Female rats display greater nicotine withdrawal-induced cellular activation of a central portion of the interpeduncular nucleus versus males: A study of Fos immunoreactivity within provisionally assigned interpeduncular subnuclei.

BACKGROUND: The interpeduncular nucleus (>1840) (IPN) has been shown to modulate the behavioral effects of nicotine withdrawal in male rodents. To date, the contribution of this brain structure to sex differences in withdrawal is largely unexplored. METHODS: This study compared neuronal activation, as reported by observable Fos expression in the IPN of nicotine-dependent female and male rats experiencing withdrawal. We provisionally localized the Fos-expressing cells to certain IPN subnuclei within Swanson's standardized brain atlas (2018). Adult female and male rats were prepared with a pump that delivered nicotine (3.2 mg/kg/day; base) continuously. Controls received a sham surgery. Fourteen days later, the rats received administration of saline or the nicotinic receptor antagonist, mecamylamine (3.0 mg/kg; salt), and physical signs and anxiety-like behavior were assessed. The rats were then euthanized and brain sections containing the IPN were processed for Fos immunofluorescence to infer the possible IPN subnuclei displaying differential activation between sexes. RESULTS: Both female and male rats displayed withdrawal-induced Fos expression within the IPN. Compared to males, female rats displayed greater numbers of withdrawal-induced Fos-positive cells within a circumscribed portion of the IPN that may fall within the cytoarchitectural boundaries of the central subnucleus (>1840) (IPNc). The withdrawal-induced activation of the IPN was correlated with negative affective states in females, but not males. CONCLUSION: These data suggest that a centrally located group of IPN cells, presumably situated partly or completely within the IPNc, play a role in modulating sex differences in negative affective states produced by withdrawal.

A case series and literature review on patients with rhinological complications secondary to the use of cocaine and levamisole.

BACKGROUND: Levamisole is an increasingly common cutting agent used with cocaine. Both cocaine and levamisole can have local and systemic effects on patients. METHODS: A retrospective case series was conducted of patients with a cocaine-induced midline destructive lesion or levamisole-induced vasculitis, who presented to a Dundee hospital or the practice of a single surgeon in Paisley, from April 2016 to April 2019. A literature review on the topic was also carried out. RESULTS: Nine patients from the two centres were identified. One patient appeared to have levamisole-induced vasculitis, with raised proteinase 3, perinuclear antineutrophil cytoplasmic antibodies positivity and arthralgia which improved on systemic steroids. The other eight patients had features of a cocaine-induced midline destructive lesion. CONCLUSION: As the use of cocaine increases, ENT surgeons will see more of the complications associated with it. This paper highlights some of the diagnostic issues and proposes a management strategy as a guide to this complex patient group. Often, multidisciplinary management is needed.

Synergistic improvement effect of nicotine-ghrelin co-injection into the anterior ventral tegmental area on morphine-induced amnesia.

In the present study the effect of ghrelin or ghrelin/nicotine injection into the anterior ventral tegmental area (aVTA) on morphine-induced amnesia in passive avoidance learning have been evaluated. Also, the role of the aVTA nicotinic receptors in possible ghrelin-induced effects has been investigated. All animals were bilaterally implanted with chronic cannulas in the aVTA. A step-through type passive avoidance task was used for measurement of memory. We found that post-training subcutaneous (s.c.) injection of morphine (0.5-7.5 mg/kg) dose-dependently reduced the step-through latency, indicating morphine-induced amnesia. Post-training bilateral infusion of ghrelin (0.3, 1.5 and 3 nmol/µl) in a dose-dependent manner reversed amnesia induced by morphine (7.5 mg/kg, s.c.). Furthermore, reversal effect of ghrelin (3 nmol/µl) was blocked by pre-treatment of intra-aVTA administration of mecamylamine (1-3 µg/rat), a nicotinic acetylcholine receptor antagonist. Intra-aVTA administration of the higher dose of mecamylamine (3 µg/rat) into the aVTA by itself decreased the step-through latency and induced amnesia. In addition, post-training intra-aVTA administration of nicotine (0.25, 0.5, 1 µg/rat) which alone cannot affect memory consolidation, decreased significantly the amnesia induced by morphine (7.5 mg/kg, s.c.). Co-treatment of an ineffective dose of ghrelin (0.3 nmol/µl) with an ineffective dose of nicotine (0.25 µg/rat) significantly increased step-through latency of morphine (7.5 mg/kg, s.c.) treated animals, indicating the synergistic effect of the drugs. Taken together, our results suggest that intra-aVTA administration of ghrelin reversed morphine-induced amnesia and that ghrelin interacts synergistically with nicotine to mitigate morphine-induced amnesia.

Muscarinic and Nicotinic Modulation of Memory but not Verbal Problem-solving.

Aspects of cognitive flexibility are modulated by the noradrenergic system, which is important in arousal and attention. Acetylcholine also modulates arousal and attention, as well as working memory. Effects of muscarinic and nicotinic antagonism on memory are well established. Our purpose was to test whether muscarinic and nicotinic antagonism affect aspects of cognitive flexibility, specifically verbal problem-solving, as well as memory, given acetylcholine's role in attention and arousal. Eighteen participants attended three testing sessions. Two hours before testing, participants received either 0.6 mg scopolamine, 10 mg mecamylamine, or placebo. Then, participants were tested on three memory tasks (Buschke Selective Reminding Test [BSRT], California Verbal Learning Test [CVLT], Rey Complex Figure Test), two verbal problem-solving/cognitive flexibility tasks (Compound Remote Associates Test, a timed anagram test), and a spatial inductive reasoning task (Raven's Progressive Matrices). Task order and drug order were counterbalanced. Memory impairment was seen on one BSRT measure and multiple CVLT measures with scopolamine, and with one BSRT measure with mecamylamine. There were no effects of either drug on any of the tasks involving cognitive flexibility, including verbal problem-solving. Specific memory impairments were detected using muscarinic, and to a marginal extent, nicotinic antagonists, as expected, but no effect was seen on cognitive flexibility. Therefore, although both the noradrenergic and cholinergic systems play important roles in arousal and cortical signal-to-noise processing, the cholinergic system does not appear to have the same effect as the noradrenergic system on cognitive flexibility, including verbal problem-solving.

An EEG nicotinic acetylcholine index to assess the efficacy of pro-cognitive compounds.

OBJECTIVES: Cognitive impairment models are used in clinical studies aimed at proving pharmacology of drugs being developed for Alzheimer's disease and other cognitive disorders. Due to rising interest in nicotinic agonists, we aimed to establish a method to monitor neurophysiological effects of modulating the nicotinic cholinergic system. METHODS: In a four-way cross-over study, eyes-closed rest EEG was recorded in 28 healthy subjects receiving mecamylamine-a nicotinic acetylcholine receptor (nAChR) antagonist, which induces temporary cognitive dysfunction in healthy subjects-with co-administration of placebo, nicotine or galantamine. RESULTS: Using machine learning to optimally contrast the effects of 30 mg of mecamylamine and placebo on the brain, we developed a nAChR index that consists of 10 EEG biomarkers and shows high classification accuracy (∼95% non-cross-validated, ∼70% cross-validated). Importantly, using the nAChR index, we demonstrate reversal of mecamylamine-induced neurophysiological effects due to 16 mg of galantamine as well as administering 21 mg of nicotine transdermally. CONCLUSIONS: Our findings indicate that the mecamylamine challenge model jointly with the nAChR index-a measure of the nicotinic EEG profile-could aid future proof-of-pharmacology studies to demonstrate effects of nicotinic cholinergic compounds. SIGNIFICANCE: This novel measure for quantifying nicotinic cholinergic effects on the EEG could serve as a useful tool in drug development of pro-cognitive compounds.

α7-Nicotinic acetylcholine receptor inhibition by indinavir: implications for cognitive dysfunction in treated HIV disease.

OBJECTIVE: The study set out to determine if the HIV protease inhibitor, indinavir, alters responsiveness of α7-nicotinic acetylcholine receptors to acetylcholine. DESIGN: Treatment with HAART has dramatically reduced development of HIV-associated dementia and more severe forms of cognitive impairment. However, many individuals continue to experience cognitive decline of uncertain cause. Previous studies have failed to demonstrate significant alterations of functional brain connectivity, structural brain changes, or changes in cerebral blood flow sufficient to explain cognitive decline in virally suppressed individuals. This suggests that the mechanisms underlying development and progression of cognitive problems likely occurs at a micro rather than macro level, such as disruptions in neurotransmitter system signaling. MATERIALS AND METHODS: Indinavir's effects on α7-nicotinic acetylcholine receptor activity was tested using a ScreenPatch IonWorks Barracuda-based assay in a mammalian cell model. RESULTS: At low concentrations (0.0003-10 µmol/l) indinavir acts as a positive allosteric modulator (EC50 = 0.021 µmol/l), whereas at concentrations greater than 10 µmol/l (30-100 µmol/l) indinavir acts as an inhibitor of the α7-nicotinic acetylcholine receptor. CONCLUSION: At concentrations greater than 10 µmol/l indinavir reduces synaptic transmission in the acetylcholine neurotransmitter system, which could possibly contribute to cognitive dysfunction. These results suggest that further experiments should be considered to assess whether patients might benefit from treatment with cholinesterase inhibitors that counteract the effects of indinavir.

Conotoxin Interactions with α9α10-nAChRs: Is the α9α10-Nicotinic Acetylcholine Receptor an Important Therapeutic Target for Pain Management?

The α9α10-nicotinic acetylcholine receptor (nAChR) has been implicated in pain and has been proposed to be a novel target for analgesics. However, the evidence to support the involvement of the α9α10-nAChR in pain is conflicted. This receptor was first implicated in pain with the characterisation of conotoxin Vc1.1, which is highly selective for α9α10-nAChRs and is an efficacious analgesic in chronic pain models with restorative capacities and no reported side effects. Numerous other analgesic conotoxin and non-conotoxin molecules have been subsequently characterised that also inhibit α9α10-nAChRs. However, there is evidence that α9α10-nAChR inhibition is neither necessary nor sufficient for analgesia. α9α10-nAChR-inhibiting analogues of Vc1.1 have no analgesic effects. Genetically-modified α9-nAChR knockout mice have a phenotype that is markedly different from the analgesic profile of Vc1.1 and similar conotoxins, suggesting that the conotoxin effects are largely independent of α9α10-nAChRs. Furthermore, an alternative mechanism of analgesia by Vc1.1 and other similar conotoxins involving non-canonical coupling of GABAB receptors to voltage-gated calcium channels is known. Additional incongruities regarding α9α10-nAChRs in analgesia are discussed. A more comprehensive characterisation of the role of α9α10-nAChRs in pain is crucial for understanding the analgesic action of conotoxins and for improved drug design.

Efficacy and tolerability of flexibly-dosed adjunct TC-5214 (dexmecamylamine) in patients with major depressive disorder and inadequate response to prior antidepressant.

This paper reports the efficacy and tolerability of the nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy for patients with major depressive disorder who have an inadequate response to initial antidepressant treatment in 2 Phase III studies. These double-blind, placebo-controlled studies (NCT01157078, D4130C00002 [Study 002] conducted in the US and India; NCT01180400, D4130C00003 [Study 003] conducted in Europe) comprised 8 weeks of open-label antidepressant treatment followed by 8 weeks of active treatment during which patients were randomized to flexibly-dosed TC-5214 1-4 mg twice daily (BID) or placebo as an adjunct to ongoing therapy with SSRI/SNRI. The primary efficacy endpoint in both studies was change in Montgomery Åsberg Depression Rating Scale (MADRS) total score from randomization (week 8) to treatment end (week 16). Secondary endpoints included change in Sheehan Disability Scale and Hamilton Depression Rating Scale 17-item scores. Study 002 randomized 319 patients and Study 003 randomized 295 patients to TC-5214 or placebo. At treatment end, no significant differences were seen for change in MADRS total score with TC-5214 versus placebo. Furthermore, there were no significant differences in any of the secondary endpoints. The most commonly reported (≥ 10%) adverse events with TC-5214 in these studies were constipation and headache. In these 2 flexibly-dosed studies, no specific therapeutic effects were observed for TC-5214 (1-4 mg BID) adjunct to antidepressant in the primary endpoint or any secondary endpoint; however, TC-5214 was generally well tolerated. In conclusion, no antidepressant effect of TC-5214 was observed in these studies.

Pharmacological modulation of farnesyltransferase subtype I attenuates mecamylamine-precipitated nicotine withdrawal syndrome in mice.

This study was designed to investigate the effect of FTI-276 trifluoroacetate, a selective inhibitor of subtype I, on the development of the mecamylamine-induced nicotine withdrawal syndrome. Mice were administered nicotine (2.5 mg/kg, subcutaneously) four times daily for 7 days. To precipitate nicotine withdrawal, mice were administered one injection of mecamylamine (3 mg/kg, intraperitoneally) 1 h after the last nicotine injection on the test day (day 8). Behavioral observations were made for a period of 30 min immediately after mecamylamine treatment. FTI-276 trifluoroacetate treatment markedly and dose-dependently attenuated the precipitated nicotine withdrawal syndrome, measured by a composite withdrawal severity score, jumping frequency, hyperalgesia in the tail flick test, and anxiety-like behavior in the elevated plus maze test. The results suggest that FTI-276 trifluoroacetate can inhibit the development of a precipitated nicotine withdrawal syndrome, and thus that farnesyltransferase subtype I may be a viable pharmacological target to tackle the problem of nicotine addiction.

Targeting neuronal nicotinic receptors in cancer: new ligands and potential side-effects.

In the nervous system, the neuronal nicotinic acetylcholine receptors (nAChRs) mediate fast excitatory postsynaptic potentials as well as slower paracrine actions of ACh. They are also widely expressed in non-nervous tissue, including the neoplastic, which is intriguing as smoking is an established risk factor for cancer. Moreover, recent evidence attributes to the gene cluster coding for the α3/α5/ß4 nAChR subunits a role in both development of lung cancer and nicotine addiction. Many cellular effects of nicotine and the tobacco-derived carcinogenic N-nitrosamines are probably caused by nAChR activation, which regulates cell proliferation, migration, apoptosis and neoangiogenesis. Nonetheless, the precise nAChR roles in tumors are difficult to determine because cancer cells express a wide variety of nicotinic subunits, whose function is unclear. Patented compounds which selectively target nAChRs subtypes are increasingly available and will hopefully allow better understanding of the physiology of these channels in specific cell types, as well as suggest novel diagnostic and therapeutic approaches. At the present state, however, thorough functional studies of these compounds are still limited and whether they act as agonists, antagonists or partial agonists is often unclear. Such a blurred distinction between activators and inhibitors makes detailed studies in expression systems sorely needed for both physiological understanding and outlining the possible side-effects.

Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine.

Dopamine transporter knockout (DAT KO) mice exhibit elevated extracellular dopamine levels in brain regions that include the striatum and the nucleus accumbens, but not the prefrontal cortex. DAT KO mice model some aspects of psychiatric disorders, including schizophrenia. Smoking is more common in patients with schizophrenia, suggesting that nicotine might ameliorate aspects of the behavioral abnormalities and/or treatment side effects seen in these individuals. We report nicotine-induced normalization of effects on locomotion and prepulse inhibition of acoustic startle (PPI) in DAT KO mice that require intact serotonin 5-HT1A systems. First, we observed that the marked hyperactivity displayed by DAT KO mice was reduced by administration of nicotine. This nicotine effect was blocked by pretreatment with the non-specific nicotinic acetylcholine (nACh) receptor antagonist mecamylamine, or the 5-HT1A antagonist WAY100635. Secondly, we examined the effects of nicotine on PPI in DAT KO mice. Treatment with nicotine significantly ameliorated the PPI deficits observed in DAT KO mice. The ameliorating action of nicotine on PPI deficits in DAT KO mice was blocked by mecamylamine, the α7 nACh receptor antagonist methyllycaconitine or WAY100635, while the α4ß2 nACh receptor antagonist dihydro-ß-erythroidinehydrobromide (DHßE) produced only a non-significant trend toward attenuation of nicotine effects. Finally, we observed that administration of the 5-HT1A receptor agonist 8-OH-DPAT also ameliorated the deficit in PPI observed in DAT KO mice. This amelioration was antagonized by pretreatment with WAY100635. These data support the idea that nicotine might ameliorate some of the cognitive dysfunctions found in schizophrenia in a 5-HT1A-dependent fashion. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Rate dependent effects of acute nicotine on risk taking in young adults are not related to ADHD diagnosis.

Beneficial effects of nicotine on cognition and behavioral control are hypothesized to relate to the high rates of cigarette smoking in Attention-Deficit/Hyperactivity Disorder (ADHD). Given that ADHD is associated with both impulsivity and elevated risk taking, we hypothesized that nicotine modulates risk taking, as it does impulsivity. 26 non-smoking young adults (15 controls with normal impulsivity and 11 ADHD with high impulsivity) received 7 mg transdermal nicotine, 20mg oral mecamylamine, and placebo on separate days, followed by the Balloon Analog Risk Task (BART). Statistical analyses found no group differences in baseline risk taking. Reexamination of the data using a median split on baseline risk taking, to create high (HRT) and low (LRT) risk taking groups, revealed significant effects of nicotinic drugs that differed by group. Nicotine reduced risk taking in HRT and mecamylamine increased risk taking in LRT. This finding supports the hypothesis that nicotinic receptor function modulates risk taking broadly, beyond those with ADHD, and is consistent with rate dependent cholinergic modulation of other cognitive functions. Further, the results demonstrate that high impulsivity is separable from high risk taking in young adults with ADHD, supporting the utility of these differential behavioral phenotypes for neurobiological studies.

Varenicline to stop long-term nicotine replacement use: a double-blind, randomized, placebo-controlled trial.

INTRODUCTION: This study evaluated the effect of varenicline in combination with counseling to assist long-term nicotine replacement therapy (NRT) users to quit NRT. METHODS: This was a double-blind, placebo-controlled, randomized trial of varenicline or placebo for 12 weeks, with 52-week follow-up, performed in 1 hospital-based smoking cessation specialist clinic. At the first visit, 139 ex-smokers and long-term NRT users were allocated to treatment according to a computer-generated list with random numbers. Visits were scheduled at Weeks 0, 2, 4, 6, 9, 12, and 52. At each visit, nurse-led counseling was delivered, carbon monoxide in expired air, plasma cotinine, and body weight were assessed, and subjects were asked about craving, nausea, and dreams. The primary outcome was 12-week point prevalence quit rate (PPR) of nicotine replacement therapy use. RESULTS: At all time points, the PPR was superior for varenicline versus placebo, although the difference was only statistically significant at 12 and 36 weeks. The PPR was 64.3% (varenicline) versus 40.6% (placebo) at 12 weeks (p = .006), and 42.9% (varenicline) versus 36.2% (placebo) at 52 weeks (NS). The continuous abstinence rate from Week 9 to Week 12 was 48.6 % (varenicline) versus 30.4 % (placebo) (p = .03). Withdrawal symptoms were statistically significantly lower in the varenicline group than the placebo group. CONCLUSION: Varenicline for 12 weeks combined with supportive visits was superior to placebo to get long-term NRT users to quit NRT. A larger study is needed to evaluate long-term efficacy.

Activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) reverses referred mechanical hyperalgesia induced by colonic inflammation in mice.

In the current study, we investigated the effect of the activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) on dextran sulphate sodium (DSS)-induced colitis and referred mechanical hyperalgesia in mice. Colitis was induced in CD1 male mice through the intake of 4% DSS in tap water for 7 days. Control mice received unadulterated water. Referred mechanical hyperalgesia was evaluated for 7 days after the beginning of 4% DSS intake. Referred mechanical hyperalgesia started within 1 day after beginning DSS drinking, peaked at 3 days and persisted for 7 days. This time course profile perfectly matched with the appearance of signs of colitis. Both acute and chronic oral treatments with nicotine (0.1-1.0 mg/kg, p.o.) were effective in inhibiting the established referred mechanical hyperalgesia. The antinociceptive effect of nicotine was completely abrogated by cotreatment with the selective α7 nAchR antagonist methyllycaconitine (MLA) (1.0 mg/kg). Consistent with these results, i.p. treatment with the selective α7 nAchR agonist PNU 282987 (0.1-1.0 mg/kg) reduced referred mechanical hyperalgesia at all periods of evaluation. Despite their antinociceptive effects, nicotinic agonists did not affect DSS-induced colonic damage or inflammation. Taken together, the data generated in the present study show the potential relevance of using α7 nAchR agonists to treat referred pain and discomfort associated with inflammatory bowel diseases.

Ability of baclofen to prevent somatic manifestations and neurochemical changes during nicotine withdrawal.

BACKGROUND: Nicotine (NIC), the major active component of tobacco, is critical in the maintenance of the smoking habit. The aims of the present study were to analyze the behavioural and neurochemical variations during NIC withdrawal syndrome in mice, and whether they are prevented with baclofen (BAC, GABA(B) receptor agonist). METHODS: Swiss-Webster albino mice received NIC (2.5 mg/kg, s.c.) 4 times daily, for 7 consecutive days. On day 8 (the day of the experiment), NIC-treated mice received the nicotine antagonist mecamylamine (MEC, 2 mg/kg, i.p.) 1h after the last dose of NIC. A second group of dependent mice received BAC (2mg/kg, i.p.) before MEC-precipitated abstinence. The somatic signs were measured for 30 min. Dopamine (DA), serotonin (5-hydroxytryptamine; 5-HT) and its metabolites concentrations were determined by HPLC in the striatum, cortex and hippocampus. RESULTS: The global score was greater in the abstinent group compared to the control group. Moreover, the global score time course showed a higher increase at 10 min compared to the global score at 5 min or 30 min after MEC-precipitated NIC withdrawal. In addition, the global score was attenuated by BAC. The DA and dihydroxyphenyl acetic acid (DOPAC) cortical levels decreased in the abstinent group, while BAC reestablished these levels 10 min after NIC withdrawal. Furthermore, DA and 5-HT striatal levels decreased during NIC withdrawal, and BAC reverted this decrease. CONCLUSION: In conclusion, the prevention of NIC withdrawal signs by BAC could be related to changes in dopaminergic and serotonergic activity.

Topical mecamylamine for diabetic macular edema.

PURPOSE: Stimulation of nicotinic acetylcholine (nACh) receptors on vascular endothelial cells promotes angiogenesis and vascular permeability in animal models. The safety and bioactivity of topical mecamylamine, an antagonist of nACh receptors, was tested in patients with diabetic macular edema. DESIGN: A multicenter phase I/II clinical trial. METHODS: Twenty-three patients with chronic diabetic macular edema received 1% mecamylamine topically twice daily for 12 weeks, the primary end point. Patients underwent safety assessments, measurement of best-corrected visual acuity (BCVA), and measurement of foveal thickness using optical coherence tomography at baseline, 1, 4, 8, 12, and 16 weeks. RESULTS: Mecamylamine drops were well tolerated and there were no drug-related safety problems. Mean improvement in BCVA at 1, 4, 8, 12, and 16 weeks was 2.8, 1.9, 2.4, 0.8, and 3.1 letters, respectively. There was little change in mean excess foveal thickness. There was substantial heterogeneity in response, because 8 patients showed convincing improvement in BCVA, foveal thickness, or both, 9 patients showed equivocal or no substantial changes, and 4 patients showed worsening. Five patients showed a substantial improvement in BCVA, foveal thickness, or both between their last visit while receiving mecamylamine and 1 month after stopping mecamylamine. CONCLUSIONS: This study suggested that administration of topical mecamylamine, a nonspecific nACh receptor blocker, may have heterogeneous effects in patients with diabetic macular edema. Variable expression of nACh receptor subtypes on endothelial cells that have different effects on permeability would provide an explanation for these results and should be investigated, because more specific nACh receptor blockers may dissociate antipermeability and propermeability effects.

The antidepressant effects of anticholinergic drugs.

Acetylcholine is a neurotransmitter that is important for communication between neurons and muscle, is involved in direct neurotransmission in the autonomic parasympathetic nervous system, and has been implicated in cognitive processing, arousal, and attention in the brain. The cholinergic-adrenergic hypothesis of mood disorders states that a given affective state might represent a balance between central cholinergic and adrenergic neurotransmitter activity in those areas of the brain regulating moods. According to this hypothesis, depression would be the clinical manifestation of a state of cholinergic dominance, whereas mania would reflect adrenergic dominance. On the basis of this hypothesis, anticholinergic drugs have been investigated as potential treatments for depression, but study results have not shown consistent antidepressant effects. However, the dosage dependency of scopolamine's effect across different studies and the lack of antidepressant effects with other anticholinergic drugs suggest that a specific muscarinic receptor subtype might be most relevant to the potential antidepressant mechanism of action of anticholinergic drugs.