Nicotinic acetylcholine receptors as targets for antidepressants.

While the monoamine deficiency hypothesis of depression is still most commonly used to explain the actions of antidepressant drugs, a growing body of evidence has accumulated that is not adequately explained by the hypothesis. This article draws attention to contributions from another apparently common pharmacological property of antidepressant medications--the inhibition of nicotinic acetylcholine receptors (nAChR). Evidence is presented suggesting the hypercholinergic neurotransmission, which is associated with depressed mood states, may be mediated through excessive neuronal nicotinic receptor activation and that the therapeutic actions of many antidepressants may be, in part, mediated through inhibition of these receptors. In support of this hypothesis, preliminary evidence is presented suggesting that the potent, centrally acting nAChR antagonist, mecamylamine, which is devoid of monoamine reuptake inhibition, may reduce symptoms of depression and mood instability in patients with comorbid depression and bipolar disorder. If this hypothesis is supported by further preclinical and clinical research, nicotinic acetylcholine receptor antagonists may represent a novel class of therapeutic agents for treating mood disorders.

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.

Mecamylamine effects on haloperidol-induced catalepsy and defecation.

Recent clinical experience with Tourette syndrome (TS) patients suggests that the nicotinic receptor antagonist, mecamylamine (Inversine), may be a useful adjunct to neuroleptic therapy for controlling tic symptom. This is consistent with previous preclinical findings demonstrating that mecamylamine can potentiate the cataleptic effects of neuroleptics in rats. However, these earlier preclinical studies employed high doses (1-2.5 mg/kg) of mecamylamine that may not be clinically relevant since human doses of mecamylamine used to treat TS have been much lower (0.03-0.1 mg/kg). In order to test the potential therapeutic properties of mecamylamine preclinically, we conducted catalepsy experiments in rats employing both a low and high dose of mecamylamine in combination with haloperidol. Sixty-four male Sprague Dawley rats were randomized into four treatment groups (n = 16/group). Each rat received an injection of either saline or mecamylamine (0.1 or 3.0 mg/kg s.c.) followed one hour later with a second injection of either saline or haloperidol (0.4 mg/kg s.c.). The bar test was used to measure duration of catalepsy at 3 hrs following the second injection. The results demonstrated that only the mecamylamine treated rats showed statistically significant haloperidol-induced catalepsy when measured at 3 hrs. In addition, haloperidol-induced defecation was not affected by the 0.1 mg/kg mecamylamine dose, but completely abolished by the 3.0 mg/kg dose. These findings suggest that a clinically relevant dose of mecamylamine (0.1 mg/kg) can affect the duration of haloperidol-induced catalepsy without having significant effects on gastrointestinal function.

Nicotine induced seizures blocked by mecamylamine and its stereoisomers.

Recent genetic research has shown that certain forms of epilepsy may arise from mutations in the genes encoding for the alpha7 and alpha4 neuronal nicotinic acetylcholine receptor (nAChR) ion channels. These receptors are also involved with the induction of nicotine-induced seizures. (+/-)-Mecamylamine (Inversine), a classic nAChR antagonist, potently inhibits nicotine-induced seizures. The purpose of the present study was to assess the inhibitory effects of (+/-)-mecamylamine and its stereoisomers on nicotine-induced seizures in male Sprague-Dawley rats. Rats received saline, (+/-)-mecamylamine, R-(-)-mecamylamine, or S-(+)-mecamylamine (s.c.) at doses of 0.1, 0.3, or 1.0 mg/kg 15 minutes prior to nicotine injection, 3.6 mg/kg (s.c.), an optimal dose for seizure induction. Rats were observed for 30 minutes with seizure latency, duration, and severity as primary measures and locomotor activity recorded as a secondary measure at 5-minute intervals. The results indicate that mecamylamine and each of its stereoisomers block nicotine-induced seizures in a dose-related manner and suggest that the S-(+/-)- mecamylamine isomer has inhibitory properties more similar to the racemic than to the R-(-)-mecamylamine isomer. The results of this study may be clinically important for the future design of novel anti-seizure medications.

Transdermal nicotine and haloperidol in Tourette's disorder: a double-blind placebo-controlled study.

BACKGROUND: Preclinical animal and open-trial clinical trials using nicotine gum and the transdermal nicotine patch found that treatment with nicotine potentiates the effects of neuroleptics in reducing the dyskinetic symptoms of Tourette's disorder. We sought to verify and expand these findings in a prospective double-blind placebo-controlled trial. METHOD: Seventy patients with DSM-IV Tourette's disorder were treated with either transdermal nicotine (7 mg/24 hours) or placebo patches in a 33-day, randomized, double-blind study. Each patient received an individually based optimal dose of haloperidol for at least 2 weeks prior to random assignment to nicotine or placebo treatment. A new patch was worn each day for the first 5 days. On the sixth day, the dose of haloperidol was reduced by 50%. Daily patch applications were then continued for an additional 2 weeks (through day 19), at which time the patch was discontinued, but the 50% dose of haloperidol was continued for an additional 2 weeks (through day 33). Clinical and safety assessments were made at each visit. RESULTS: Patients who completed all 19 days of nicotine (N = 27) or placebo (N = 29) patch treatment were used in efficacy analyses. As documented by the Clinician- and Parent-rated Global Improvement scales, transdermal nicotine was superior to placebo in reducing the symptoms of Tourette's disorder. The Yale Global Tic Severity Scale was less sensitive in detecting a placebo/drug difference than were the global improvement scores, suggesting that some of the improvement may not have been related to treatment-related changes in tic severity, but to the emotional and behavioral symptoms. The side effects of nausea and vomiting were significantly more common in the nicotine group (71% [N = 25] and 40% [N = 14]) than in the placebo group (17% [N = 6] and 9% [N = 3]) (nausea, p = .0001; vomiting, p = .004). CONCLUSION: Transdermal nicotine was superior to placebo in reducing behavioral symptoms when patients were receiving an optimal dose of haloperidol, when the dose of haloperidol was reduced by 50%, and when the patch had been discontinued for 2 weeks. These findings confirm earlier open-label findings and suggest that combining nicotinic receptor modulation and neuroleptics could be a therapeutic option for the treatment of Tourette's disorder. While side effects limit chronic use of nicotine, it may be useful on a p.r.n. basis. Further clinical research is warranted to investigate the use of novel nicotinic receptor modulating agents with improved safety profiles over nicotine.

Multicenter, double-blind, placebo-controlled study of mecamylamine monotherapy for Tourette's disorder.

OBJECTIVE: The safety and efficacy of mecamylamine as a monotherapy in children and adolescents with Tourette's disorder (TD) was investigated in an 8-week multicenter, double-blind, placebo-controlled study. METHOD: Eligible subjects included subjects with TD (DSM-IV), with a naturalistic mix of comorbid diagnoses, nonsmokers, aged 8 to 17 years, whose behavioral and emotional symptoms (according to parents) were more disturbing than tics. After a washout period of all psychotropic medication, subjects were randomly assigned to either mecamylamine (n = 29) or placebo (n = 32). Mecamylamine doses ranged from 2.5 to 7.5 mg/day. Primary efficacy measures included the Tourette's Disorder Scale-Clinician Rated (TODS-CR) and 21-point Clinical Global Improvement scale; secondary efficacy measures included the Yale Global Tic Severity Scale and a rage-attack scale (RAScal). RESULTS: Of the 61 subjects who were randomized, 50 (82%) completed at least 3 weeks on medication and 38 (62%) completed the full 8-week trial. Study withdrawals included 12/29 on mecamylamine and 11/32 on placebo. For the total sample, mecamylamine was no more effective than placebo on any of the outcome measures. However, an item analysis of the TODS-CR suggested that mecamylamine may have reduced sudden mood changes and depression in moderately to severely affected subjects. Except for a slight increase in heart rate during the 1st week in both the mecamylamine and the placebo groups, there where no significant mecamylamine-related changes in vital signs, electrocardiogram, complete blood cell count, or blood chemistry values. CONCLUSIONS: Mecamylamine, in doses up to 7.5 mg/day, is well tolerated in children and adolescents, but as a monotherapy it does not appear to be an effective treatment for tics or for the total spectrum of symptoms associated with TD. However, further studies should be conducted to investigate its possible therapeutic effects in subjects with comorbid mood disorders and as an adjunct to neuroleptic medication.

Mecamylamine: new therapeutic uses and toxicity/risk profile.

BACKGROUND: Mecamylamine hydrochloride was initially developed for its ganglion-blocking activity and has been marketed as an antihypertensive agent in the United States for >40 years. Several other potential therapeutic applications are being investigated, most of them focusing on the drug's ability to cross the blood-brain barrier and selectively antagonize neuronal nicotinic acetylcholine receptors. This central activity of mecamylamine is demonstrable at much lower doses than the effective antihypertensive dose, thus avoiding many of the bothersome side effects associated with the drug's inhibition of parasympathetic activity. OBJECTIVE: Because investigations are being conducted in new patient populations, including pediatric patients, an update of the toxicity/risk profile of mecamylamine is timely. This review describes nonclinical and clinical data pertaining to the pharmacology, toxicity, and tolerability of mecamylamine, including some previously unpublished toxicology and clinical pharmacokinetics data. Potential new therapeutic applications are discussed, including the use of mecamylamine in treating autonomic dysreflexia; dependencies on nicotine, cocaine, and other substances of abuse; Tourette's syndrome; and other neuropsychiatric disorders. METHODS: Information for this review of mecamylamine was identified through a search of MEDLINE from 1966 to the present, as well as from the master files of Merck & Co, Inc, the drug's original manufacturer, and Layton BioScience, Inc, its present manufacturer. CONCLUSIONS: The available data concerning potential new applications of mecamylamine, although sparse, suggest that the drug's toxicity/risk profile may be much improved at lower doses.

Corticosterone-attenuating and anxiolytic properties of mecamylamine in the rat.

1. The available evidence suggests that stress induced release of acetylcholine (ACh) in the brain has a significant role in mediating neuroendocrine, emotional, and physiological responses to stress. Recent findings also suggest that stress indirectly (via acetylcholine) and nicotine directly stimulates the HPA axis through activation of nAChRs. 2. Our working hypothesis is that under stressful conditions, nicotinic receptor antagonists, such as mecamylamine, should act to attenuate the activation of the HPA axis and exhibit anxiolytic behavioral effects. The purpose of this study was to determine whether or not mecamylamine would: a) produce anxiolytic effects in rats on the elevated plus maze and b) blunt the plasma corticosterone response to predator stress in rats. 3. Results suggested that mecamylamine has anxiolytic properties under stressful conditions. In the EPM experiment, mecamylamine (0.3 mg/kg) produced increased time spent in the open arms. Similarly, in the predator stressor experiment, mecamylamine blunted the stress-induced plasma corticosterone response, with the lowest dose of mecamylamine (0.1 mg/kg). 4. These findings may have important therapeutic implications since clinical observations have shown that low doses of mecamylamine reduce tension and anxiety in patients with Tourette syndrome.

Analysis of mecamylamine stereoisomers on human nicotinic receptor subtypes.

Because mecamylamine, a nicotinic receptor antagonist, is used so often in nicotine research and because mecamylamine may have important therapeutic properties clinically, it is important to fully explore and understand its pharmacology. In the present study, the efficacy and potency of mecamylamine and its stereoisomers were evaluated as inhibitors of human alpha 3 beta 4, alpha 3 beta 2, alpha 7, and alpha 4 beta 2 nicotinic acetylcholine receptors (nAChRs), as well as mouse adult type muscle nAChRs and rat N-methyl-D-aspartate (NMDA) receptors expressed in Xenopus oocytes. The selectivity of mecamylamine for neuronal nAChR was manifested primarily in terms of slow recovery rates from mecamylamine-induced inhibition. Neuronal receptors showed a prolonged inhibition after exposure to low micromolar concentrations of mecamylamine. Muscle-type receptors showed a transient inhibition by similar concentrations of mecamylamine, and NMDA receptors were only transiently inhibited by higher micromolar concentrations. Mecamylamine inhibition of neuronal nAChR was noncompetitive and voltage dependent. Although there was little difference between S-(+)-mecamylamine and R-(-)-mecamylamine in terms of 50% inhibition concentration values for a given receptor subtype, there appeared to be significant differences in the off-rates for the mecamylamine isomers from the receptors. Specifically, S-(+)-mecamylamine appeared to dissociate more slowly from alpha 4 beta 2 and alpha 3 beta 4 receptors than did R-(-)-mecamylamine. In addition, it was found that muscle-type receptors appeared to be somewhat more sensitive to R-(-)-mecamylamine than to S-(+)-mecamylamine. Together, these findings suggest that in chronic (i.e., therapeutic) application, S-(+)-mecamylamine might be preferable to R-(-)-mecamylamine in terms of equilibrium inactivation of neuronal receptors with decreased side effects associated with muscle-type receptors.

Comorbid bipolar disorder in Tourette's syndrome responds to the nicotinic receptor antagonist mecamylamine (Inversine).

BACKGROUND: We have previously proposed that the therapeutic effect of transdermal nicotine in Tourette's syndrome may involve nicotinic receptor inactivation resulting from a prolonged continuous exposure to nicotine. In vitro studies with nicotine and preliminary positive experience with mecamylamine (Inversine), a nicotinic receptor antagonist, in the clinical treatment of Tourette's syndrome patients, further supports the receptor inactivation hypothesis. METHODS: We retrospectively documented an unexpected therapeutic response to mecamylamine (2.5-7.5 mg/day) in two Tourette's syndrome patients who were subsequently found to have comorbid bipolar disorder as defined by DSM-IV criteria. RESULTS: In patient 1, the mood-stabilizing effect of mecamylamine was noticed by the patient during the course of mecamylamine treatment and brought to our attention, whereas for patient 2, manic symptoms were only apparent clinically following cessation of mecamylamine treatment. CONCLUSIONS: The clinical observations presented here suggest that nicotinic antagonists might be potential therapeutic agents for the treatment of bipolar disorder. Double-blind, placebo-controlled studies are now necessary to investigate these observations under more rigorous conditions.

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.

Locomotor behavioral effects of prenatal and postnatal nicotine exposure in rat offspring.

The purpose of this study was to determine if prenatal/postnatal nicotine exposure results in hyperactive offspring. Rat offspring were exposed to nicotine, through implantation of osmotic minipumps in dams, at levels of 0.75, 1.5 and 3.0 mg/kg/day, for 19 days prenatally and 16 days postnatally. Offspring were measured for gestation length, body weight, litter size, sex difference and locomotor activity. No significant effects were shown for gestation length, litter size or male to female pup ratio. However, higher percentage of pup deaths resulted from nicotine-exposed dams than from control dams. Significantly less litter body weight was shown in nicotine-exposed offspring on postnatal day 1 when compared to controls. However, these offspring surpassed the control groups in litter body weight on postnatal day 14 and 21. Hyperactivity was shown in offspring exposed to prenatal/postnatal nicotine at levels of 0.75 and 3.0 mg/kg/day on postnatal day 14, but not on postnatal day 21 or at the 1.5 mg/kg/day condition. Results are consistent with the hypothesis that rat offspring are susceptible to the neurochemical and neurobehavioral effects of prenatal/postnatal nicotine exposure.

Nicotine for the treatment of Tourette's syndrome.

Recent evidence has demonstrated that nicotine may obtund the symptoms of Tourette's syndrome (TS). TS is a neuropsychiatric disorder characterized by motor and vocal tics, obsessions and compulsions, and frequently with impulsivity, distractibility, and visual-motor deficits. While neuroleptics, such as haloperidol, are most effective for treatment of the motor and vocal tics of TS, these medications have many side effects. In this article, we review the evidence, consistent with findings in animals, that administration of nicotine (either 2 mg nicotine gum or 7 mg transdermal nicotine patch) potentiates the therapeutic properties of neuroleptics in treating TS patients and that a single patch may be effective for a variable number of days. These findings suggest that transdermal nicotine could serve as an effective adjunct to neuroleptic therapy for TS.

Case study: long-term potentiation of neuroleptics with transdermal nicotine in Tourette's syndrome.

Sixteen Tourette's syndrome patients, aged 9 to 15 years, whose symptoms were not controlled with neuroleptics, were followed for various lengths of time after the application of a transdermal nicotine patch (TNP) (7 mg/24 hours) as part of an ongoing case study. While there was a broad range in individual response, application on the TNP produced significant reductions (p < .001) in Yale Global Tic Severity Scale scores relative to baseline, with an average duration of effect lasting between 1 and 2 weeks. Side effects, for the most part, were transient. Clinical implications for the use of TNP as an adjunct to neuroleptic treatment of Tourette's syndrome are discussed.

(-)-nicotine protects against systemic kainic acid-induced excitotoxic effects.

(-)-Nicotine was shown to produce in vivo protection against neurobehavioral effects caused by systemically administered kainic acid (KA), an excitotoxin that has been widely used to induce temporal lobe convulsions including "wet dog shakes" in experimental animals. Rats pretreated with (-)-nicotine (0.5 mg/kg sc) 15 min before receiving KA (12.0 mg/kg sc) exhibited a marked reduction (P < 0.5) in the number of wet dog shakes when compared to saline-pretreated rats. Similarly, little visible brain damage was found in the (-)-nicotine-pretreated rats, but a widespread reduction in acetylcholinesterase-positive neurons was noted in the hippocampal areas of the saline-pretreated animals. While the mechanism of neuroprotection of (-)-nicotine is still not known, these findings suggest that (-)-nicotine may act as a therapeutic agent for putative excitotoxin-mediated disorders.

Nicotine blocks kainic acid-induced wet dog shakes in rats.

Systemic or central administration of kainic acid (KA) in rats results in the expression of wet dog shakes (WDS) followed by motoric seizures and convulsions, which are associated with limbic neurotoxicity. Although a number of neurotransmitter systems are thought to be involved with this KA-induced syndrome, little is known about the possible influence of cholinergic nicotinic receptor modulation. In the study presented here, we pretreated rats with saline or 0.5 mg/kg nicotine base followed 15 minutes later by 12.0 mg/kg KA and then observed the incidence of WDS between 45 and 120 minutes post-KA injection. Rats pretreated with nicotine exhibited significantly less WDS than those pretreated with saline (p < .001). Whereas the mechanism for this nicotine effect is currently not known, future experiments will look at dose-response relationships, the role of nicotine receptors, and possible neuroprotective potential of nicotine in this KA-induced syndrome.