Repeated nicotine vapor inhalation induces behavioral sensitization in male and female C57BL/6 mice.

Electronic cigarette use has significantly increased over the past decade. However, there is limited preclinical research on the behavioral and abuse-related effects of nicotine vapor inhalation in rodents. The present study evaluates the effects of repeated nicotine vapor inhalation in male and female mice using a nicotine behavioral sensitization model. Male and female C57BL/6 mice were administered vaporized nicotine (0-10.0 mg/ml) or the positive control of intraperitoneally administered nicotine (0.5 mg/kg) once daily for 5 days, and locomotor activity was assessed. Body temperatures were measured before and after nicotine vapor inhalation to assess hypothermia. Nicotine vapor inhalation (1.0-3.0 mg/ml) produced a dose-dependent behavioral sensitization effect and produced hypothermia in male and female mice. Nicotine (0.5 mg/kg) also produced significant behavioral sensitization. No sex differences were found for nicotine behavioral sensitization with either route of administration. Pretreatment with the nonselective nicotinic antagonist mecamylamine blocked the behavioral sensitization produced by 1.0 mg/ml of nicotine vapor inhalation. These results established that nicotine vapor inhalation produces behavioral sensitization in an inverted U-shaped curve that is similar to the effects of injected nicotine across several behavioral models. Additionally, pretreatment with mecamylamine demonstrated that nicotinic receptor activation was responsible for the behavioral sensitization produced by nicotine vapor inhalation and was not a conditioned response to the vapor. The methods used in the present study provide an additional behavioral approach for evaluating the behavioral effects of repeated nicotine vapor inhalation that allows the manipulation of several variables, including e-liquid oil blend, e-liquid flavors, puff duration, etc.

Reversal of mecamylamine-induced effects in healthy subjects by nicotine receptor agonists: Cognitive and (electro) physiological responses.

AIMS: Establishing a pharmacological challenge model could yield an important tool to understand the complex role of the nicotinic cholinergic system in cognition and to develop novel compounds acting on the nicotinic acetylcholine receptor. METHODS: This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study examined the effects of the nicotinic antagonist mecamylamine on a battery of cognitive and neurophysiological test with coadministration of a placebo, nicotine or galantamine in order to reverse the cognitive impairment caused by mecamylamine. RESULTS: Thirty-three healthy subjects received a single oral dose of 30 mg of mecamylamine (or placebo) in combination with either 16 mg of oral galantamine or 21 mg of transdermal nicotine (or its double-dummy). Mecamylamine 30 mg induced significant disturbances of cognitive functions. Attention and execution of visual (fine) motor tasks was decreased, short- and long-term memory was impaired and the reaction velocity during the test was slower when compared to placebo. Mecamylamine 30 mg produced a decrease in posterior α and ß power in the surface electroencephalogram, effects that were reversed by nicotine coadministration. Memory and motor coordination tests could be partially reversed by the coadministration of nicotine. CONCLUSIONS: Mecamylamine administration induced slowing of the electroencephalogram and produced decrease in performance of tests evaluating motor coordination, sustained attention and short- and long-term memory. These effects could be partially reversed by the coadministration of nicotine, and to a lesser extent by galantamine.

Wheel running during chronic nicotine exposure is protective against mecamylamine-precipitated withdrawal and up-regulates hippocampal α7 nACh receptors in mice.

BACKGROUND AND PURPOSE: Evidence suggests that exercise decreases nicotine withdrawal symptoms in humans; however, the mechanisms mediating this effect are unclear. We investigated, in a mouse model, the effect of exercise intensity during chronic nicotine exposure on nicotine withdrawal severity, binding of α4ß2*, α7 nicotinic acetylcholine (nAChR), µ-opioid (µ receptors) and D2 dopamine receptors and on brain-derived neurotrophic factor (BDNF) and plasma corticosterone levels. EXPERIMENTAL APPROACH: Male C57Bl/6J mice treated with nicotine (minipump, 24 mg·kg-1 ·day-1 ) or saline for 14 days underwent one of three concurrent exercise regimes: 24, 2 or 0 h·day-1 voluntary wheel running. Mecamylamine-precipitated withdrawal symptoms were assessed on day 14. Quantitative autoradiography of α4ß2*, α7 nAChRs, µ receptors and D2 receptor binding was performed in brain sections of these mice. Plasma corticosterone and brain BDNF levels were also measured. KEY RESULTS: Nicotine-treated mice undertaking 2 or 24 h·day-1 wheel running displayed a significant reduction in withdrawal symptom severity compared with the sedentary group. Wheel running induced a significant up-regulation of α7 nAChR binding in the CA2/3 area of the hippocampus of nicotine-treated mice. Neither exercise nor nicotine treatment affected µ or D2 receptor binding or BDNF levels. Nicotine withdrawal increased plasma corticosterone levels and α4ß2* nAChR binding, irrespective of exercise regimen. CONCLUSIONS AND IMPLICATIONS: We demonstrated for the first time a profound effect of exercise on α7 nAChRs in nicotine-dependent animals, irrespective of exercise intensity. These findings shed light onto the mechanism underlining the protective effect of exercise on the development of nicotine dependence. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.

Beneficial effects of resveratrol on scopolamine but not mecamylamine induced memory impairment in the passive avoidance and Morris water maze tests in rats.

Resveratrol (3,5,4-trihydroxy-trans-stilbene), which is found in grapes and red wine has been shown to protect neuronal cells with its antioxidant activity, improve memory function in dementia and reverse acetylcholine esterase (AChE) activity. The aim of this study was to investigate the effect of resveratrol on emotional and spatial memory in naive rats, as well as on scopolamine- and mecamylamine-induced memory impairment in the passive avoidance and Morris water maze (MWM) tests. Resveratrol (12.5, 25 and 50 mg/kg), scopolamine (0.6 mg/kg) and mecamylamine (10mg/kg) were administered to male Wistar rats. In the passive avoidance test, there was no significant difference in the first day latency between all groups, whereas scopolamine and mecamylamine significantly shortened the second day latency compared to the control group. Resveratrol reversed the effect of scopolamine at all doses used, but it had no effect on mecamylamine-induced memory impairment in the passive avoidance test. Both scopolamine and mecamylamine significantly decreased the time spent in the escape platform quadrant during the probe trial of the MWM test compared to the control group. Resveratrol reversed the effect of scopolamine at all doses, but did not change the effect of mecamylamine in the MWM test. There were no significant differences in the locomotor activities of any of the groups. In conclusion, we suggested that resveratrol had improving effects on learning and memory by acting on muscarinic cholinergic receptors and at least in part, may reverse AChE activity.

Attenuation of pharmacologically-induced attentional impairment by methylphenidate in rats.

Methylphenidate is widely used as a treatment option for attention deficit hyperactivity disorder. In animal models of attentional impairment, it is an important validation to determine whether this clinically effective treatment attenuates deficits. The purpose of the current study was to determine whether methylphenidate can diminish attentional impairment induced by three pharmacological agents with different mechanisms of action: scopolamine, mecamylamine, and dizocilpine. Female rats were trained on an operant visual signal detection task. Ten min before the test, the rats were injected subcutaneously with methylphenidate (0, 0.1, 0.3 mg/kg), scopolamine (0, 0.005, 0.01 mg/kg), mecamylamine (0, 2, 4 mg/kg), dizocilpine (0, 0.025, 0.05 mg/kg) or combinations of methylphenidate with these drugs. In each of the experiments, all rats received every treatment in a repeated measures counterbalanced order. Correction rejection accuracy was impaired by all three of the antagonists and these effects were attenuated by methylphenidate. Both scopolamine at 0.01 and dizocilpine at 0.05 mg/kg significantly impaired percent correct rejection choice accuracy, an effect that was ameliorated by methylphenidate. Mecamylamine (4 mg/kg) impaired attentional performance by reducing percent hit and percent correct rejection. Co-administration of methylphenidate failed to significantly affect the mecamylamine-induced attentional impairment. Methylphenidate alone at 0.3 mg/kg significantly improved percent hit choice accuracy only in low-performing rats in one experiment, an effect which was reversed by scopolamine. These data show that methylphenidate effectively reverses the attentional impairment caused by scopolamine and dizocilpine. These findings further validate the operant visual signal detection task for assessing attentional impairments and their reversal.

Effect of huperzine A, a novel acetylcholinesterase inhibitor, on radial maze performance in rats.

Rats were trained to run in a spatial, radial arm maze using a procedure to determine two memory functions, working and reference memory. The muscarinic antagonist, not the nicotinic antagonist, impaired both working and reference memory of rats. Scopolamine (0.125, 0.15, and 0.2 mg/kg, IP, 30 min before a session) significantly impaired choice accuracy in the eight-arm maze. In contrast, mecamylamine (5, 10, and 15 mg/kg) did not affect the performance. Huperzine A (0.1, 0.2, and 0.3 mg/kg, IP, 30 min before testing) and physostigmine (0.3 mg/kg, IP, 20 min before testing) could reverse scopolamine-induced deficits in the task. Chronic treatment with huperzine A (0.25 mg/kg, PO, once a day) for 8 consecutive days was as potent as acute treatment on attenuating the scopolamine-induced amnesia.

Diisopropylfluorophosphate and tetanic stimulation fail to reverse mecamylamine antagonism of Renshaw cells.

Mecamylamine-induced antagonism of Renshaw cells was studied in the spinal cord of DIAL anesthetized adult male or spayed female mongrel cats. Renshaw cell unit responses to 1- or 2-Hz supramaximal antidromic stimulation of lumbar segment 7 ventral root were recorded by conventional means from glass micropipettes (2.7 M NaCl, tip diameter 1.0 to 1.6 micron, 2.0 to 4.0 M omega resistance). Data were analyzed by computer. Mecamylamine (1.0 mg/kg iv) antagonizes the response to 1- or 2-Hz stimulation. The onset occurs within 60 sec, only the first one or two spikes remain after 2 min, and this antagonism is observed 30 min after injection. Persistence of action of acetylcholine (ACh) induced by diisopropylfluorophosphate (DFP 2.0 to 2.5 mg/kg iv) increases the spike frequency of the Renshaw cell burst and reduces the variability in the number of spikes per discharge in response to 1- or 2-Hz antidromic stimulation. Excess ACh generated by 2 min of 20-Hz antidromic stimulation fails to reverse the mecamylamine-induced antagonism to 1- or 2-Hz antidromic stimulation. Also, DFP-induced persistence of action of ACh or 20-Hz (2 min) antidromic stimulation to induce excess ACh in the presence of DFP, fails to reverse the mecamylamine-induced antagonism of response to 1- or 2-Hz antidromic stimulation. It is concluded that the data agree with a mechanism of action of mecamylamine as a noncompetitive open channel blocker of the nicotinic receptor ion-channel complex which renders it nonresponsive to the agonist ACh and to the open channel blocker, DFP.