Nicotinic Cholinergic Systems Research Articles

Long-term effects of early postnatal nicotine exposure on cholinergic function in the mouse hippocampal CA1 region

In rodent models of smoking during pregnancy, early postnatal nicotine exposure results in impaired hippocampus-dependent memory, but the underlying mechanism remains elusive. Given that hippocampal cholinergic systems modulate memory and rapid development of hippocampal cholinergic systems occurs during nicotine exposure, here we investigated its impacts on cholinergic function. Both nicotinic and muscarinic activation produce transient or long-lasting depression of excitatory synaptic transmission in the hippocampal CA1 region. We found that postnatal nicotine exposure impairs both the induction and nicotinic modulation of NMDAR-dependent long-term depression (LTD). Activation of muscarinic receptors decreases excitatory synaptic transmission and CA1 network activity in both wild-type and α2 knockout mice. These muscarinic effects are still observed in nicotine-exposed mice. M1 muscarinic receptor activity is required for mGluR-dependent LTD. Early postnatal nicotine exposure has no effect on mGluR-dependent LTD induction, suggesting that it has no effect on the function of m1 muscarinic receptors involved in this form of LTD. Our results demonstrate that early postnatal nicotine exposure has more pronounced effects on nicotinic function than muscarinic function in the hippocampal CA1 region. Thus, impaired hippocampus-dependent memory may arise from the developmental disruption of nicotinic cholinergic systems in the hippocampal CA1 region.

Chronic obstructive pulmonary disease and smoking in COVID-19.

COPD is a chronic disease that progressively worsens the patient's respiratory function. Infection with SARS-CoV-2 in a patient with COPD with initially low respiratory rates should theoretically lead to a more severe course and a high probability of lethal outcome. However, at present, no direct connection has been found between the presence of COPD, smoking and a high risk of being infected or severe course of SARS-CoV-2 infection. Of great importance in the study of these paradoxical facts is the interaction between the reninangiotensin and nicotinic cholinergic systems. In this review, we perform an extensive literature search for studies of the relationship between COPD, smoking, and SARS-CoV-2 infection.

Effects of chronic nicotine exposure on Δ9-tetrahydrocannabinol-induced locomotor activity and neural activation in male and female adolescent and adult rats

RationaleHigh rates of comorbid tobacco and cannabis use in adolescents and young adults may be related to functional interactions between the nicotinic cholinergic and cannabinoid systems in the brain during development. This study examined the effects of chronic exposure to nicotine (the psychoactive component in tobacco) on acute exposure to delta-9-tetrahydrocannabinol (THC) (the psychoactive component of cannabis). MethodsMale and female adolescent and adult Sprague-Dawley rats (N = 112) were injected daily with nicotine (1 mg/kg, i.p.) or vehicle for 14 days, followed by a 14-day drug-free period. On test day, rats were injected with THC (5 mg/kg, i.p.) or vehicle, locomotor activity was recorded for 2 h, and brains harvested for c-Fos immunoreactivity (IR). ResultsLocomotor activity and c-Fos IR changes induced by THC challenge were altered by nicotine pre-exposure and modified by age and sex. THC-induced suppression of locomotor activity was attenuated by nicotine pre-exposure in adult but not adolescent males. THC-induced suppression of locomotor activity was potentiated by nicotine pre-exposure in female adolescents, with no effects of THC or nicotine observed in female adults. THC increased c-Fos IR in the caudate, nucleus accumbens, stria terminalis, septum, amygdala, hypothalamus, and thalamus. Nicotine pre-exposure potentiated this effect in all regions. Several brain regions showed age and sex differences in c-Fos IR such that expression was greater in adults than adolescents and in females than males. ConclusionsChronic nicotine pre-exposure produces lasting effects on cannabinoid-mediated signalling in the brain and on behaviour that are mediated by age and sex. Funding supportNSERC.

Chronic memantine decreases nicotine self-administration in rats

Neurobehavioral bases of tobacco addiction and nicotine reinforcement are complex, involving more than only nicotinic cholinergic or dopaminergic systems. Memantine is an NMDA glutamate antagonist used to improve cognitive function in people with Alzheimer's disease. Glutamate may be an important component of the reinforcing effects of nicotine, so memantine was evaluated as a potential smoking cessation aid. Two studies were conducted with adult female rats, one testing acute effects of memantine over a range of doses for changing nicotine self-administration and the other testing the chronic effects of memantine to reduce nicotine self-administration. Acute memantine injections slightly, but significantly, increased nicotine self-administration in a dose-related manner. In contrast, chronic memantine treatment significantly reduced nicotine self-administration. During the first day of memantine administration in the chronic study, nicotine self-administration was significantly elevated replicating the acute study. Starting in the second week of treatment there was a significant reduction of nicotine self-administration relative to controls. This was seen because memantine treatment prevented the increase in nicotine self-administration shown by controls. There even continued to be a memantine-induced lowered nicotine self-administration during the week after the cessation of memantine treatment. Memantine or other drugs affecting NMDA glutamate receptors may be useful aids to smoking cessation. Full efficacy for reducing nicotine self-administration was seen as the NMDA drug treatment is given chronically. Importantly, the effect persisted even after treatment is ended, indicating the high potential for NMDA glutamate receptors to impact nicotine addiction.

Insights Into Nicotinic Receptor Signaling in Nicotine Addiction: Implications for Prevention and Treatment.

BackgroundNicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop ligand-gated ion-channel (LGIC) superfamily, which also includes the GABA, glycine, and serotonin receptors. Many nAChR subunits have been identified and shown to be involved in signal transduction on binding to them of either the neurotransmitter acetylcholine or exogenous ligands such as nicotine. The nAChRs are pentameric assemblies of homologous subunits surrounding a central pore that gates cation flux, and they are expressed at neuromuscular junctions throughout the nervous system.Methods and ResultsBecause different nAChR subunits assemble into a variety of pharmacologically distinct receptor subtypes, and different nAChRs are implicated in various physiological functions and pathophysiological conditions, nAChRs represent potential molecular targets for drug addiction and medical therapeutic research. This review intends to provide insights into recent advances in nAChR signaling, considering the subtypes and subunits of nAChRs and their roles in nicotinic cholinergic systems, including structure, diversity, functional allosteric modulation, targeted knockout mutations, and rare variations of specific subunits, and the potency and functional effects of mutations by focusing on their effects on nicotine addiction (NA) and smoking cessation (SC). Furthermore, we review the possible mechanisms of action of nAChRs in NA and SC based on our current knowledge.ConclusionUnderstanding these cellular and molecular mechanisms will lead to better translational and therapeutic operations and outcomes for the prevention and treatment of NA and other drug addictions, as well as chronic diseases, such as Alzheimer’s and Parkinson’s. Finally, we put forward some suggestions and recommendations for therapy and treatment of NA and other chronic diseases.

Nicotinic cholinergic and dopaminergic receptor mRNA expression in male and female rats with high or low preference for nicotine

ABSTRACTBackground: Nicotine exerts its central actions through nicotinic acetylcholine receptors (nAChRs), which in turn regulate major neurotransmitter systems including dopamine. Nicotinic and dopaminergic systems play significant roles in physiological functions, neuropsychiatric disorders, and addiction. Objectives: To evaluate possible differences in the expression of nAChR subunit and dopamine receptor (DR) mRNAs following voluntary nicotine intake. Methods: Male and female rats (n = 67) were exposed to long-term free-choice oral nicotine (24 hours/day, 6 weeks); rats with maximum and minimum nicotine preference/intake were selected. The mRNA levels of genes encoding α4,β2,α5, and α7 nAChR subunits and DR Drd1and Drd2 subtypes were evaluated in the striatum (STR), prefrontal cortex (PFC), and hippocampus using quantitative real-time polymerase chain reaction in selected rats (n = 30) and their control groups (n = 15). Results: In addition to baseline differences, expression changes were observed in the mRNA levels of evaluated genes in rats exposed to voluntary oral nicotine in a brain region-, sex-, and preference-related manner. Nicotine intake is correlated negatively with Chrnb2, Chrna7 and positively with Drd1 expression. In the cholinergic system, regional differences in Chnrb2 and Chrna5, sex differences in Chrna4 and Chrna5, and nicotine preference effects in the expression of all subunits except α4 were observed. Chrna5 was lower in maximum than in minimum preferring, and in male than female rats, supporting the inhibitory role of the α5 subunit in nicotine dependence. Nicotine increased Drd2 mRNA expression only in minimum preferring female rats in STR and PFC. Conclusion: Modulation of nAChR and DR gene expression by nicotine may have clinical implications and aid drug development. Pharmaceuticals targeting the nicotinic cholinergic and dopaminergic systems might be expected to have differential efficacy that varies with the patient’s sex or smoking status.

Activation of α7 nicotinic acetylcholine receptors protects potentiated synapses from depotentiation during theta pattern stimulation in the hippocampal CA1 region of rats

Long-term potentiation (LTP) shows memory-like consolidation and thus becomes increasingly resistant to disruption by low-frequency stimulation (LFS). However, it is known that nicotine application during LFS uniquely depotentiates consolidated LTP. Here, we investigated how nicotine contributes to the disruption of stabilized LTP in the hippocampal CA1 region. We found that nicotine-induced depotentiation is not due to masking LTP by inducing long-term depression and requires the activation of GluN2A-containing NMDARs. We further examined whether nicotine-induced depotentiation involves the reversal of LTP mechanisms. LTP causes phosphorylation of Ser-831 on GluA1 subunits of AMPARs that increases the single-channel conductance of AMPARs. This phosphorylation remained unchanged after depotentiation. LTP involves the insertion of new AMPARs into the synapse and the internalization of AMPARs is associated with dephosphorylation of Ser-845 on GluA1 and caspase-3 activity. Nicotine-induced depotentiation occurred without dephosphorylation of the Ser-845 and in the presence of a caspase-3 inhibitor. LTP is also accompanied by increased filamentous actin (F-actin), which controls spine size. Nicotine-induced depotentiation was prevented by jasplakinolide, which stabilizes F-actin, suggesting that nicotine depotentiates consolidated LTP by destabilizing F-actin. α7 nicotinic acetylcholine receptor (nAChR) antagonists mimicked the effect of nicotine and selective removal of hippocampal cholinergic input caused depotentiation in the absence of nicotine, suggesting that nicotine depotentiates consolidated LTP by inducing α7 nAChR desensitization. Our results demonstrate a new role for nicotinic cholinergic systems in protecting potentiated synapses from depotentiation by preventing GluN2A-NMDAR-mediated signaling for actin destabilization.

Interactions between the endocannabinoid and nicotinic cholinergic systems: preclinical evidence and therapeutic perspectives.

Several lines of evidence suggest that endocannabinoid and nicotinic cholinergic systems are implicated in the regulation of different physiological processes, including reward, and in the neuropathological mechanisms of psychiatric diseases, such as addiction. A crosstalk between these two systems is substantiated by the overlapping distribution of cannabinoid and nicotinic acetylcholine receptors in many brain structures. We will review recent preclinical data showing how the endocannabinoid and nicotinic cholinergic systems interact bidirectionally at the level of the brain reward pathways, and how this interaction plays a key role in modulating nicotine and cannabinoid intake and dependence. Many behavioral and neurochemical effects of nicotine that are related to its addictive potential are reduced by pharmacological blockade or genetic deletion of type-1 cannabinoid receptors, inhibition of endocannabinoid uptake or metabolic degradation, and activation of peroxisome proliferator-activated-receptor-α. On the other hand, cholinergic antagonists at α7 nicotinic acetylcholine receptors as well as endogenous negative allosteric modulators of these receptors are effective in blocking dependence-related effects of cannabinoids. Pharmacological manipulation of the endocannabinoid system and endocannabinoid-like neuromodulators shows promise in the treatment of nicotine dependence and in relapse prevention. Likewise, drugs acting at nicotinic acetylcholine receptors might prove useful in the therapy of cannabinoid dependence. Research by Steven R. Goldberg has significantly contributed to the progress in this research field.

Effect of Salvia sahendica Extracts on Neuromuscular Transmission in Chick Biventer Cervicis Muscle

The Salvia sahendica, a known folk medicine, possesses antibacterial, antifungal, anticancer properties and the improvement effect on the memory system. Because memory improving effects of the other species of this genus (salvia officinalis) is mediated by interacting with muscarinic and nicotinic cholinergic systems. It seems that S. sahendica may also follow the same mechanisms.The purpose of the present study is to investigate the anticholinesterase effect of Salvia sahendica extracts,in the pharmacologic methods. Method: The study was done by using the Dose-response curves and Twitch tension techniques in chick biventer cervicis. The ability of extracts to modulate cholinesterase activity were assessed by obtaining concentration–response curves to acetylcholine and carbacol in the absence or presence of extracts. The isolated tissues were exposed to extracts (methanol, dichloromethane and hexane extracts) and responses were recorded, with p < 0.05 indicating significance. Results: Based on our finding, methanol extract of S. sahendica, has not significant change in the dose-response curve for acetylcholine, enzyme but elicited reduction effect at carbacol dose-response curve. All other extracts showed the significant reduction in Dose-response curves and Twitch tension. There was a direct relationship between hexane extract´s concentration and reduction of contraction on log dose-response curves for acetylcholine and carbachol. Hexane extract (75µg/ml) blocked muscle twitching and yield in a complete blockage in the presence of tubocurarine, dichloromethane extract decreased twitch height. The effect of tubocurarine was not abolished by extract but also had cumulative effects. Conclusion: These results suggest that the relaxant effects of S. sahendica extracts on neuromuscular junction are elicited by post junctionally and curare–mimetic effects. It seems that, methanol extract has anticholinsterase activity but this effect will be affected by the inhibitory effect of the extract and inhibited.

Endogenous ACh suppresses LTD induction and nicotine relieves the suppression via different nicotinic ACh receptor subtypes in the mouse hippocampus

AimsStudying the normal role of nicotinic cholinergic systems in hippocampal synaptic plasticity is critical for understanding how cholinergic loss in Alzheimer's disease (AD) and tobacco use affect cognitive function. However, it is largely unknown how nicotinic cholinergic systems regulate the induction of long-term depression (LTD). Main methodsExtracellular field potential recordings were performed in hippocampal slices prepared from wild-type, α2, α7, and β2 knockout (KO) mice. Effects of nicotine and nicotinic antagonists on LTD induction in wild-type, α2, α7, and β2 KO mice were compared. Key findingsActivation of α7 nicotinic acetylcholine receptors (nAChRs) occurs during LTD-inducing stimulation to suppress LTD induction at CA3–CA1 synapses. Nicotine relieves this suppression, causing larger LTD. This nicotine effect was mediated by the activation of non-α7 nAChR subtypes, which were not activated by ACh released during LTD-inducing stimulation, and requires the presence of endogenous ACh-induced α7 nAChR activation. Furthermore, the effect of nicotine was prevented in the presence of mecamylamine, but not dihydro-β-erythroidine, and was still observed in both α2 KO and β2 KO mice. SignificanceThis is the first report to evaluate the involvement of different nAChR subtypes in LTD induction. Findings indicate the involvement of unique non-α7 nAChR subtypes, which have not been considered in the nicotinic modulation of hippocampal long-term potentiation, in the control of LTD induction. The implication of our results is that the loss of cholinergic projections to the hippocampus, which reduces ACh release as seen in AD patients, and nicotine from tobacco smoking can differentially affect LTD induction.

A randomized, double-blind, placebo-controlled crossover study of α4β2* nicotinic acetylcholine receptor agonist AZD1446 (TC-6683) in adults with attention-deficit/hyperactivity disorder

Stimulation of nicotinic cholinergic systems has been shown to alleviate ADHD symptoms and to improve cognitive performance. AZD1446 is a selective α4β2* nicotinic acetylcholine receptor agonist with potential effect on the symptoms of ADHD. The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of AZD1446 in adults with ADHD treated for 2 weeks. This was a randomized, double-blind, placebo-controlled crossover trial. Participants were 79 adults with ADHD, grouped according to their use of nicotine-containing products. Nicotine non-users received placebo and two of three AZD1446 treatment regimens (80 mg tid, 80 mg qd, 10 mg tid). Nicotine users received placebo, AZD1446 80 mg tid and 80 mg qd. Efficacy measures included the Conners' Adult ADHD Rating Scale and cognitive measures of immediate and delayed verbal episodic memory, learning, attention, working memory, executive functioning, and spatial problem solving (CogState computerized test battery). There was no significant effect of AZD1446 on any of the clinical scores irrespective of dose, schedule, or concomitant use of nicotine products. A statistically significant improvement was seen on the Groton Maze Learning Task, a measure of executive functioning, in nicotine non-users after treatment with AZD1446 80 mg qd. AZD1446 was well tolerated, but did not significantly improve ADHD symptoms after 2 weeks of treatment compared to placebo. While the present study does not support the therapeutic utility of AZD1446 in ADHD, its potential pro-cognitive effects remain to be explored in other neuropsychiatric disorders.

The effects of nicotine on nitric oxide induced anxiogenic-like behaviors in the dorsal hippocampus

Nicotine, an active tobacco derived alkaloid, regulates the activity of the neuronal nitric oxide synthase (nNOS) as well as the release of nitric oxide (NO) in the nervous system. Nicotinic acetylcholine receptors and nNOS are abundantly co-expressed in the hippocampal neurons and are found to alter anxiety-like behaviors in rodents. Dorsal hippocampus may be a site for modulation of anxiety. Therefore, in this study, we investigated the possible interactions between nicotine and NO systems of the dorsal hippocampus and the resultant effect on anxiety-like behaviors. The elevated plus-maze (EPM) test has been used to test the anxiety. Intraperitoneal administration of nicotine (0.5mg/kg) decreased the open arm time percentage (%OAT) and open arm entries percentage (%OAE) but not the locomotor activity, indicating an anxiogenic-like response. Intra-CA1 injection of l-arginine (a NO precursor) or l-NAME (a NOS inhibitor) also caused anxiogenic-like effects. On the other hand, injection of the low dose nicotine before different doses of l-arginine or l-NAME blocked the anxiogenic-like response induced by the drugs. Our results suggested that, both NO and nicotinic cholinergic systems not only play a part in the modulation of the anxiety in mice dorsal hippocampus, but also demonstrate a complex interaction in this respect.

Nicotine increases brain functional network efficiency

Despite the use of cholinergic therapies in Alzheimer's disease and the development of cholinergic strategies for schizophrenia, relatively little is known about how the system modulates the connectivity and structure of large-scale brain networks. To better understand how nicotinic cholinergic systems alter these networks, this study examined the effects of nicotine on measures of whole-brain network communication efficiency. Resting state fMRI was acquired from fifteen healthy subjects before and after the application of nicotine or placebo transdermal patches in a single blind, crossover design. Data, which were previously examined for default network activity, were analyzed with network topology techniques to measure changes in the communication efficiency of whole-brain networks. Nicotine significantly increased local efficiency, a parameter that estimates the network's tolerance to local errors in communication. Nicotine also significantly enhanced the regional efficiency of limbic and paralimbic areas of the brain, areas which are especially altered in diseases such as Alzheimer's disease and schizophrenia. These changes in network topology may be one mechanism by which cholinergic therapies improve brain function.

α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

Parkinson's disease is a debilitating movement disorder characterized by a generalized dysfunction of the nervous system, with a particularly prominent decline in the nigrostriatal dopaminergic pathway. Although there is currently no cure, drugs targeting the dopaminergic system provide major symptomatic relief. As well, agents directed to other neurotransmitter systems are of therapeutic benefit. Such drugs may act by directly improving functional deficits in these other systems, or they may restore aberrant motor activity that arises as a result of a dopaminergic imbalance. Recent research attention has focused on a role for drugs targeting the nicotinic cholinergic systems. The rationale for such work stems from basic research findings that there is an extensive overlap in the organization and function of the nicotinic cholinergic and dopaminergic systems in the basal ganglia. In addition, nicotinic acetylcholine receptor (nAChR) drugs could have clinical potential for Parkinson's disease. Evidence for this proposition stems from studies with experimental animal models showing that nicotine protects against neurotoxin-induced nigrostriatal damage and improves motor complications associated with l-DOPA, the "gold standard" for Parkinson's disease treatment. Nicotine interacts with multiple central nervous system receptors to generate therapeutic responses but also produces side effects. It is important therefore to identify the nAChR subtypes most beneficial for treating Parkinson's disease. Here we review nAChRs with particular emphasis on the subtypes that contribute to basal ganglia function. Accumulating evidence suggests that drugs targeting α6β2* and α4β2* nAChR may prove useful in the management of Parkinson's disease.

Alpha7 Neuronal Nicotinic Receptors as Targets for Novel Therapies to Treat Multiple Domains of Schizophrenia

A number of hypotheses have been put forth to explain the underlying abnormalities of schizophrenia. The widely held dopamine hypothesis suggests that positive symptoms are related to elevated subcortical dopamine transmission and that negative symptoms and cognitive impairments are associated with decreased cortical dopamine function. However, recent evidence suggests broader involvement of serotonergic, glutamatergic and other neurotransmitter systems and a growing body of evidence supports a role for nicotinic cholinergic systems. Based on post-mortem studies, there is a decreased density of neuronal nicotinic receptors (NNRs), especially the alpha7 NNR subtype, in the brains of schizophrenics. The alpha7 NNR subtype is the most abundant in the mammalian brain and has been shown to modulate multiple neuronal pathways that are compromised in schizophrenia, including dopaminergic, serotonergic, glutamatergic and GABAergic pathways. Familial linkage studies have associated regions of chromosome 15, which contains the alpha7 NNR gene, with schizophrenia and polymorphisms have been described in the promoter region of the alpha7 NNR gene. Observations from both animal and human studies that alpha7 NNR agonists can improve positive and negative symptoms as well as cognition to varying degrees further support the involvement of this receptor subtype in multiple deficits of schizophrenia and suggest that it may be feasible to develop novel therapies targeting alpha7 NNRs to treat all domains of the disease.

Lack of nAChR Activity Depresses Cochlear Maturation and Up-Regulates GABA System Components: Temporal Profiling of Gene Expression in α9 Null Mice

BackgroundIt has previously been shown that deletion of chrna9, the gene encoding the α9 nicotinic acetylcholine receptor (nAChR) subunit, results in abnormal synaptic terminal structure. Additionally, all nAChR-mediated cochlear activity is lost, as characterized by a failure of the descending efferent system to suppress cochlear responses to sound. In an effort to characterize the molecular mechanisms underlying the structural and functional consequences following loss of α9 subunit expression, we performed whole-transcriptome gene expression analyses on cochleae of wild type and α9 knockout (α9−/−) mice during postnatal days spanning critical periods of synapse formation and maturation.Principal FindingsData revealed that loss of α9 receptor subunit expression leads to an up-regulation of genes involved in synaptic transmission and ion channel activity. Unexpectedly, loss of α9 receptor subunit expression also resulted in an increased expression of genes encoding GABA receptor subunits and the GABA synthetic enzyme, glutamic acid decarboxylase. These data suggest the existence of a previously unrecognized association between the nicotinic cholinergic and GABAergic systems in the cochlea. Computational analyses have highlighted differential expression of several gene sets upon loss of nicotinic cholinergic activity in the cochlea. Time-series analysis of whole transcriptome patterns, represented as self-organizing maps, revealed a disparate pattern of gene expression between α9−/− and wild type cochleae at the onset of hearing (P13), with knockout samples resembling immature postnatal ages.ConclusionsWe have taken a systems biology approach to provide insight into molecular programs influenced by the loss of nicotinic receptor-based cholinergic activity in the cochlea and to identify candidate genes that may be involved in nicotinic cholinergic synapse formation, stabilization or function within the inner ear. Additionally, our data indicate a change in the GABAergic system upon loss of α9 nicotinic receptor subunit within the cochlea.

Varenicline and Adult ADHD

Back to table of contents Previous article Next article LETTERFull AccessVarenicline and Adult ADHDJames A. Cocores M.D.,Mark S. Gold M.D.,James A. Cocores M.D.Search for more papers by this author,Mark S. Gold M.D.Search for more papers by this author,Published Online:1 Oct 2008AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Nicotine dependence is perpetuated by biobehavioral rewards generated as the result of nicotine’s interaction with the brain’s neurochemical systems. 1 Nicotine’s memory-enhancing reward is believed to result from its effects on specific nicotinic acetylcholine receptors. 2 Nicotine’s attentional, antidepressant, and antianxiety rewards are thought to be due to pathways between nicotinic acetylcholine receptors and noncholinergic neuronal subtypes that selectively traffic dopamine, norepinephrine, 5-hydroxytryptamine, and gamma-aminobutyric acid. 3 Varenicline is a new treatment for nicotine dependence and a member of the selective alpha4beta2 nicotinic acetylcholine receptor partial agonist class. 4 Central nicotinic acetylcholine receptors have been implicated in attention deficit hyperactivity disorder (ADHD), 5 and an alpha4beta2 antagonist counteracted nicotine-induced improvement in an animal model of ADHD. 6The first case of adult ADHD that responded to the addition of varenicline is reported here.Case ReportMs. A, a 26-year-old white woman, was self-referred in 2007 for difficulties staying focused, staying on task, and with reading comprehension. She fulfilled DSM-IV-TR criteria for ADHD, but was against the initial recommendation to begin taking a prescription stimulant. The administration of the antidepressants bupropion (150 mg) and venlafaxine (up to 150 mg), each alone or in combination with valproic acid, was met with either side effects or undesirable results. The medicine selected was based on office sample availability at Ms. A’s request because of financial problems. A wealthier patient had previously donated a barely used varenicline prescription that she had abandoned due to nausea. Ms. A agreed to undergo a trial of varenicline taking 0.5 mg in the morning, after eating a low-acid breakfast, with an 8-oz glass of water. Her reading comprehension and ability to focus improved substantially after reaching 1 mg b.i.d. Her mild hyperactivity improved marginally. She complained of no side effects as she completed 6 weeks, including weekends, of the clinic’s subsidized varenicline treatment trial. Her problematic ADHD symptoms fully resurfaced about 2 days after she ran out of varenicline. Ms. A agreed to continue medicine trials using affordable antidepressant, dopamine agonist, or nicotine replacement generics.CommentAlthough this report does not rule out the placebo effect, and a therapeutic connection between varenicline and ADHD cannot be established with certainty, this case does suggest that the new selective alpha4beta2 nicotinic acetylcholine receptor partial agonist class of medicines is useful in the management of adult ADHD. In particular, the varenicline-ADHD interface warrants further investigation using larger groups of subjects, more sophisticated study designs, and a variety of memory deficits such as depression and mild cognitive impairment.Nutritional Neuropsychiatry, Southcoast Psychotherapy and Education Associates, Boca Raton, Florida; Visiting Clinical Assistant Professor, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FloridaEminent Scholar, Distinguished Professor and Chairman, Department of Psychiatry, McKnight Brain Institute; College of Medicine, University of Florida, Gainesville, FloridaReferences1 . Rosecrans JA: The biobehavioral effects of nicotine: interaction with brain neurochemical systems, in The Clinical Management of Nicotine Dependence. Edited by Cocores JA. New York, Springer-Verlag, 1991, pp 53–65Google Scholar2 . Mansvelder HD, van Aerde KI, Couey JJ, et al: Nicotinic modulation of neuronal networks: from receptors to cognition. Psychopharmacology (Berl) 2006; 184:292–305Google Scholar3 . Rosecrans JA, Krynock GM, Newlon PG, et al: Central mechanisms of drugs as discriminative stimuli: involvement of serotonin pathways, in Stimulus Properties: Ten Years of Progress. Edited by Colapaert FC, Rosecrans JA. Amsterdam, Elsevier/North-Holland Press, 1978, pp 83–98Google Scholar4 . Lam S, Patel PN: Varenicline: a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist approved for cessation. Cardiol Rev 2007; 15:154–161Google Scholar5 . Potter AS, Newhouse PA, Bucci DJ: Central nicotinic cholinergic systems: a role in the cognitive dysfunction in attention-deficit/hyperactivity disorder? Behav Brain Res 2006; 175:201–211Google Scholar6 . Ueno K, Togashi H, Matsumoto M: Alpha4beta2 nicotinic acetylcholine receptor activation ameliorates impairment of spontaneous alternation behavior in stroke-prone spontaneously hypertensive rats, an animal model of attention deficit hyperactivity disorder. J Pharmacol Exp Ther 2002; 302:95–100Google Scholar FiguresReferencesCited byDetailsCited ByNeuropsychopharmacology, Vol. 38, No. 3Expert Opinion on Drug Safety, Vol. 9, No. 3 Volume 20Issue 4 Fall, 2008Pages 494-495 Metrics PDF download History Published online 1 October 2008 Published in print 1 October 2008

Varenicline and Adult ADHD

Back to table of contents Previous article Next article LETTERFull AccessVarenicline and Adult ADHDJames A. Cocores M.D.,Mark S. Gold M.D.,James A. Cocores M.D.Search for more papers by this author,Mark S. Gold M.D.Search for more papers by this author,Published Online:1 Oct 2008AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Nicotine dependence is perpetuated by biobehavioral rewards generated as the result of nicotine’s interaction with the brain’s neurochemical systems. 1 Nicotine’s memory-enhancing reward is believed to result from its effects on specific nicotinic acetylcholine receptors. 2 Nicotine’s attentional, antidepressant, and antianxiety rewards are thought to be due to pathways between nicotinic acetylcholine receptors and noncholinergic neuronal subtypes that selectively traffic dopamine, norepinephrine, 5-hydroxytryptamine, and gamma-aminobutyric acid. 3 Varenicline is a new treatment for nicotine dependence and a member of the selective alpha4beta2 nicotinic acetylcholine receptor partial agonist class. 4 Central nicotinic acetylcholine receptors have been implicated in attention deficit hyperactivity disorder (ADHD), 5 and an alpha4beta2 antagonist counteracted nicotine-induced improvement in an animal model of ADHD. 6The first case of adult ADHD that responded to the addition of varenicline is reported here.Case ReportMs. A, a 26-year-old white woman, was self-referred in 2007 for difficulties staying focused, staying on task, and with reading comprehension. She fulfilled DSM-IV-TR criteria for ADHD, but was against the initial recommendation to begin taking a prescription stimulant. The administration of the antidepressants bupropion (150 mg) and venlafaxine (up to 150 mg), each alone or in combination with valproic acid, was met with either side effects or undesirable results. The medicine selected was based on office sample availability at Ms. A’s request because of financial problems. A wealthier patient had previously donated a barely used varenicline prescription that she had abandoned due to nausea. Ms. A agreed to undergo a trial of varenicline taking 0.5 mg in the morning, after eating a low-acid breakfast, with an 8-oz glass of water. Her reading comprehension and ability to focus improved substantially after reaching 1 mg b.i.d. Her mild hyperactivity improved marginally. She complained of no side effects as she completed 6 weeks, including weekends, of the clinic’s subsidized varenicline treatment trial. Her problematic ADHD symptoms fully resurfaced about 2 days after she ran out of varenicline. Ms. A agreed to continue medicine trials using affordable antidepressant, dopamine agonist, or nicotine replacement generics.CommentAlthough this report does not rule out the placebo effect, and a therapeutic connection between varenicline and ADHD cannot be established with certainty, this case does suggest that the new selective alpha4beta2 nicotinic acetylcholine receptor partial agonist class of medicines is useful in the management of adult ADHD. In particular, the varenicline-ADHD interface warrants further investigation using larger groups of subjects, more sophisticated study designs, and a variety of memory deficits such as depression and mild cognitive impairment.Nutritional Neuropsychiatry, Southcoast Psychotherapy and Education Associates, Boca Raton, Florida; Visiting Clinical Assistant Professor, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FloridaEminent Scholar, Distinguished Professor and Chairman, Department of Psychiatry, McKnight Brain Institute; College of Medicine, University of Florida, Gainesville, FloridaReferences1 . Rosecrans JA: The biobehavioral effects of nicotine: interaction with brain neurochemical systems, in The Clinical Management of Nicotine Dependence. Edited by Cocores JA. New York, Springer-Verlag, 1991, pp 53–65Google Scholar2 . Mansvelder HD, van Aerde KI, Couey JJ, et al: Nicotinic modulation of neuronal networks: from receptors to cognition. Psychopharmacology (Berl) 2006; 184:292–305Google Scholar3 . Rosecrans JA, Krynock GM, Newlon PG, et al: Central mechanisms of drugs as discriminative stimuli: involvement of serotonin pathways, in Stimulus Properties: Ten Years of Progress. Edited by Colapaert FC, Rosecrans JA. Amsterdam, Elsevier/North-Holland Press, 1978, pp 83–98Google Scholar4 . Lam S, Patel PN: Varenicline: a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist approved for cessation. Cardiol Rev 2007; 15:154–161Google Scholar5 . Potter AS, Newhouse PA, Bucci DJ: Central nicotinic cholinergic systems: a role in the cognitive dysfunction in attention-deficit/hyperactivity disorder? Behav Brain Res 2006; 175:201–211Google Scholar6 . Ueno K, Togashi H, Matsumoto M: Alpha4beta2 nicotinic acetylcholine receptor activation ameliorates impairment of spontaneous alternation behavior in stroke-prone spontaneously hypertensive rats, an animal model of attention deficit hyperactivity disorder. J Pharmacol Exp Ther 2002; 302:95–100Google Scholar FiguresReferencesCited byDetailsCited ByNeuropsychopharmacology, Vol. 38, No. 3Expert Opinion on Drug Safety, Vol. 9, No. 3 Volume 20Issue 4 Fall, 2008Pages 494-495 Metrics PDF download History Published online 1 October 2008 Published in print 1 October 2008

Effects of Salvia officinalis L. (sage) leaves on memory retention and its interaction with the cholinergic system in rats

Objective The leaves of sage ( Salvia officinalis L., Lamiaceae) are reported to have a wide range of biological activities, such as anti-bacterial, fungistatic, virustatic, astringent, eupeptic and anti-hydrotic effects. To determine the mnemogenic effect of sage leaves, we investigated the effects of ethanolic extract of sage leaves and its interaction with cholinergic system on memory retention of passive avoidance learning in rats. Methods Post-training intracerebroventricular (i.c.v) injections were carried out in all the experiments except ethanolic extract (i.p. intraperitoneally). Results Administration of ethanolic extract (50 mg/kg), pilocarpine (0.5 and 1 mg/rat), the muscarinic cholinoceptor agonist, and nicotine (0.1 and 1 μg/rat) increased, while mecamylamine (1, 5 μg/rat), the muscarinic cholinoceptor antagonist, and mecamylamine (0.01 and 0.1 μg/rat), the nicotine cholinoceptor antagonist decreased memory retention in rats. Activation of muscarinic cholinoceptors by pilocarpine potentiated the response of ethanolic extract. Also, pharmacological blockade of scopolamine attenuated potentiating effect of ethanolic extract. Activation of nicotinic cholinoceptor by nicotine potentiated the response of ethanolic extract. Blockade of nicotinic cholinoceptor by mecamylamine attenuated the response of ethanolic extract. Conclusion It is concluded that the ethanolic extract of salvia officinalis potentiated memory retention and also it has an interaction with muscarinic and nicotinic cholinergic systems that is involved in the memory retention process.

Nicotine and clozapine actions on pre-pulse inhibition deficits caused by N-methyl- d-aspartate (NMDA) glutamatergic receptor blockade

Pre-pulse inhibition (PPI) is a phenomenon of neurobehavioral plasticity in which the motor response to a startling stimulus is inhibited by a preceding stimulus of a lower intensity. Most often this is tested in the auditory mode. PPI is impaired in a variety of clinical states, most notably schizophrenia. PPI is easily modeled in experimental animals and serves as a useful basis for determining the neural bases for behavioral plasticity. In the current study we examined the interactions of N-methyl- d-aspartate (NMDA) glutamate and nicotinic cholinergic receptor systems in the expression of PPI. Female Sprague–Dawley rats were tested for auditory PPI after sc injections of the NMDA antagonist dizocilpine (also known as MK-801), the prototypic nicotinic agonist nicotine or both. Vehicle (saline) injections served as the control. Nicotine (0.2–0.8 mg/kg) by itself caused a modest but significant dose-related improvement in PPI. Dizocilpine (25–100 μg/kg) caused a dramatic dose-related impairment in PPI. Interestingly, the low to moderate doses of nicotine potentiated the PPI impairment by dizocilpine. In a second experiment nicotine and dizocilpine interactions with the atypical antipsychotic drug clozapine were assessed. As in the first experiment, nicotine potentiated the adverse effects of dizocilpine on PPI. The combination of nicotine with clozapine effectively attenuated the PPI impairment caused by dizocilpine when neither alone was effective. Inasmuch as PPI is impaired in schizophrenia, its reversal by the antipsychotic drug clozapine may depend on co-administration of nicotine by smoking in the patients. Development of nicotinic-based co-treatments for schizophrenia may achieve this benefit of nicotine without the hazards of smoking. Sensory modulation deficit, which is a syndrome of sensory over-responsiveness may also benefit from such combination therapy.