...
BACKGROUND
Ethanol (EtOH) and nicotine abuse are 2 leading causes of preventable mortality in the world, but little is known about the pharmacological mechanisms mediating co-abuse. Few studies have examined the interaction of the acute effects of EtOH and nicotine. Here, we examine the effects of nicotine administration on the duration of EtOH-induced loss of righting reflex (LORR) and characterize the nature of their pharmacological interactions in C57BL/6J mice.
METHODS
We assessed the effects of EtOH and nicotine and the nature of their interaction in the LORR test using isobolographic analysis after acute injection in C57BL/6J male mice. Next, we examined the importance of receptor efficacy using nicotinic partial agonists varenicline and sazetidine. We evaluated the involvement of major nicotinic acetylcholine receptor (nAChR) subtypes using nicotinic antagonist mecamylamine and nicotinic α4- and α7-knockout mice. The selectivity of nicotine's actions on EtOH-induced LORR was examined by testing nicotine's effects on the hypnotic properties of ketamine and pentobarbital. We also assessed the development of tolerance after repeated nicotine exposure. Last, we assessed whether the effects of nicotine on EtOH-induced LORR extend to hypothermia and EtOH intake in the drinking in the dark (DID) paradigm.
RESULTS
We found that acute nicotine injection enhances EtOH's hypnotic effects in a synergistic manner and that receptor efficacy plays an important role in this interaction. Furthermore, tolerance developed to the enhancement of EtOH's hypnotic effects by nicotine after repeated exposure of the drug. α4* and α7 nAChRs seem to play an important role in nicotine-EtOH interaction in the LORR test. In addition, the magnitude of EtOH-induced LORR enhancement by nicotine was more pronounced in C57BL/6J than DBA/2J mice. Furthermore, acute nicotine enhanced ketamine and pentobarbital hypnotic effects in the mouse. Finally, nicotine enhanced EtOH-induced hypothermia but decreased EtOH intake in the DID test.
CONCLUSIONS
Our results demonstrate that nicotine synergistically enhances EtOH-induced LORR in the mouse.
Topics: Animals; Azetidines; Body Temperature; Central Nervous System Depressants; Drug Interactions; Ethanol; Hypnotics and Sedatives; Hypothermia; Ketamine; Mecamylamine; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Pentobarbital; Pyridines; Receptors, Nicotinic; Reflex, Righting; Varenicline; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 26727524
DOI: 10.1111/acer.12918 -
Experimental Animals 2012Pentobarbital (PB) and ketamine (Ket) influence the concentration of neurotransmitters in the brain. PB has been reported to decrease the extracellular nitric oxide (NO)...
Pentobarbital (PB) and ketamine (Ket) influence the concentration of neurotransmitters in the brain. PB has been reported to decrease the extracellular nitric oxide (NO) concentration through a decrease in acetylcholine (ACh) release, while Ket has been shown to increase the NO concentration via an increase in ACh release. Here, we investigated effects of PB and Ket on NO release and the relationship between NO and ACh in the rat striatum by in vivo microdialysis experiments. Male Sprague-Dawley rats were used. A microdialysis probe was inserted into the right striatum and perfused with modified Ringer's solution. Samples were collected every 15 min and injected into an HPLC system. The rats were freely moving, and PB and Ket were administered intraperitoneally. Neostigmine (1 and 10 µM) and mecamylamine (100 µM) were added to the perfusate. Calcium and magnesium concentrations were modified for each anesthetic to influence ACh release. PB decreased NO products (NOx) while Ket increased them. While perfusion with neostigmine showed no effect on baseline NOx concentrations, it diminished the PB-induced NOx reduction at low concentrations and abolished it at high concentrations. Magnesium-free perfusion had no effect on baseline NOx concentrations, whereas perfusion at a low magnesium concentration antagonized the PB-induced NOx reduction. Mecamylamine and calcium-free perfusion had no effect on baseline NOx concentrations and Ket-induced NOx increases. PB may decrease NO release through reduction in ACh release, whereas Ket may increase NO release independent of ACh regulation.
Topics: Acetylcholine; Animals; Cholinergic Neurons; Chromatography, High Pressure Liquid; Corpus Striatum; Excitatory Amino Acid Antagonists; Hypnotics and Sedatives; Injections, Intraperitoneal; Ketamine; Male; Mecamylamine; Microdialysis; Neostigmine; Nicotinic Antagonists; Nitric Oxide; Parasympathomimetics; Pentobarbital; Rats; Rats, Sprague-Dawley
PubMed: 22531732
DOI: 10.1538/expanim.61.165 -
Behavioural Brain Research Sep 2012In the present study, we determined the effects of environmental enrichment (EE; Kong Toys and Nestlets) on sexually diergic HPA axis responses to single-dose nicotine...
Influence of environmental enrichment on hypothalamic-pituitary-adrenal (HPA) responses to single-dose nicotine, continuous nicotine by osmotic mini-pumps, and nicotine withdrawal by mecamylamine in male and female rats.
In the present study, we determined the effects of environmental enrichment (EE; Kong Toys and Nestlets) on sexually diergic HPA axis responses to single-dose nicotine (NIC), single-dose NIC following continuous NIC administration for two weeks, and NIC withdrawal by single-dose mecamylamine (MEC) in male and female rats. Blood sampling occurred before and after MEC and NIC administrations for the determination of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Supporting and extending our previous findings, EE appeared to produce anxiolytic effects by reducing hormone responses: Male and female rats housed with EE had lower baseline ACTH and significantly lower HPA axis responses to the mild stress of saline (SAL) injection than did those housed without EE. The sexually diergic responses to single dose NIC, continuous NIC, and MEC-induced NIC withdrawal were reduced by EE in many male and female groups. ACTH responses to continuous NIC and MEC-induced NIC withdrawal were blunted to a greater extent in female EE groups than in male EE groups, suggesting that females are more sensitive to the anxiolytic effects of EE. Because EE lowered stress-responsive hormones of the HPA axis in most groups, EE may be a useful intervention for stress reduction in animal models of NIC addiction. As well, the effectiveness of EE in animal studies of NIC withdrawal may enlighten human studies addressing coping styles and tobacco cessation in men and women.
Topics: Adrenocorticotropic Hormone; Animals; Corticosterone; Female; Hypothalamus; Male; Mecamylamine; Nicotine; Osmotic Pressure; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Sex Characteristics; Stress, Physiological; Substance Withdrawal Syndrome
PubMed: 22705101
DOI: 10.1016/j.bbr.2012.06.003 -
Diabetes Nov 2019The contribution of the sympathetic nervous system (SNS) versus the parasympathetic nervous system (PSNS) in mediating fatal cardiac arrhythmias during insulin-induced...
The contribution of the sympathetic nervous system (SNS) versus the parasympathetic nervous system (PSNS) in mediating fatal cardiac arrhythmias during insulin-induced severe hypoglycemia is not well understood. Therefore, experimental protocols were performed in nondiabetic Sprague-Dawley rats to test the SNS with ) adrenal demedullation and ) chemical sympathectomy, and to test the PSNS with ) surgical vagotomy, ) nicotinic receptor (mecamylamine) and muscarinic receptor (AQ-RA 741) blockade, and ) ex vivo heart perfusions with normal or low glucose, acetylcholine (ACh), and/or mecamylamine. In protocols 1-4, 3-h hyperinsulinemic (0.2 units/kg/min) and hypoglycemic (10-15 mg/dL) clamps were performed. Adrenal demedullation and chemical sympathectomy had no effect on mortality or arrhythmias during severe hypoglycemia compared with controls. Vagotomy led to a 6.9-fold decrease in mortality; reduced first- and second-degree heart block 4.6- and 4-fold, respectively; and prevented third-degree heart block compared with controls. Pharmacological blockade of nicotinic receptors, but not muscarinic receptors, prevented heart block and mortality versus controls. Ex vivo heart perfusions demonstrated that neither low glucose nor ACh alone caused arrhythmias, but their combination induced heart block that could be abrogated by nicotinic receptor blockade. Taken together, ACh activation of nicotinic receptors via the vagus nerve is the primary mediator of severe hypoglycemia-induced fatal cardiac arrhythmias.
Topics: Animals; Arrhythmias, Cardiac; Benzodiazepinones; Disease Models, Animal; Hypoglycemia; Male; Mecamylamine; Muscarinic Antagonists; Nicotinic Antagonists; Parasympathetic Nervous System; Piperidines; Rats; Rats, Sprague-Dawley; Sympathectomy, Chemical; Vagotomy
PubMed: 31439645
DOI: 10.2337/db19-0306 -
Addiction Biology Jul 2014Humans escalate their cigarette smoking over time, and a major obstacle in the field of pre-clinical nicotine addiction research has been the inability to produce...
Humans escalate their cigarette smoking over time, and a major obstacle in the field of pre-clinical nicotine addiction research has been the inability to produce escalated nicotine self-administration in rats. In experiment 1, male Wistar rats were trained to respond for nicotine in 2-hour operant sessions, then exposed to chronic intermittent (12 hours/day) nicotine vapor and repeatedly tested for nicotine self-administration at 8-12 hours of withdrawal. Rats were tested intermittently on days 1, 3 and 5 of the vapor exposure procedure, then tested with nicotine vapor exposure on 6-15 consecutive days. Rats exhibited transient increases in operant nicotine responding during intermittent testing, regardless of vapor condition, and this responding returned to baseline levels upon resumption of consecutive-days testing (i.e. nicotine deprivation effect). Nicotine vapor-exposed rats then escalated nicotine self-administration relative to both their own baseline (∼200% increase) and non-dependent controls (∼3× higher). In experiment 2, rats were exposed or not exposed to chronic intermittent nicotine vapor, then tested for spontaneous and precipitated somatic signs of nicotine withdrawal. Eight hours following removal from nicotine vapor, rats exhibited robust mecamylamine-precipitated somatic signs of withdrawal. There was a strong correlation between nicotine flow rate and air-nicotine concentration, and the air-nicotine concentrations used in experiments 1 and 2 resemble concentrations experienced by human smokers. Collectively, these results suggest that chronic intermittent nicotine vapor inhalation produces somatic and motivational signs of nicotine dependence, the latter of which is evidenced by escalation of nicotine self-administration.
Topics: Analysis of Variance; Animals; Behavior, Animal; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mecamylamine; Molecular Sequence Data; Nicotine; Nicotinic Antagonists; Rats; Rats, Wistar; Self Administration; Substance Withdrawal Syndrome; Tobacco Use Disorder; Volatilization
PubMed: 23240929
DOI: 10.1111/adb.12021 -
Journal of Medicinal Food Apr 2020(EO) includes a large number of polyphenolic compounds such as phenolics, flavonoids, and anthocyanins that have antioxidant activities. was suggested to ease the...
(EO) includes a large number of polyphenolic compounds such as phenolics, flavonoids, and anthocyanins that have antioxidant activities. was suggested to ease the oxidative stress and inflammation in brain cells. Our aim was to analyze the effects of on learning and memory. Seventy-two (250 ± 25 g) male Wistar albino rats were used for this study. The groups consisted of control, EO100 mg/kg, EO300 mg/kg, scopolamine 1.5 mg/kg, mecamylamine 7.5 mg/kg, combinations of scopolamine with EO100 mg/kg, EO300 mg/kg, and rivastigmine 1.5 mg/kg; and mecamylamine combined with EO100 mg/kg. Before the start of the study, doses were provided once a day for a period of 15 days and for a 6-day experimental period. Thirty minutes after intraperitoneal scopolamine and mecamylamine injections, gastrogavage was applied to each group. Ninety minutes after the drug treatments, locomotor activity and Morris water maze tests were performed. Rats were killed and each hippocampus was used for the quantification of acetylcholine (Ach). Statistical analyses were calculated using one-way and two-way analyses of variance (ANOVA), and a value of < .05 was considered significant. In groups EO100 mg/kg and EO300 mg/kg the results did not show any significant changes on learning and memory compared with the control group. Mecamylamine and scopolamine enhanced the latency for the escape platform, and decreased the time spent in escape platform quadrant when the memory tests were applied in reference to the control value of < .05. Scopolamine and mecamylamine combinations of EO100 mg/kg, EO300 mg/kg, and rivastigmine were proven to improve the memory. There was significant difference between the first and fifth days of the learning tests in all the groups, but no significant difference occurred between the groups. Ach levels in hippocampi supported all memory tests. We suggest that made no alterations on learning and memory, but still improved nicotinic and muscarinic receptor-mediated and impaired memory just as rivastigmine.
Topics: Acetylcholine; Animals; Cholinergic Agents; Dose-Response Relationship, Drug; Euterpe; Hippocampus; Male; Maze Learning; Mecamylamine; Memory; Memory Disorders; Rats; Rats, Wistar; Receptors, Muscarinic; Receptors, Nicotinic; Scopolamine
PubMed: 31580752
DOI: 10.1089/jmf.2018.0197 -
Behavioural Pharmacology Jun 2011A conjunctive variable-interval differential-reinforcement-of-low-rate (VI-DRL, n=18) responding schedule and a stop-signal task (n=18) were used to evaluate the...
A conjunctive variable-interval differential-reinforcement-of-low-rate (VI-DRL, n=18) responding schedule and a stop-signal task (n=18) were used to evaluate the disinhibiting effects of nicotine on response withholding in rats. Sucrose solution was used to reinforce responding, and after a stable baseline was achieved under saline-administration conditions, 0.3 mg/kg nicotine was delivered before each session. Experiment 1 showed that repeated, but not the initial, administration of nicotine decreased performance on both tasks, and the effect of sensitization followed a similar timeline; 10 consecutive doses resulted in poorer proportion-correct VI-DRL trials and percent correct stop trials than the initial dose of nicotine. Furthermore, sensitization to 0.3 mg/kg nicotine decreased performance regardless of whether a spaced or consecutive-dosing regimen was followed. Experiment 2 was designed to test whether mecamylamine hydrochloride (0.1-1.0 mg/kg) could attenuate the effects of repeated 0.3 mg/kg nicotine administration, and the degree to which mecamylamine attenuation of the effect of nicotine to produce impulsive action was relative to dose. Results from experiment 2 showed that response disinhibition, as evaluated using the VI-DRL and stop-signal tasks, is related in a systematic manner to nicotinic-acetylcholine receptor activation.
Topics: Animals; Dose-Response Relationship, Drug; Impulsive Behavior; Male; Mecamylamine; Nicotine; Rats; Rats, Sprague-Dawley; Reinforcement Schedule
PubMed: 21448062
DOI: 10.1097/FBP.0b013e328345ca1c -
PloS One 2016Excess sugar consumption has been shown to contribute directly to weight gain, thus contributing to the growing worldwide obesity epidemic. Interestingly, increased...
Excess sugar consumption has been shown to contribute directly to weight gain, thus contributing to the growing worldwide obesity epidemic. Interestingly, increased sugar consumption has been shown to repeatedly elevate dopamine levels in the nucleus accumbens (NAc), in the mesolimbic reward pathway of the brain similar to many drugs of abuse. We report that varenicline, an FDA-approved nicotinic acetylcholine receptor (nAChR) partial agonist that modulates dopamine in the mesolimbic reward pathway of the brain, significantly reduces sucrose consumption, especially in a long-term consumption paradigm. Similar results were observed with other nAChR drugs, namely mecamylamine and cytisine. Furthermore, we show that long-term sucrose consumption increases α4β2 * and decreases α6β2* nAChRs in the nucleus accumbens, a key brain region associated with reward. Taken together, our results suggest that nAChR drugs such as varenicline may represent a novel treatment strategy for reducing sugar consumption.
Topics: Alkaloids; Animals; Azocines; Drug Evaluation, Preclinical; Food Preferences; Male; Mecamylamine; Nicotinic Agonists; Nicotinic Antagonists; Nucleus Accumbens; Quinolizines; Rats, Wistar; Receptors, Nicotinic; Sucrose; Varenicline
PubMed: 27028298
DOI: 10.1371/journal.pone.0150270 -
Journal of Psychopharmacology (Oxford,... Mar 2024Addiction to tobacco and nicotine products has adverse health effects and afflicts more than a billion people worldwide. Therefore, there is an urgent need for new...
BACKGROUND
Addiction to tobacco and nicotine products has adverse health effects and afflicts more than a billion people worldwide. Therefore, there is an urgent need for new treatments to reduce tobacco and nicotine use. Glucocorticoid receptor blockade shows promise as a novel treatment for drug abuse and stress-related disorders.
AIM
These studies aim to investigate whether glucocorticoid receptor blockade with mifepristone diminishes the reinforcing properties of nicotine in rats with intermittent or daily long access to nicotine.
METHODS
The rats self-administered 0.06 mg/kg/inf of nicotine for 6 h per day, with either intermittent or daily access for 4 weeks before treatment with mifepristone. Daily nicotine self-administration models regular smoking, while intermittent nicotine self-administration models occasional smoking. To determine whether the rats were dependent, they were treated with the nicotinic acetylcholine receptor antagonist mecamylamine, and somatic signs were recorded.
RESULTS
The rats with intermittent access to nicotine had a higher level of nicotine intake per session than those with daily access but only the rats with daily access to nicotine showed signs of physical dependence. Furthermore, mecamylamine increased nicotine intake during the first hour of access in rats with daily access but not in those with intermittent access. Mifepristone decreased total nicotine intake in rats with intermittent and daily access to nicotine. Moreover, mifepristone decreased the distance traveled and rearing in the open field test and operant responding for food pellets.
CONCLUSION
These findings indicate that mifepristone decreases nicotine intake but this effect may be partially attributed to the sedative effects of mifepristone.
Topics: Humans; Rats; Animals; Nicotine; Mecamylamine; Mifepristone; Smoking; Receptors, Glucocorticoid; Tobacco Use Disorder; Substance Withdrawal Syndrome; Rats, Wistar; Self Administration; Dose-Response Relationship, Drug
PubMed: 38332661
DOI: 10.1177/02698811241230255 -
Neuropharmacology Nov 2019The medial habenula-interpeduncular nucleus (MHb-IPN) pathway modulates negative affective states produced by nicotine withdrawal. Sex differences in the contribution of...
The medial habenula-interpeduncular nucleus (MHb-IPN) pathway modulates negative affective states produced by nicotine withdrawal. Sex differences in the contribution of acetylcholine (ACh) systems in this pathway have not been explored. Thus, this study assessed ACh levels and gene expression of α- and β-containing nicotinic acetylcholine receptor (nAChR) subunits in the IPN of female and male rats following nicotine treatment and withdrawal. Rats were prepared with a pump that delivered nicotine for 14 days, and naïve controls received a sham surgery. In Study 1, rats were prepared with a probe in the IPN, and ACh levels were measured following saline and then mecamylamine administration. In Study 2, separate groups of naïve control or nicotine-treated rats received saline or mecamylamine and physical signs and anxiety-like behavior were assessed using elevated plus maze (EPM) procedures. The IPN was then dissected and mRNA levels were assessed using RT-qPCR methods. Nicotine treatment increased ACh levels to a larger extent in females than males. Nicotine withdrawal produced a similar increase in physical signs; however, females displayed greater anxiety-like behavior than males. In females, gene expression of α5 increased following nicotine treatment and withdrawal. In males, α7 increased following nicotine treatment and α2 and α3 increased during nicotine withdrawal. Both females and males displayed an increase in β3 and β4 during nicotine withdrawal. In females, anxiety-like behavior was correlated with α4, α5, and β2 gene expression in the IPN. These results suggest that sex differences in withdrawal are modulated via cholinergic systems in the IPN.
Topics: Animals; Anxiety; Behavior, Animal; Female; Gene Expression; Interpeduncular Nucleus; Male; Mecamylamine; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; RNA, Messenger; Rats; Receptors, Nicotinic; Sex Factors; Substance Withdrawal Syndrome; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 31325431
DOI: 10.1016/j.neuropharm.2019.107714