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PubMed1999

Mecamylamine blocks the development of tolerance to nicotine in rats: implications for the mechanisms of tolerance.

Chronic injections of nicotine in rats produce upregulation of nicotinic cholinergic receptors. It has been proposed that this upregulation is a reflection of receptor desensitization and is the basis of functional tolerance. Mecamylamine, a non-competitive antagonist that blocks activation of nicotinic receptors, does not prevent upregulation produced by nicotine injections. This suggests that receptor activation is not a prerequisite for nicotine-induced receptor upregulation. Therefore, the present experiments tested whether mecamylamine would also fail to prevent the development of tolerance to nicotine. Six daily pairings of mecamylamine (1 mg/kg SC) with nicotine did block the development of tolerance to nicotine-induced antinociception (0.35 mg/kg) and to the ability of nicotine to suppress milk intake (0.66 mg/kg). In another experiment, six daily injections of mecamylamine, when given alone, did not alter the effects of a subsequent, acute injection of nicotine (0.35 mg/kg) in inducing antinociception in rats. There was no evidence that after six pairings of mecamylamine with nicotine, the cues associated with mecamylamine delivery took on conditioned antagonistic properties. These findings suggest that, unlike the receptor upregulation that results from either continuous or repeated nicotine administration, the tolerance following a short series of intermittent nicotine injections is dependent on receptor activation.

Analgesics↗

PubMed1988

Mecamylamine reduces some EEG effects of nicotine chewing gum in humans.

Spontaneous EEG was recorded in nine cigarette smokers who had been abstinent from tobacco for 12 hr. Subjects were treated with a capsule containing either centrally acting nicotine blocker, mecamylamine (10 mg), or placebo. At each of three 60-min intervals after the capsule was ingested, the subjects chewed two pieces of gum containing a total of 0, 4 or 8 mg of nicotine. Nicotine and mecamylamine dose combinations were randomized across subjects. Two three-minute periods of spontaneous EEG were recorded before the capsule and before and after gum chewing from bipolar electrode montages at the following positions: Cz-T5, Cz-T6, Cz-F7 and Cz-F8. During one period the subjects relaxed with eyes closed, in the other period they performed a math task with eyes open. When the drugs were given individually, mecamylamine decreased beta power and nicotine gum (4 and 8 mg) increased alpha frequency. Mecamylamine pretreatment prevented the increase in alpha frequency caused by the 4 mg gum dose but not the 8 mg dose. Alpha power was increased by the 8 mg gum dose and that increase was prevented by mecamylamine. Self-reported ratings of the "strength" of the gum were significantly diminished by mecamylamine pretreatment. The data are consistent with the results of earlier studies which indicate that the effects of tobacco administration and withdrawal are mediated by central actions of nicotine.

Adult↗

PubMed2005

Mecamylamine moderates cue-induced emotional responses in smokers.

The nicotinic antagonist, mecamylamine, has been shown to reduce cue-elicited cocaine craving and to aid in smoking cessation. In a within-subjects design, 16 dependent smokers received mecamylamine (10 mg) or placebo capsules on two different days. Subjects imagined smoking urge and non-urge scenarios after smoking their usual brand vs. denicotinized cigarettes. Smoking usual-brand cigarettes produced greater positive effects and mecamylamine blocked heart rate (HR) boost and cigarette sensory impact. Mecamylamine also resulted in greater craving and less calmness, regardless of cigarette smoked. Urge script imagination in the mecamylamine+denicotinized condition resulted in calmness similar to usual-brand conditions and higher than the placebo+denicotinized condition. A similar trend was observed for negative affect. These results suggest that mecamylamine can moderate smoking cue-induced emotional responses in smokers.

Adult↗

PubMed2006

Neurochemical and behavioral effects of bupropion and mecamylamine in the presence of nicotine.

The primary mechanism of action of bupropion, a smoking cessation drug, is commonly believed to involve the dopaminergic system although evidence exists that bupropion also has effects at nicotinic acetylcholine receptors (nAChRs). This study evaluated the disruptive effects of nicotine on response rates in the presence of bupropion and the nAChR antagonist, mecamylamine, as well as the ability of these drugs to alter nicotine-stimulated nAChR function in various brain areas. Rats were trained to respond on a single lever under a variable interval 15 (VI15) schedule for food reinforcement. Initially, dose effect curves were generated for nicotine, bupropion and mecamylamine. Upon determining the dose of nicotine (1.2 mg/kg) effective in completely disrupting rates of responding, it was established that both mecamylamine and bupropion block nicotine's rate-reducing effects. This result suggests that bupropion shares behavioral effects with mecamylamine when administered in the presence of nicotine. To explore this relationship further, the effect of in vivo administration of bupropion or mecamylamine on nicotine-stimulated (86)Rb(+) efflux was studied in synaptosomes prepared from the frontal cortex, hippocampus, striatum and thalamus. Nicotine-stimulated (86)Rb(+) efflux from all brain regions was significantly reduced in rats administered 3.0 mg/kg mecamylamine (s.c.) 15 min prior to dissection compared to control rats. In contrast, a significant increase in nicotine-stimulated (86)Rb(+) efflux was observed in all brain regions from rats administered 30.0 mg/kg bupropion (s.c.) 15 min prior to dissection compared to control rats. Taken together these results demonstrate that when administered in the presence of nicotine, bupropion elicits unique pharmacological differences such that it exhibits both nAChR agonist- and antagonistic-like effects.

Animals↗

PubMed1998

Voluntary ethanol intake in the rat and the associated accumbal dopamine overflow are blocked by ventral tegmental mecamylamine.

The mesocorticolimbic dopamine system is believed to be involved in mediating the positive reinforcing effects of drugs of abuse, including ethanol. The nicotinic acetylcholine receptor antagonist mecamylamine perfused via reversed microdialysis in the ventral tegmental area antagonizes the increase of accumbal extracellular dopamine levels after systemic ethanol, and, after systemic injection, lowers ethanol intake in the rat. In the present study the effect of ventral tegmental mecamylamine on ethanol intake and preference, as well as on extracellular accumbal dopamine levels, was investigated in the same animal. To this end, in vivo microdialysis using a double probe approach (one in the nucleus accumbens and one in the ventral tegmental area) was combined with an ethanol preference model invoking a free choice between a bottle of water and a bottle of ethanol 6% (v/v) solution. Wistar rats drinking more than 60% of their total daily fluid intake from the ethanol solution (ethanol high-preferring animals) were selected during a screening period and used for the experiments. The animals received vehicle or mecamylamine (100 microM) in the ventral tegmental area and were then presented with a choice between water and ethanol in a limited access paradigm to which they previously had been adapted. On the next day the rats that received vehicle day 1 now received mecamylamine, and vice versa. When treated with vehicle, ethanol intake and preference were unaltered, as compared to baseline behavior, and accumbal dopamine levels increased significantly to approximately 130% of the pre-drug baseline level. When receiving mecamylamine, ethanol intake and preference were reduced markedly and dopamine levels were unaltered, as compared to pre-drug baseline levels. The present results further indicate that nicotinic acetylcholine receptors in the ventral tegmental area are involved in the positive reinforcing effects of ethanol. Thus, mecamylamine or other antagonists specifically aimed at ventral tegmental nicotinic acetylcholine receptors could represent a new pharmacological treatment principle against alcohol abuse, the efficacy of which should be explored in high-scale alcohol consumers or alcoholics.

Alcohol Drinking↗

PubMed1998

Mecamylamine inhibits nicotine but not capsaicin irritation on the tongue: psychophysical evidence that nicotine and capsaicin activate separate molecular receptors.

Using a two-alternative forced-choice (2-AFC) discrimination test coupled with category intensity ratings, we investigated the effect of mecamylamine, an antagonist of neuronal nicotinic acetylcholine receptors (nAchRs), on oral irritation elicited by nicotine or capsaicin. Mecamylamine (0.075%) was first delivered to one side of the tongue with distilled H2O delivered to the other side. After 10 min either capsaicin (1 ppm) or nicotine (0.12%) was applied bilaterally to the tongue, and subjects were asked to choose which side yielded a stronger sensation (2-AFC) as well as to provide a rating of the irritation intensity difference between the two sides of the tongue. When nicotine was given after mecamylamine, a significant proportion of subjects chose the mecamylamine-untreated side as yielding stronger irritation. When capsaicin was given after mecamylamine, both sides of the tongue were chosen in equal numbers. These data indicate that mecamylamine reduced irritation elicited by nicotine but not capsaicin, and provide further evidence that nicotine oral irritation is mediated via a neuronal nAchR while capsaicin activates trigeminal fibers via a separate molecular receptor.

Adult↗

PubMed2002

Mecamylamine (Inversine): an old antihypertensive with new research directions.

Mecamylamine (Inversine), the first orally available antihypertensive agent, is now rarely used. Although celebrated in the 1950s, mecamylamine fell out of favour because of its widespread ganglionic side effects at antihypertensive doses (30-90 mg/day). However, recent studies suggest that mecamylamine is very effective at relatively low doses (2.5-5 mg b.i.d.) for blocking the physiological effects of nicotine and improving abstinence rates in smoking cessation studies, particularly for women. When these lower doses of mecamylamine are given, patients do not experience the severity of side effects that made the drug unpopular for the treatment of hypertension. Tobacco smoking is a strong risk factor for cardiovascular morbidity, including accelerated atherosclerosis and increased risk of heart attacks. Though currently untested, the available evidence suggests that low-dose mecamylamine therapy might reduce blood pressure variability and atherogenetic lipid profile in smokers. With this in mind, mecamylamine should be an important research tool in the field of hypertension research, particularly in recalcitrant smokers with mild to moderate hypertension.

Antihypertensive Agents↗

PubMed2006

The influence of mecamylamine on trigeminal and olfactory chemoreception of nicotine.

Nicotine presented to the nasal cavity at low concentrations evokes 'odorous' sensations, and at higher concentrations 'burning' and 'stinging' sensations. A study in smokers and nonsmokers provided evidence of a relationship between the experience with the pharmacological action of S-(-)-nicotine and the perceived pleasantness/unpleasantness following nasal stimulation with S-(-)-nicotine. Mecamylamine, a nicotinic acetylcholine-receptor-(nAch-R) antagonist, was able to block painful responses following chemical stimulation of the human tongue and to block responses from the rat's ethmoidal nerve. The aim of our study in humans was to investigate the effects of mecamylamine on the olfactory and the trigeminal chemoreception of nicotine enantiomers. In order to achieve this aim, we determined-before and after mecamylamine-(1) detection thresholds, trigeminal thresholds, and intensity estimates (stimulus intensity) and (2) recorded the negative mucosal potential (NMP) following nasal stimulation with nicotine in a placebo-controlled double blind study (n = 15). CO(2) was used as a trigeminal and H(2)S as an olfactory control stimulus. Mecamylamine significantly increased trigeminal thresholds of S-(-)-nicotine and reduced intensity estimates and NMPs following stimulation with nicotine enantiomers, whereas mecamylamine did not influence NMPs and trigeminal intensity estimates following stimulation with CO(2). In contrast, mecamylamine did neither influence detection thresholds nor olfactory intensity estimates following stimulation with olfactory nicotine concentrations. These results demonstrate that the trigeminal nasal chemoreception of nicotine enantiomers, in contrast to CO(2), is mediated by nAch-Receptors and give evidence that the olfactory chemoreception of nicotine is independent from peripheral nAch-Receptors.

Adolescent↗

PubMed2006

Mecamylamine attenuates cue-induced reinstatement of nicotine-seeking behavior in rats.

Mecamylamine, a noncompetitive nicotinic cholinergic antagonist, inhibits nicotine self-administration in animals and may attenuate tobacco smoking in humans trying to quit. Our preliminary data suggested that this agent, at a dose of 2 mg/kg (subcutaneous (s.c.)), also attenuates cue-induced relapse to nicotine-seeking behavior in rats. This study determined whether mecamylamine-induced attenuation can be obtained at doses lower than the high 2 mg/kg dose used in the first study, and whether it is specific to nicotine-associated cues. Male Sprague-Dawley rats were trained to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed-ratio 5 schedule. Each infusion was accompanied by a visual cue (1 s onset of a lever light followed by offset of a house light for 20 s during which time no infusions could be obtained). After the nicotine-maintained responding was extinguished by withholding the delivery of nicotine (saline substitution) and its associated cue, reinstatement tests were conducted. Response-contingent re-presentation of the cue without further availability of nicotine significantly reinstated extinguished responding at the previously nicotine-reinforced lever. Pretreatment with mecamylamine (0.5, 1, and 2 mg/kg, s.c.) dose-dependently attenuated the cue-induced reinstatement of lever responding. Mecamylamine did not change food-taking and -seeking responses, whereas the highest dose (2 mg/kg) decreased nicotine self-administration behavior. The results confirm previous findings that stimuli conditioned to nicotine self-administration effectively elicit reinstatement of nicotine-seeking behavior after extinction and demonstrate that mecamylamine, besides suppressing self-administration of nicotine, effectively attenuates cue-induced nicotine-seeking behavior. These findings suggest that the response-reinstatement procedures used in this study may be useful for studying neurobiological mechanisms of nicotine-seeking behavior and that mecamylamine-like drugs may be potential candidates for pharmacological treatment and prevention of relapse to tobacco smoking in abstinent smokers.

Analysis of Variance↗

PubMed2000

Mecamylamine in Tourette's syndrome: a two-year retrospective case study.

OBJECTIVE: To test the efficacy and safety of a nicotinic, acetylcholine antagonist, mecamylamine, in the treatment of Tourette's syndrome (TS). METHODS: This is a retrospective, open-label study of 24 patients; 18 of whom were not responding to accepted medication for treatment of their TS and six of whom were receiving no medication. All 24 of them received mecamylamine in 2.5-6.25 mgm/day dose, at varying starting dates during the years June 1997 to June 1999. There were four females, 20 males, with 19 patients under the age of 18 years and five over the age of 18. Efficacy was evaluated by the Clinical Global Impression Scale (CGI); safety by adverse events notes during the time mecamylamine was administered. RESULTS: The number of days each patient received mecamylamine varied from 8 days to 550 days; with nine patients more than 200 days, six patients from 100-200 days, five patients for 50-100 days, and four patients 0-50 days. Comparing baseline CGI with that obtained on the date of last evaluation for each patient, a significant improvement in clinical assessment of severity of illness was obtained for the total group (Wilcoxon signed rank test, p < 0.0001). The six patients who received mecamylamine only also significantly improved (Wilcoxon signed rank test, p < 0.2). Case vignettes are described. CONCLUSIONS: Mecamylamine at 2.5-6.25 mgm/day has no significant peripheral parasympathetic activity and may be safely taken long term (up to 550 days in this study). It has a significant effect in relieving motor and vocal tics and in mood and behavior disturbances of children, adolescents, and adults with TS.

Adolescent↗

PubMed2003

Mecamylamine attenuates the subjective stimulant-like effects of alcohol in social drinkers.

BACKGROUND: Recent studies have implicated central nicotinic cholinergic receptor systems in the reinforcing properties of alcohol. In laboratory animals, mecamylamine, a central nicotinic receptor antagonist, reduces the consumption of and preference for alcohol. This study investigated the effect of mecamylamine on the subjective responses to alcohol in humans. It was hypothesized that mecamylamine (7.5 and 15 mg) would attenuate the stimulant-like subjective effects of alcohol (0.8 g/kg) and decrease the self-reported desire to consume additional alcohol beverages. METHODS: Fourteen male and 13 female nonsmokers participated in 6 laboratory sessions. During each session, subjects received, in randomized order under double-blinded conditions, a capsule containing mecamylamine (7.5 or 15 mg) or placebo followed by a beverage containing alcohol (0.8 g/kg) or placebo. Physiologic and subjective-effect measures were taken at 30-min intervals for 2 hr after beverage consumption. RESULTS: Mecamylamine attenuated the stimulant and euphoric effects of alcohol and reduced the self-reported desire to consume additional alcohol beverages. This effect was most pronounced in men, even though women exhibited greater physiologic reactions to mecamylamine. CONCLUSIONS: These findings suggest that nicotinic cholinergic receptors are involved in mediating some of the stimulant-like effects of alcohol.

Adult↗

PubMed1978

Effect of mecamylamine on the fate of dopamine in striatal and mesolimbic areas of rat brain; interaction with morphine and haloperidol.

1 The effects of the nicotinic cholinoceptor blocking drug, mecamylamine (alone or in combination with morphine or haloperidol) were investigated on the striatal homovanillic acid (HVA) concentration and on the alpha-methyl-p-tyrosine (AMPT)-induced depletion of striatal or mesolimbic dopamine content in the brain of rats. 2 Mecamylamine (2 mg/kg) alone did not alter the striatal HVA concentration, but it reduced the probenecid-induced accumulation of HVA. Mecamylamine pretreatment reduced the morphine- and haloperidol-induced elevation of striatal HVA concentrations. Hexamethonium did not alter the striatal HVA concentration when given alone or in probenecid- or morphine-treated rats, whereas pempidine (8 mg/kg) clearly reduced the probenecid-induced accumulation of HVA in the striatum. 3 Mecamylamine (2 and 8 mg/kg) slowed the rate of AMPT-induced depletion of dopamine from the striatum and mesolimbic area both in the brain of control rats treated with morphine or haloperidol. 4 Mecamylamine slightly prolonged the cataleptic effect of morphine. 5 The results indicate that mecamylamine inhibits the release of dopamine both from the striatal and mesolimbic dopaminergic neurones.

Animals↗

PubMed1984

Differential effects of mecamylamine on the nicotine induced changes in amine levels and turnover in hypothalamic dopamine and noradrenaline nerve terminal systems and in the secretion of adenohypophyseal hormones in the castrated female rat. Evidence for involvement of cholinergic nicotine-like receptors.

The effects of mecamylamine on the nicotine induced changes in hypothalamic catecholamine (CA) levels and turnover in female rats ovariectomized for one month have been evaluated using a quantitative microfluorimetric approach to measure CA levels in sections of brains treated according to the Falck-Hillarp procedure for the cellular demonstration of CA. In the same group of animals the serum prolactin, LH, FSH, TSH, GH and corticosterone levels were measured using radioimmunoassay procedures. The nicotine treatment induced a significant depletion of amine stores and an increase of amine turnover in dopamine (DA) and noradrenaline (NA) nerve terminals of the median eminence and of the peri- and paraventricular and dorsomedial NA systems of the hypothalamus using the tyrosine hydroxylase (TH) inhibition model. Mecamylamine (2 X 1 mg/kg) partly counteracted the nicotine induced reduction of amine stores in peri- (anterior part) and paraventricular NA nerve terminal systems as well as the nicotine induced increase of NA turnover in these systems, but not the action of nicotine on the CA systems of the median eminence. Nicotine (4 X 2 mg/kg) significantly and markedly reduced prolactin, LH, TSH, and GH secretion increased corticosterone secretin but did not influence FSH secretion. These effects were partly counteracted by mecamylamine (2 X 1 mg/kg) in the case of prolactin, LH and TSH secretion but not in the case of GH and corticosterone secretion. Taken together the results show that mecamylamine treatment (2 X 1 mg/kg) differentially counteract nicotine induced changes of amine levels and turnover in peri- (anterior part) and paraventricular NA nerve terminal systems indicating that the cholinergic nicotine-like receptors located in peri- (anterior part) and paraventricular areas may be more susceptible to the blocking activity of mecamylamine than those located in the median eminence area. Furthermore, the inhibitory effects of nicotine on prolactin, LH and TSH secretion are differentially counteracted by mecamylamine. In conclusion, other inhibitory systems than the tuberoinfundibular DA neurons in the MPZ and LPZ must also be involved in mediating the inhibitory effects of nicotine on prolactin, LH and TSH secretion and different types of cholinergic nicotine-like receptors may exist.

Animals↗

PubMed1994

Sensitivity to nicotine and brain nicotinic receptors are altered by chronic nicotine and mecamylamine infusion.

DBA/2 mice were chronically infused with saline (control), 4 mg/kg/hr of nicotine, 4 mg/kg/hr of mecamylamine or nicotine+mecamylamine for 7 days. The binding of L-[3H]nicotine was significantly increased in seven of eight brain regions dissected from mice 5 hr after cessation of drug treatment. Similarly, [3H]nicotine binding was increased in six of eight regions by chronic mecamylamine treatment. Treatment with both drugs led to increases in [3H]nicotine binding that were at least the sum of the those observed with either drug alone. These increases were partially reversed 48 hr after cessation of treatment. No significant effects of nicotine or mecamylamine treatment on alpha-[125I]bungarotoxin binding were observed 5 hr after treatment was stopped when assayed using a single ligand concentration. However, saturation analyses of the cerebral cortex detected small increases from control after treatment with nicotine or both drugs. No effects of chronic treatment on alpha-[125I]bungarotoxin binding were evident 48 hr after treatment was stopped. Mice treated with nicotine, mecamylamine or both drugs tested 5 hr after withdrawal were less sensitive to acute injection with nicotine than were saline-infused mice. However, the effects of mecamylamine may have been influenced by continued presence of this drug at the time of testing. Mice tested 48 hr after cessation of treatment were more sensitive to nicotine than those tested after 5 hr, but some tolerance to the effects of nicotine persisted in the nicotine-treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Antagonism of the nicotine-induced changes of the striatal dopamine metabolism in mice by mecamylamine and pempidine.

The ability of nicotinic receptor blockers, mecamylamine and pempidine, to antagonize the changes in striatal dopamine (DA) metabolism induced by repeated nicotine administration was studied. The contents of DA and its metabolites 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. Mice kept at 20-22 degrees C were given nicotine, 3 mg/kg, s.c., four times, at 30 min intervals, and sacrificed 20 min after the last dose. Hexamethonium, 10 mg/kg, i.p., was administered at 30 min before the first nicotine dose in order to prevent the peripheral effects of nicotine. Mecamylamine, 0.6 or 10 mg/kg, i.p., and pempidine, 0.6 or 20 mg/kg, i.p., were given at 60 min before sacrifice. Mecamylamine and pempidine decreased clearly the striatal 3-MT content, which suggests that the nigrostriatal dopaminergic neurons are physiologically controlled by a stimulatory nicotinic mechanism. The repeatedly administered nicotine caused deep hypothermia, and increased the striatal DOPAC content but decreased the 3-MT and HVA contents. The small dose of mecamylamine, which was the only dose found to effectively antagonize the nicotine-induced hypothermia, antagonized the decrease of HVA content. The large but not the small doses of mecamylamine and pempidine antagonized the nicotine-induced increase of DOPAC content but none of the doses studied antagonized the decrease of 3-MT content. Thus it seems that nicotine decreases the 3-MT content by a mechanism distinct from the mechanism mediating the increase of the DOPAC content. The decreased 3-MT content most probably results from desensitization of nicotinic cholinergic receptors (nAChR) and following decrease of cholinergic regulation of nigrostriatal dopaminergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Effects of mecamylamine on human cigarette smoking and subjective ratings.

Multiple measures of cigarette smoking, subjective effect and physiological effect were collected during 90-min test sessions in normal volunteers. Before sessions subjects received oral doses of mecamylamine (2.5, 5.0, 10, 20 mg) or placebo. Each dose and placebo was given three times in a randomized block sequence. Mecamylamine increased several measures of cigarette smoking, including number of cigarettes, number of puffs per cigarette, and expired air carbon monoxide level. Mecamylamine also produced modest, dose-related decreases in standing blood pressure and increases in standing heart rate. The subjective effects produced by mecamylamine were not characteristic of those of psychoactive drugs. Mecamylamine appears to have increased cigarette smoking by decreasing the effective dose level of nicotine available from cigarette smoking.

Adult↗

PubMed1986

Mecamylamine blockade of nicotine responses: evidence for two brain nicotinic receptors.

Mice of two inbred strains, DBA and C3H, were pretreated with mecamylamine before challenge with nicotine. Mecamylamine blocked nicotine-induced seizures, enhanced startle, and alterations in respiratory rate, Y-maze activity, heart rate and body temperature. Mecamylamine blocked nicotine-induced seizures and enhanced startle with IC50 values of less than 0.1 mg/kg. The other nicotine effects were blocked by mecamylamine with IC50 values between 0.8 and 2.3 mg/kg. Strain differences in sensitivity to mecamylamine blockade were also detected. These results suggest that nicotine elicits its effects at two receptors, which may be those labeled with [125I]-alpha-bungarotoxin and with [3H]-nicotine.

Animals↗

PubMed1984

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.

Acetylcholine↗