Central Nicotinic Acetylcholine Receptors Research Articles

Src Family Kinases Play a Role in the Functional Clustering of Central Postsynaptic Nicotinic Acetylcholine Receptors

The mechanism of postsynaptic neurotransmitter receptor clustering has been best described at the neuromuscular junction (NMJ), where packets of nicotinic acetylcholine receptors (nAChRs) in muscle fibre are redistributed to the synaptic site upon motor neuron innervation. This process of receptor localisation is facilitated by agrin signalling, and the stability of the resulting nAChR clusters depends upon the activation of Src family kinases (SFKs). In contrast to the NMJ however, the cellular signalling mechanisms orchestrating the clustering of nAChRs in the central nervous system (CNS) remain poorly defined. Furthermore, our understanding of the role of SFKs in the CNS is also limited. Here we provide evidence that SFK activation is required for synapse formation between pairs of identified neurons isolated from the CNS of Lymnaea stagnalis. Furthermore, we suggest that SFKs are involved in the functional redistribution of nAChRs to the synaptic contact sites in isolated axons. To the best of our knowledge, this study is the first to demonstrate a role for SFKs in the clustering of nAChRs in central neurons, suggesting that the mechanisms of receptor clustering between the peripheral and central nervous system are likely conserved.

3,4-Methylenedioxy-methamphetamine induces in vivo regional up-regulation of central nicotinic receptors in rats and potentiates the regulatory effects of nicotine on these receptors

Nicotine (NIC), the main psychostimulant compound of smoked tobacco, exerts its effects through activation of central nicotinic acetylcholine receptors (nAChR), which become up-regulated after chronic administration. Recent work has demonstrated that the recreational drug 3,4-methylenedioxy-methamphetamine (MDMA) has affinity for nAChR and also induces up-regulation of nAChR in PC 12 cells. Tobacco and MDMA are often consumed together. In the present work we studied the in vivo effect of a classic chronic dosing schedule of MDMA in rats, alone or combined with a chronic schedule of NIC, on the density of nAChR and on serotonin reuptake transporters. MDMA induced significant decreases in [3H]paroxetine binding in the cortex and hippocampus measured 24h after the last dose and these decreases were not modified by the association with NIC. In the prefrontal cortex, NIC and MDMA each induced significant increases in [3H]epibatidine binding (29.5 and 34.6%, respectively) with respect to saline-treated rats, and these increases were significantly potentiated (up to 72.1%) when the two drugs were associated. Also in this area, [3H]methyllycaconitine binding was increased a 42.1% with NIC+MDMA but not when they were given alone. In the hippocampus, MDMA potentiated the α7 regulatory effects of NIC (raising a 25.5% increase to 52.5%) but alone was devoid of effect. MDMA had no effect on heteromeric nAChR in striatum and a coronal section of the midbrain containing superior colliculi, geniculate nuclei, substantia nigra and ventral tegmental area. Specific immunoprecipitation of solubilised receptors suggests that the up-regulated heteromeric nAChRs contain α4 and β2 subunits. Western blots with specific α4 and α7 antibodies showed no significant differences between the groups, indicating that, as reported for nicotine, up-regulation caused by MDMA is due to post-translational events rather than increased receptor synthesis.

Enhanced attenuation of nicotine discrimination in rats by combining nicotine-specific antibodies with a nicotinic receptor antagonist

Tobacco addiction requires activation by nicotine of a variety of central nicotinic acetylcholine receptors (nAChRs). In animals, both nAChR antagonists and immunization against nicotine can reduce nAChR activation by nicotine and block a variety of addiction-relevant behaviors. However, clinical use of nAChR antagonists for smoking cessation is limited by dose-related side effects, and immunization does not reliably produce sufficient antibody levels in smokers to enhance smoking cessation rates. Combining these approaches may be one way of addressing the limitations of each while enhancing overall efficacy. This study examined the individual and combined effects of passive immunization with the monoclonal nicotine-specific antibody Nic311 and the nicotinic receptor antagonist mecamylamine (MEC) on nicotine's discriminative stimulus effects. Rats were trained to discriminate 0.4mg/kg of nicotine from saline using a two-lever operant discrimination procedure. Antagonism of nicotine discrimination by Nic311 (160mg/kg i.v.) and ascending doses of MEC (0.03, 0.1, 0.3, and 1.0mg/kg s.c.) was assessed across four consecutive daily 2-min extinction test sessions using a 2×2 design. Nic311 alone produced a 24–48% reduction in % nicotine-lever responding (%NLR) across all four test sessions. MEC produced a dose-dependent decrease in %NLR, with no effect at the two lowest doses and 80–93% attenuation at the two highest doses. Nic311 combined with MEC significantly suppressed %NLR at every MEC dose (85–92% reduction across all four test sessions). Very low doses of MEC that were ineffective alone completely blocked nicotine discrimination when combined with Nic311. These data demonstrate that nicotine-specific antibodies and MEC can work synergistically to suppress the subjective effects of nicotine and suggest that low doses of MEC may significantly enhance the efficacy of immunotherapy.

Synthesis and binding of 3-aminopyridine derivatives at central nicotinic receptors.

A series of secondary and tertiary pyridyl amides as potential central nicotinic acetylcholine receptors (nAChRs) ligands were prepared. Amides displayed negligible or very low affinity, whereas two amines achieved by reduction of corresponding secondary amides, showed affinity in the nanomolar range for nAChRs.

Central nicotinic acetylcholine receptor involved in Ca2+-calmodulin-endothelial nitric oxide synthase pathway modulated hypotensive effects

Recent evidence has suggested that nicotine decreases blood pressure (BP) and heart rate (HR) in the nucleus tractus solitarii (NTS), indicating that nicotinic acetylcholine receptors (nAChRs) play an important role in BP control in the NTS. However, the signalling mechanisms involved in nAChR-mediated depressor effects in the NTS are unclear. Hence, the aim of this study was to investigate these signalling mechanisms. Depressor responses to nicotine microinjected into the NTS of Wistar-Kyoto rats were elicited in the absence and presence of an antagonist of α7 nAChR, the calcium chelator ethylene glycol tetraacetic acid, a calmodulin-specific inhibitor, nitric oxide (NO) synthase (NOS) inhibitor, endothelial NOS (eNOS)-selective inhibitor or neuronal NOS (nNOS)-specific inhibitor. Microinjection of nicotine into the NTS produced a dose-dependent decrease in BP and HR, and increased nitrate levels. This depressor effect of nicotine was attenuated after pretreatment with a nAChR antagonist or blockers of the calmodulin-eNOS pathway. In contrast, N5-(1-Imino-3-butenyl)-L-ornithine (vinyl-L-NIO), nNOS-specific inhibitor, did not diminish these nicotine-mediated effects. Calmodulin was found to bind eNOS after nicotine injection into NTS. However, nicotine did not affect the eNOS phosphorylation level or eNOS upstream extracellular signal-regulated kinases (ERK)1/2 and Akt phosphorylation levels. Furthermore, pretreatment with an ERK1/2 or Akt inhibitor did not attenuate nicotine-induced depressor effects in the NTS. These results suggest that the nAChR-Ca(2+) -calmodulin-eNOS-NO signalling pathway, but not nNOS, plays a significant role in central BP regulation, and neither the ERK1/2 nor Akt signalling pathway are significantly involved in the activation of eNOS by nAChRs in the NTS.

Therapeutic Effect of Nicotine in a Mouse Model of Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) resulting from the leakage of blood into the brain parenchyma triggers severe tissue damage involving neurodegeneration and inflammation. Increasing lines of evidence indicate that the stimulation of central nicotinic acetylcholine receptors affords neuroprotection against various insults and also suppresses the proinflammatory activation of microglia. Therefore, the present study aimed to determine whether the administration of nicotine modifies the pathological consequences of ICH, using a mouse model of ICH induced by intrastriatal injection of collagenase. Daily intraperitoneal administration of nicotine (2 mg/kg), starting from 3 h after the induction of ICH, inhibited apoptosis and decreased the number of remaining striatal neurons at 3 days after the insult. We also found that nicotine administration increased the relative expression level of the antiapoptotic protein B cell lymphoma-2 versus that of the proapoptotic protein Bax in the brain. In addition, nicotine administration attenuated the activation of microglia/macrophages, infiltration of neutrophils, and increases in oxidative stress associated with ICH, without affecting hematoma expansion and brain edema. It is noteworthy that mice treated with nicotine exhibited improved sensorimotor performance and a marked increase in survival rate after ICH. These results indicate that nicotinic acetylcholine receptors may serve as a novel target for emergency therapy for ICH.

Synthesis and evaluation of new imaging agent for central nicotinic acetylcholine receptor α7 subtype

The nicotinic acetylcholine receptor (nAChR) alpha7 subtype (alpha(7) nAChR) is one of the major nAChR subtypes in the brain. We synthesized C-11 labeled alpha(7) nAChR ligands, (R)-2-[(11)C]methylamino-benzoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester ([(11)C](R)-MeQAA) and its isomer (S)-[(11)C]MeQAA, for in vivo investigation with positron emission tomography (PET). Then, the potential of (R)- and (S)-[(11)C]MeQAA for in vivo imaging of alpha(7) nAChR in the brain was evaluated in mice and monkeys. The binding affinity for alpha(7) nAChR was measured using rat brain. Biodistribution and in vivo receptor blocking studies were undertaken in mice. Dynamic PET scans were performed in conscious monkeys. The affinity for alpha(7) nAChR was 41 and 182 nM for (R)- and (S)-MeQAA, respectively. The initial uptake in the mouse brain was high ([(11)C](R)-MeQAA: 7.68 and [(11)C](S)-MeQAA: 6.65 %dose/g at 5 min). The clearance of [(11)C](R)-MeQAA was slow in the hippocampus (alpha(7) nAChR-rich region) but was rapid in the cerebellum (alpha(7) nAChR-poor region). On the other hand, the clearance was fast for [(11)C](S)-MeQAA in all regions. The brain uptake of [(11)C](R)-MeQAA was decreased by methyllycaconitine (alpha(7) nAChR antagonist) treatment. In monkeys, alpha(7) nAChRs were highly distributed in the thalamus and cortex but poorly distributed in the cerebellum. The high accumulation was observed in the cortex and thalamus for [(11)C](R)-MeQAA, while the uptake was rather homogeneous for [(11)C](S)-MeQAA. [(11)C](R)-MeQAA was successfully synthesized and showed high uptake to the brain. However, since the in vivo selectivity for alpha(7) nAChR was not enough, further PET kinetic analysis or structure optimization is needed for specific visualization of brain alpha(7) nAChRs in vivo.

Catestatin attenuates the effects of intrathecal nicotine and isoproterenol

Catestatin (Cts; human chromogranin A 352-372) is a neuropeptide derived from chromogranin A (ChgA). In the periphery it is released from the terminals of preganglionic neurons. In the adrenal medulla it inhibits catecholamine release by non-competitively antagonizing nicotinic cholinergic receptors. ChgA is present in the central nervous system, but the extent to which it is present within bulbospinal sympathoexcitatory neurons is unknown. We investigated the distribution of ChgA in the brainstem and its relationship to sympathoexcitatory neurons by combining immunofluorescence and in situ hybridization. A possible role for Cts in modulating the effect of other neurotransmitter systems in the spinal cord was examined by intrathecal injection of Cts, in conjunction with nicotine (1 μg–100 μg) and isoproterenol (0.12 μg–2.5 μg), in the anesthetized rat. Cts attenuated the hypotensive effect of isoproterenol on mean arterial pressure (maximum dose, 2.5 μg isoproterenol; − 27 mmHg pre-Cts to − 18 mmHg post-Cts), splanchnic sympathetic nerve activity (at 2.5 μg isoproterenol; 10.5% pre-Cts to 2.4% post-Cts), HR (at 2.5 μg isoproterenol; 1.1% pre-Cts to − 1.6% post-Cts), and the d p/d t max of carotid pulse pressure (at 2.5 μg isoproterenol 17.3% pre-Cts to 9.3% post-Cts). Cts attenuated the hypertensive effect of nicotine on mean arterial pressure (at 10 μg nicotine, 19.3 mmHg pre-Cts to 6.8 mmHg post-Cts), splanchnic sympathetic nerve activity (at 10 μg nicotine, 10.7% pre-Cts to 4.5% post-Cts), and HR (at 10 μg nicotine, 4.1% pre-Cts to 2.0% post-Cts). The results indicate that Cts antagonizes both central nicotinic acetylcholine receptors and β-adrenoceptors that are involved in cardiovascular regulation in vivo.

18F-ZW-104: A New Radioligand for Imaging Neuronal Nicotinic Acetylcholine Receptors—In Vitro Binding Properties and PET Studies in Baboons

An extensive series of radioligands has been developed for imaging central nicotinic acetylcholine receptors (nAChRs) with PET. Two halogeno-derivatives of A-85380 are being used in humans. Nevertheless, these derivatives still display too-slow brain kinetics and low signal-to-noise ratio. A novel nAChR radioligand, 5-(6-fluorohexyn-1-yl)-3-[2(S)-2-azetidinylmethoxy]pyridine (ZW-104), was characterized in vitro using competition binding assays (nAChR subtypes heterologously expressed in HEK 293 cells and in native alpha4beta2 nAChRs from rat brain). (18)F-ZW-104 was prepared as follows: no-carrier-added nucleophilic aliphatic radiofluorination of the corresponding N-Boc-protected tosyloxy derivative 5-(6-tosyloxyhexyn-1-yl)-3-[2(S)-(N-(tert-butoxycarbonyl))-2-azetidinylmethoxy] pyridine) with the activated 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo-[8,8,8]hexacosane (K-(18)F-F-Kryptofix 222 [K(222)] complex), followed by quantitative trifluoroacetic acid-induced removal of the N-Boc protective group. (18)F-ZW-104 was then studied in baboons using PET. ZW-104 showed high binding affinities for rat alpha4beta2 nAChRs (K(i), 0.2 nM) and other subtypes containing the beta2 subunit but much lower affinities for rat alpha3beta4 nAChRs (K(i), 5,500 nM) and other subtypes containing the beta4 subunit. The regional radioactivity distribution in the baboon brain matched that of the alpha4beta2 nAChR, which was similar to that of 2-(18)F-fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-(18)F-A-85380), a radioligand used in humans. Comparison between (18)F-ZW-104 and 2-(18)F-A-85380 demonstrated better in vivo binding properties of the new radioligand: a substantially greater amount of radioactivity accumulated in the brain, and the occurrence of peak uptake in the thalamus was earlier than that of 2-(18)F-A-85380 and was followed by washout. Distribution volume values in different brain regions were 2-fold higher for (18)F-ZW-104 than for 2-(18)F-A-85380. Displacement by nicotine or unlabeled ZW-104 demonstrated a lower nonspecific binding than that of 2-F-A-85380. These results suggest that (18)F-ZW-104 is a promising PET radioligand for studying nAChRs containing the beta2 subunits in humans.

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

Regional differential effects of chronic nicotine on brain α4-containing and α6-containing receptors

Chronic nicotine upregulates central nicotinic acetylcholine receptors (nAChRs), a plasticity process thought to contribute to its addictive properties. To analyze this process in vivo, we chronically exposed mice to nicotine using minipump delivering nicotine at concentrations close to those found in tobacco smokers. Binding studies show upregulation of high-affinity nAChRs after 21 days of treatment in cortical areas, caudate putamen, nucleus accumbens, hippocampus, ventral tegmental area, and superior colliculi. No upregulation was observed in thalamus and discrete cortical areas. Using wild type and alpha 6-/- mice, we observed a downregulation of alpha 6*-nAChRs in superior colliculi and no effects in other structures. The complex pattern of upregulation/downregulation observed in this study depends on both nAChR composition and regional distribution.

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

Nicotine and methamphetamine share discriminative stimulus effects

Background Nicotine and methamphetamine are both abused in similar settings, sometimes together. Because there are known interactions between central nicotinic acetylcholine receptors and dopamine receptors, it is of interest to characterize the nature of the interaction of these two compounds in vivo. Methods The purpose of this study was to characterize the extent to which these two compounds produce similar discriminative stimulus effects and to identify pharmacological mechanisms for their interaction. Male Sprague–Dawley rats were trained to discriminate methamphetamine or nicotine from saline. First, the ability of methamphetamine and nicotine to cross-substitute in rats trained to the other compound was tested. Subsequently, the ability of a dopamine antagonist (haloperidol) and a centrally acting nicotinic antagonist (mecamylamine) to block the discriminative stimulus effects of methamphetamine and nicotine were also tested. Results Nicotine fully substituted in methamphetamine-trained rats, but methamphetamine only partially substituted in nicotine-trained rats. In nicotine-trained rats, mecamylamine fully antagonized the discriminative stimulus effects of nicotine, but haloperidol had no effect. The partial substitution of methamphetamine was partially attenuated by haloperidol, but not altered by mecamylamine. In methamphetamine-trained rats, mecamylamine failed to antagonize the discriminative stimulus effects of methamphetamine, but haloperidol fully blocked the methamphetamine cue. Mecamylamine blocked the ability of nicotine to substitute for methamphetamine, but haloperidol had no effect. Conclusions These results indicate that nicotine and methamphetamine share discriminative stimulus effects in some subjects and that the two compounds do not act at the same site, but produce their interaction indirectly. These findings suggest that these two compounds might be at least partially interchangeable in human users, and that there are potentially interesting pharmacological reasons for the commonly observed co-administration of nicotine and methamphetamine.

Intracellular Ca2+ dynamics of hippocampal interneurons following nicotinic acetylcholine receptor activation

Ca2+ permeability of central nicotinic acetylcholine receptors (nAChRs), especially the α7 subunits, are exceptionally high and this important feature provide a special functional importance for these receptors at the system level. Although studies at the cellular level extensively characterized the molecular properties of Ca2+ influx following nAChR activation, much less is known about the time-related Ca2+ dynamics during nicotine administration in integration units of neurons. Such studies are of particular relevance to understanding in situ nonsynaptic actions of nicotine. Puff ejection of drugs produce a rapid drug delivery and elimination from the cell surface allowing the activation of extrasynaptic receptors within desensitization time-frame. In this report we provide evidence that rapid nicotine application is able to produce irregular Ca2+ transients in the dendrites of stratum radiatum interneurons in the hippocampal CA1 region. Potential components and mechanisms of nAChR-mediated Ca2+ influx are discussed in details to demonstrate the unique feature of activation of nAChRs involved in nonsynaptic function in interneurons as compared to other types of nicotinic activity.

Effects of ultra-low doses of nicotine on the expression of morphine-induced conditioned place preference in mice

In the present study, the effects of acute administration of nicotine, as well as nicotinic and muscarinic acetylcholine receptor antagonists, on the expression of morphine-induced conditioned place preference, have been investigated in male Swiss-Webster mice. Animals received different doses of morphine 5 days after surgical cannulation in the lateral ventricle. Subcutaneous injections of morphine (2-5 mg/kg) in mouse produced place preference in a dose-dependent manner. Furthermore, both intraperitoneal (0.0006-0.1 mg/kg) and intracerebroventricular (0.007-25 ng) nicotine administration significantly reduced the expression of morphine-induced place preference, in a dose-dependent manner. Nicotine, however, was effective over narrow ultra-low dose ranges (0.0012, 0.0025, 0.005 and 0.01 mg/kg; intraperitoneal) and (0.03, 0.1, 0.3 and 0.6 ng/mouse; intracerebroventricular). In addition, locomotor activity was reduced when higher doses of nicotine [both intraperitoneal (0.02, 0.03 and 0.1 mg/kg) and intracerebroventricular (10 and 24 ng/mouse)] were used. Nicotine alone, however, did not cause motivational effects. Intracerebroventricular injection of hexamethonium (0.03, 0.1 and 0.3 mug/mouse; 10 min before nicotine) diminished the effects of nicotine on morphine-induced conditioned place preference. This effect could neither be obtained by intraperitoneal administration of hexamethonium (1, 5 and 10 mg/kg; 30 min before nicotine), nor be reproduced after either intracerebroventricular or intraperitoneal injection of atropine (a muscarinic receptor antagonist). The antagonists, themselves, did not show any motivational effects when used alone and were unable to affect the expression of morphine-induced conditioned place preference. It appears that ultra-low doses of nicotine can reduce the expression of morphine-induced place preference, and that central nicotinic acetylcholine receptors play a role in this regard.

ROLE OF THE SUBUNIT COMPOSITION OF CENTRAL NICOTINIC ACETYLCHOLINE RECEPTORS FOR THE STIMULATORY AND DOPAMINE-ENHANCING EFFECTS OF ETHANOL

The stimulatory, rewarding, and dopamine (DA)-enhancing effects of ethanol may involve central nicotinic acetylcholine receptors (nAChR), especially those located in the ventral tegmental area (VTA). Identifying the subunit composition that mediates these effects of ethanol would increase the understanding of the neurochemical basis underlying the addictive properties of ethanol. In the present series of experiments, the role of the alpha(3)beta(2)(*) and/or beta(3)(*) and/or alpha(6)(*) subunits of the nAChR for the stimulatory and DA-enhancing effects of ethanol was investigated by using alpha-conotoxin MII (alphaCtxMII), selective to the alpha(3)beta(2)(*) and/or beta(3)(*) and/or the alpha(6)(*) subunits of the nAChR, and the alpha-conotoxin PIA-analogue (alphaCtxPIA-analogue), suggested to be selective to the alpha(6)(*) subunits. alphaCtxMII and the alphaCtxPIA-analogue were synthesized using a modified literature procedure. The purity and identity of the peptides were confirmed with HPLC and FAB-MS analyses, respectively. Locomotor activity and in vivo microdialysis in freely moving mice were used. alphaCtxMII and the alphaCtxPIA-analogue were synthesized in good yields (>95%; >90%). In addition, we found that synthesized alphaCtxMII antagonized ethanol-induced locomotor stimulation, which confirms our previous results with the commercially available alphaCtxMII. Furthermore, the synthesized alphaCtxPIA-analogue, assumably also selective for alpha(6)(*) subunits of the nAChR, did neither antagonize the stimulatory nor the accumbal DA-enhancing effects of ethanol. These results indicate that alphaCtxMII- but not alphaCtxPIA-analogue-sensitive receptors, i.e. the alpha(3)beta(2)(*) and/or beta(3)(*) rather than the alpha(6)(*) subunits of the nAChR, appear to be of greater importance for these effects of ethanol and that these subunits could constitute neurochemical targets for developing new drugs for the treatment of alcohol dependence.

Neuropsychological deficits in nonsmokers with schizophrenia: Effects of a nicotinic antagonist

Background Biochemical, physiological and genetic evidence suggests dysregulation of central nicotinic acetylcholine receptor (nAChR) systems in schizophrenia, which may contribute to neuropsychological dysfunction and the high rates of smoking in this disorder. To evaluate the effects of nAChR blockade on neuropsychological performance in schizophrenia without the confounding effects of cigarette smoking, we compared neuropsychological performance in schizophrenia and healthy control nonsmokers after pre-treatment with the centrally-acting nAChR antagonist mecamylamine (MEC). Methods Using a within-subjects, counterbalanced design, schizophrenia ( n = 14) and control ( n = 15) nonsmokers were pre-treated for 3 days with MEC (0.0, 5.0, and 10.0 mg/day). Subjects performed repeated neuropsychological assessments including visuospatial working memory (VSWM), Continuous Performance Test (CPT), Wisconsin Card Sorting Test (WCST), Word Serial Position Test (WSPT) and Stroop Color Word Test (SCWT) during three sequential test sessions per week over three test weeks. Results We found significant main effects of schizophrenia diagnosis on: VSWM 30 and 60 delays ( p's < 0.01), CPT (% Hit Rate, Reaction Time, Variability Index; p < 0.01 for all outcomes), WCST ( p < 0.01 for all outcomes) and Word Serial Position Test ( p < 0.01). However, there were no main effects of repeated test administration (Session) or MEC dose on any of these outcomes, and no significant 3-way (Diagnosis × Session × MEC dose) interactions. Conclusions Our results suggest that there are a broad range of neuropsychological deficits in nonsmokers with schizophrenia. Furthermore, pretreatment with a centrally-acting nAChR antagonist did not alter neuropsychological performance in either nonsmoking patients with schizophrenia or controls.

Chronic treatment with first or second generation antipsychotics in rodents: Effects on high affinity nicotinic and muscarinic acetylcholine receptors in the brain

Several postmortem and neuroimaging studies suggest that central nicotinic and muscarinic acetylcholine receptors are important in both the pathophysiology and pharmacotherapy of schizophrenia. However, while antipsychotic drugs are routinely used in the therapeutics of schizophrenia, little is known about their effects on the densities of these receptors when they are administered for extended periods of time (a common practice in the clinical setting). In the present study in rats, the residual effects of prior chronic exposure to representative first generation antipsychotics and second generation antipsychotics on the densities of high affinity nicotinic acetylcholine receptors and muscarinic acetylcholine receptor in the brain were investigated. Test subjects were treated with the first generation antipsychotics, haloperidol (2.0 mg/kg/day) or chlorpromazine (10.0 mg/kg/day) or the second generation antipsychotics, risperidone (2.5 mg/kg/day) or olanzapine (10.0 mg/kg/day) in drinking water for periods of 90 or 180 days, given a drug-free washout period (i.e. returned to normal drinking water) for two weeks and then killed. Quantitative receptor autoradiography was subsequently performed using 16 μm sagittal slices of whole brain incubated with [ 3H]-epibatidine, [ 3H]-pirenzepine or [ 3H]-AFDX-384 to measure high affinity nicotinic acetylcholine receptors, M 1 and M 2 muscarinic acetylcholine receptors, respectively. The most notable experimental result was a moderate, but significant ( P<0.01) increase in [ 3H]-AFDX-384 binding sites in a number of brain regions (including cortex, hippocampus, subiculum, substantia innominata, and thalamus) associated with prior exposure to olanzapine for 90, but not 180 days. Olanzapine was also associated with a significantly higher density of [ 3H]-pirenzepine binding sites in cortex lamina I after 90 days of prior drug exposure. These data indicate that chronic treatment with a commonly used second generation antipsychotic, olanzapine is associated with modest increases in M 2 muscarinic acetylcholine receptors in memory-related brain regions that may eventually abate with longer periods of chronic drug exposure.

Bases neurofisiológicas da dependência do tabaco

It is generally accepted that nicotine is the major component in tobacco smoke responsible for addiction. Several studies have demonstrated that the neural mechanisms underlying nicotine addiction have much in common with those underlying the mechanisms of addiction to other drugs. Thus, it has been shown that nicotine induces conditioning place preference and self-administration across many species. Repeated treatment with nicotine also induces behavioral sensitization in rodents. These behavioral effects of nicotine seem to mediate through the meso limbic dopamine system. Smoke cessation results in an abstinence syndrome that seems to be mediated by both peripheral and central nicotinic acetylcholine receptors. In addition, other neurotransmitters systems are involved in the mediation of nicotine addiction and withdrawal. The review of the literature evidences the complexity of the behavioral, neurochemical and molecular effects of nicotine. The integration of nicotine studies across all levels will lead to a better understanding of the neurobiological mechanisms underlying the addictive actions of nicotine. The understanding of such mechanisms is crucial to the development of pharmacological agents for the treatment of tobacco addiction and withdrawal.

Characterization of nicotine's ability to serve as a negative feature in a Pavlovian appetitive conditioning task in rats

Pavlovian feature negative discriminations have been widely used to understand inhibitory conditioning processes using exteroceptive stimuli. Comparatively little is known about inhibitory conditioning processes using a drug state as a negative feature. A negative feature signals that presentation of a conditional stimulus (CS) will not be paired with an unconditioned stimulus. The present research examined whether nicotine served as a negative feature and started characterizing its properties. In acquisition, rats received intermixed saline and nicotine (0.4 mg/kg, base) sessions. On saline sessions, a 15-s light CS was paired with 4-s access to sucrose; the CS was presented on nicotine sessions, but sucrose was withheld. The discrimination was acquired with more goal tracking during the CS on saline sessions. Nicotine's inhibition of this conditioned response (CR) was sensitive to nicotine dose (ED50=0.225) and injection to testing interval (CR returned at 200 min). Mecamylamine pretreatment, but not hexamethonium, produced a loss of inhibitory control by nicotine suggesting a role for central nicotinic acetylcholine receptors. Amphetamine, bupropion, arecoline, and chlordiazepoxide, but not caffeine, substituted for the nicotine feature. However, in locomotor tests, amphetamine and bupropion increased activity; arecoline and chlordiazepoxide decreased activity. For this reason, the motor effects of these ligands could not be dissociated from substitution via shared stimulus properties. This feature negative task provides a preclinical model for studying how drug states inhibit responding, although identifying the process(es) mediating CR inhibition will require further research.