Skip to main content

Advertisement

SpringerLink
Log in

The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Background

Alpha7 and α4β2 nicotinic acetylcholine receptor (nAChR) agonists have been shown to improve cognition in various animal models of cognitive impairment and are of interest as treatments for schizophrenia, Alzheimer’s disease, and other cognitive disorders. Increased release of dopamine (DA), acetylcholine (ACh), glutamate (Glu), and γ-aminobutyric acid (GABA) in cerebral cortex, hippocampus, and nucleus accumbens (NAC) has been suggested to contribute to their beneficial effects on cognition.

Results

Using in vivo microdialysis, we found that EVP-6124 [(R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide], a high-affinity α7 nAChR partial agonist, at 0.1 mg/kg, s.c., increased DA efflux in the medial prefrontal cortex (mPFC) and NAC. EVP-6124, 0.1 and 0.3 mg/kg, also increased efflux of ACh in the mPFC but not in the NAC. Similarly, EVP-6124, 0.1 mg/kg, but not 0.03 and 0.3 mg/kg, significantly increased mPFC Glu efflux. Thus, EVP-6124 produced an inverted U-shaped curve for DA and Glu release, as previously reported for other α7 nAChR agonists. The three doses of EVP-6124 did not produce a significant effect on GABA efflux in either region. Pretreatment with the selective α7 nAChR antagonist, methyllycaconitine (MLA, 1.0 mg/kg), significantly blocked cortical DA and Glu efflux induced by EVP-6124 (0.1 mg/kg), suggesting that the effects of EVP-6124 on these neurotransmitters were due to α7 nAChR agonism. MLA only partially blocked the effects of EVP-6124 on ACh efflux in the mPFC.

Conclusion

These results suggest increased cortical DA, ACh, and Glu release, which may contribute to the ability of the α7 nAChR agonist, EVP-6124, to treat cognitive impairment and possibly other dimensions of psychopathology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Arnold HM, Nelson CL, Sarter M, Bruno JP (2003) Sensitization of cortical acetylcholine release by repeated administration of nicotine in rats. Psychopharmacology (Berl) 165(4):346–358

    CAS  Google Scholar 

  • Arvanov VL, Wang RY (1998) M100907, a selective 5-HT2A receptor antagonist and a potential antipsychotic drug, facilitates N-methyl-d-aspartate-receptor mediated neurotransmission in the rat medial prefrontal cortical neurons in vitro. Neuropsychopharmacology 18(3):197–209

    Article  CAS  PubMed  Google Scholar 

  • Arvanov VL, Liang X, Schwartz J, Grossman S, Wang RY (1997) Clozapine and haloperidol modulate N-methyl-d-aspartate- and non-N-methyl-d-aspartate receptor-mediated neurotransmission in rat prefrontal cortical neurons in vitro. J Pharmacol Exp Ther 283(1):226–234

    CAS  PubMed  Google Scholar 

  • Biton B, Bergis OE, Galli F, Nedelec A, Lochead AW, Jegham S, Godet D, Lanneau C, Santamaria R, Chesney F, Léonardon J, Granger P, Debono MW, Bohme GA, Sgard F, Besnard F, Graham D, Coste A, Oblin A, Curet O, Vigé X, Voltz C, Rouquier L, Souilhac J, Santucci V, Gueudet C, Françon D, Steinberg R, Griebel G, Oury-Donat F, George P, Avenet P, Scatton B (2007) SSR180711, a novel selective α7 nicotinic receptor partial agonist: (I) binding and functional profile. Neuropsychopharmacology 32(1):1–16

    Article  CAS  PubMed  Google Scholar 

  • Boess FG, De Vry J, Erb C, Flessner T, Hendrix M, Luithle J, Methfessel C, Riedl B, Schnizler K, van der Staay FJ, van Kampen M, Wiese WB, Koenig G (2007) The novel α7 nicotinic acetylcholine receptor agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide improves working and recognition memory in rodents. J Pharmacol Exp Ther 321(2):716–725

    Article  CAS  PubMed  Google Scholar 

  • Bortz DM, Mikkelsen JD, Bruno JP (2013) Localized infusions of the partial alpha 7 nicotinic receptor agonist SSR180771 evoke rapid and transient increases in prefrontal glutamate release. Neuroscience 255:55–67

    Article  CAS  PubMed  Google Scholar 

  • Bourdelais AJ, Deutch AY (1994) The effects of haloperidol and clozapine on extracellular GABA levels in the prefrontal cortex of the rat: an in vivo microdialysis study. Cereb Cortex 4(1):69–77

    Article  CAS  PubMed  Google Scholar 

  • Burton S (2006) Symptom domains of schizophrenia: the role of atypical antipsychotic agents. J Psychopharmacol 20(6 Suppl):6–19

    Article  PubMed  Google Scholar 

  • Callahan PM, McNicholas KL, Ilch C, Rowe WB, Brucato FA, Kogan JH, Rose GM (2003) Characterization of nicotinic α7 receptor agonists in animal models of cognition. Society for Neuroscience 2003 Annual Meeting, 615: 8/CC4

  • Chen JP, van Praag HM, Gardner EL (1991) Activation of 5-HT3 receptor by 1-phenylbiguanide increases dopamine release in the rat nucleus accumbens. Brain Res 543(2):354–357

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Yamada K, Nabeshima T, Sokabe M (2006) Alpha7 nicotinic acetylcholine receptor as a target to rescue deficit in hippocampal LTP induction in beta-amyloid infused rats. Neuropharmacology 50(2):254–268

    Article  CAS  PubMed  Google Scholar 

  • Costall B, Naylor RJ (2004) 5-HT3 receptors. Curr Drug Targets CNS Neurol Disord 3(1):27–37

    Article  CAS  PubMed  Google Scholar 

  • Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26(4–6):365–384

    CAS  PubMed  Google Scholar 

  • Daly DA, Moghaddam B (1993) Actions of clozapine and haloperidol on the extracellular levels of excitatory amino acids in the prefrontal cortex and striatum of conscious rats. Neurosci Lett 152(1–2):61–64

    Article  CAS  PubMed  Google Scholar 

  • Désaméricq G, Schurhoff F, Meary A, Szöke A, Macquin-Mavier I, Bachoud-Lévi AC, Maison P (2014) Long-term neurocognitive effects of antipsychotics in schizophrenia: a network meta-analysis. Eur J Clin Pharmacol 70(2):127–134

    Article  PubMed  Google Scholar 

  • Di Matteo V, Pierucci M, Esposito E (2004) Selective stimulation of serotonin2c receptors blocks the enhancement of striatal and accumbal dopamine release induced by nicotine administration. J Neurochem 89(2):418–429

    Article  PubMed  Google Scholar 

  • Diez-Ariza M, Garcia-Alloza M, Lasheras B, Del Rio J, Ramirez MJ (2002) GABA(A) receptor antagonists enhance cortical acetylcholine release induced by 5-HT(3) receptor blockade in freely moving rats. Brain Res 956(1):81–85

    Article  CAS  PubMed  Google Scholar 

  • Farber L, Haus U, Spath M, Drechsler S (2004) Physiology and pathophysiology of the 5-HT3 receptor. Scand J Rheumatol 119(Suppl):2–8

    Article  CAS  Google Scholar 

  • Freedman R, Goldowitz D (2010) Studies on the hippocampal formation: from basic development to clinical applications: studies on schizophrenia. Prog Neurobiol 90(2):263–275

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gioanni Y, Rougeot C, Clarke PB, Lepousé C, Thierry AM, Vidal C (1999) Nicotinic receptors in the rat prefrontal cortex: increase in glutamate release and facilitation of mediodorsal thalamo-cortical transmission. Eur J Neurosci 11(1):18–30

    Article  CAS  PubMed  Google Scholar 

  • Giovannini MG, Ceccarelli I, Molinari B, Cecchi M, Goldfarb J, Blandina P (1998) Serotonergic modulation of acetylcholine release from cortex of freely moving rats. J Pharmacol Exp Ther 285(3):1219–1925

    CAS  PubMed  Google Scholar 

  • Gurley DA, Lanthorn TH (1998) Nicotinic agonists competitively antagonize serotonin at mouse 5-HT3 receptors expressed in Xenopus ooctyes. Neurosci Lett 247(2–3):107–110

    Article  CAS  PubMed  Google Scholar 

  • Heresco-Levy U (2005) Glutamatergic neurotransmission modulators as emerging new drugs for schizophrenia. Expert Opin Emerg Drugs 10:827–844

    Article  CAS  PubMed  Google Scholar 

  • Huang M, Felix AR, Kwon S, Lowe D, Wallace T, Santarelli L, Meltzer HY (2014a) The alpha-7 nicotinic receptor partial agonist/5-HT3 antagonist RG3487 enhances cortical and hippocampal dopamine and acetylcholine release. Psychopharmacology (Berl). 231(10):2199–2210. doi:10.1007/s00213-013-3373-5

  • Huang M, Panos JJ, Kwon S, Oyamada Y, Rajagopal L, Meltzer HY (2014b) Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5-HT)2A and DA D2 antagonism and 5-HT1A partial agonism. J Neurochem 128(6):938–949

  • Ichikawa J, Dai J, O’Laughlin IA, Fowler WL, Meltzer HY (2002) Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine efflux without an effect in the nucleus accumbens or striatum. Neuropsychopharmacology 26:325–339

    Article  CAS  PubMed  Google Scholar 

  • Kashkin VA, De Witte P (2005) Nicotine increases microdialysate brain amino acid concentrations and induces conditioned place preference. Eur Neuropsychopharmacol 15(6):625–632

    Article  CAS  PubMed  Google Scholar 

  • Kurata K, Ashby CR Jr, Oberlender R, Tanii Y, Kurachi M, Rini NJ, Strecker RE (1996) The characterization of the effect of locally applied N-methylquipazine, a 5-HT3 receptor agonist, on extracellular dopamine levels in the anterior medial prefrontal cortex in the rat: an in vivo microdialysis study. Synapse 24(4):313–321

    Article  CAS  PubMed  Google Scholar 

  • Kuroki T, Meltzer HY, Ichikawa J (1999) Effects of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens. J Pharmacol Exp Ther 288:774–781

    CAS  PubMed  Google Scholar 

  • Leiser SC, Bowlby MR, Comery TA, Dunlop J (2009) A cog in cognition: how the alpha 7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits. Pharmacol Ther 122(3):302–311

    Article  CAS  PubMed  Google Scholar 

  • Levin ED, McClernon FJ, Rezvani AH (2006) Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl) 184(3–4):523–539

    Article  CAS  Google Scholar 

  • Lieberman JA, Dunbar G, Segreti AC, Girgis RR, Seoane F, Beaver JS, Duan N, Hosford DA (2013) A randomized exploratory trial of an alpha-7 nicotinic receptor agonist (TC-5619) for cognitive enhancement in schizophrenia. Neuropsychopharmacology 38(6):968–975

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liu Q, Li Z, Ding JH, Liu SY, Wu J, Hu G (2006) Iptakalim inhibits nicotine-induced enhancement of extracellular dopamine and glutamate levels in the nucleus accumbens of rats. Brain Res 1085(1):138–143

    Article  CAS  PubMed  Google Scholar 

  • Livingstone PD, Dickinson JA, Srinivasan J, Kew JN, Wonnacott S (2010) Glutamate-dopamine crosstalk in the rat prefrontal cortex is modulated by alpha7 nicotinic receptors and potentiated by PNU-120596. J Mol Neurosci 40(1–2):172–176

    Article  CAS  PubMed  Google Scholar 

  • Maricq AV, Peterson AS, Brake AJ, Myers RM, Julius D (1991) Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Science 254(5030):432–437

    Article  CAS  PubMed  Google Scholar 

  • Martin LF, Kem WR, Freedman R (2004) Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. Psychopharmacology (Berl) 174:54–64

    Article  CAS  Google Scholar 

  • Maura G, Andrioli GC, Cavazzani P, Raiteri M (1992) 5-Hydroxytryptamine3 receptors sited on cholinergic axon terminals of human cerebral cortex mediate inhibition of acetylcholine release. J Neurochem 58(6):2334–2337

    Article  CAS  PubMed  Google Scholar 

  • Meltzer HY, Huang M (2008) In vivo actions of atypical antipsychotic drug on serotonergic and dopaminergic systems. Prog Brain Res 72:177–197

    Article  Google Scholar 

  • Mylecharane EJ (1996) Ventral tegmental area 5-HT receptors: mesolimbic dopamine release and behavioural studies. Behav Brain Res 73(1–2):1–5

    CAS  PubMed  Google Scholar 

  • O’Neill HC, Rieger K, Kem WR, Stevens KE (2003) DMXB, an alpha7 nicotinic agonist, normalizes auditory gating in isolation-reared rats. Psychopharmacology (Berl) 169(3–4):332–339

    Article  Google Scholar 

  • Obinu MC, Reibaud M, Miquet JM, Pasquet M, Rooney T (2002) Brain-selective stimulation of nicotinic receptors by TC-1734 enhances ACh transmission from frontoparietal cortex and memory in rodents. Prog Neuropsychopharmacol Biol Psychiatry 26(5):913–918

    Article  CAS  PubMed  Google Scholar 

  • Pasumarthi RK, Fadel J (2010) Stimulation of lateral hypothalamic glutamate and acetylcholine efflux by nicotine: implications for mechanisms of nicotine-induced activation of orexin neurons. J Neurochem 113(4):1023–1035

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic, New York

    Google Scholar 

  • Pichat P, Bergis OE, Terranova JP, Urani A, Duarte C, Santucci V, Gueudet C, Voltz C, Steinberg R, Stemmelin J, Oury-Donat F, Avenet P, Griebel G, Scatton B (2007) SSR180711, a novel selective α7 nicotinic receptor partial agonist: (II) efficacy in experimental models predictive of activity against cognitive symptoms of schizophrenia. Neuropsychopharmacology 32(1):17–34

    Article  CAS  PubMed  Google Scholar 

  • Preskorn SH, Gawryl M, Dgetluck N, Palfreyman M, Bauer LO, Hilt DC (2014) Normalizing effects of EVP-6124, an alpha-7 nicotinic partial agonist, on event-related potentials and cognition: a proof of concept, randomized trial in patients with schizophrenia. J Psychiatr Pract 20(1):12–24

    Article  PubMed  Google Scholar 

  • Prickaerts J, van Goethem NP, Chesworth R, Shapiro G, Boess FG, Methfessel C, Reneerkens OAH, Flood DG, Hilt D, Gawryl M, Bertrand S, Bertrand D, König G (2012) EVP-6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors. Neuropharmacology 62(2):1099–1110

    Article  CAS  PubMed  Google Scholar 

  • Reid RT, Lloyd GK, Rao TS (1999) Pharmacological characterization of nicotine-induced acetylcholine release in the rat hippocampus in vivo: evidence for a permissive dopamine synapse. Br J Pharmacol 127(6):1486–1494

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Reid MS, Fox L, Ho LB, Berger SP (2000) Nicotine stimulation of extracellular glutamate levels in the nucleus accumbens: neuropharmacological characterization. Synapse 35(2):129–136

    Article  CAS  PubMed  Google Scholar 

  • Rossi S, Singer S, Shearman E, Sershen H, Lajtha A (2005) The effects of cholinergic and dopaminergic antagonists on nicotine-induced cerebral neurotransmitter changes. Neurochem Res 30(4):541–558

    Article  CAS  PubMed  Google Scholar 

  • Schilström B, Fagerquist MV, Zhang X, Hertel P, Panagis G, Nomikos GG, Svensson TH (2000) Putative role of presynaptic alpha7* nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area. Synapse 38(4):375–383

    Article  PubMed  Google Scholar 

  • Singer S, Rossi S, Verzosa S, Hashim A, Lonow R, Cooper T, Sershen H, Lajtha A (2004) Nicotine-induced changes in neurotransmitter levels in brain areas associated with cognitive function. Neurochem Res 29(9):1779–1792

    Article  CAS  PubMed  Google Scholar 

  • Summers KL, Kem WR, Giacobini E (1997) Nicotinic agonist modulation of neurotransmitter levels in the rat frontoparietal cortex. Jpn J Pharmacol 74(2):139–146

    Article  CAS  PubMed  Google Scholar 

  • Tani Y, Saito K, Imoto M, Ohno T (1998) Pharmacological characterization of nicotinic receptor-mediated acetylcholine release in rat brain—an in vivo microdialysis study. Eur J Pharmacol 351(2):181–188

    Article  CAS  PubMed  Google Scholar 

  • Thompson AJ, Lummis SCR (2007) The 5-HT3 receptor as a therapeutic target. Expert Opin Ther Targets 11(4):527–540

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Thomsen MS, Hansen HH, Timmerman DB, Mikkelsen JD (2010) Cognitive improvement by activation of alpha7 nicotinic acetylcholine receptors: from animal models to human pathophysiology. Curr Pharm Des 16(3):323–343

    Article  CAS  PubMed  Google Scholar 

  • Toth E (1996) Effect of nicotine on the level of extracellular amino acids in the hippocampus of rat. Neurochem Res 21(8):903–907

    Article  CAS  PubMed  Google Scholar 

  • Wallace TL, Callahan PM, Tehim A, Bertrand D, Tombaugh G, Wang XW, Rowe WB, Ong V, Graham E, Terry AV Jr, Rodefer JS, Herbert B, Murray M, Porter R, Santarelli L, Lowe DA (2011) RG3487, a novel nicotinic α7 receptor partial agonist, improves cognition and sensorimotor gating in rodents. J Pharmacol Exp Ther 336(1):242–253

    Article  CAS  PubMed  Google Scholar 

  • Woodward ND, Purdon SE, Meltzer HY, Zald DH (2005) A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol 8(3):457–472

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto BK, Pehek EA, Meltzer HY (1994) Brain region effects of clozapine on amino acid and monoamine transmission. J Clin Psychiatry 55(Suppl B):8–14

    PubMed  Google Scholar 

  • Zanaletti R, Bettinetti L, Castaldo C, Cocconcelli G, Comery T, Dunlop J, Gaviraghi G, Ghiron C, Haydar SN, Jow F, Maccari L, Micco I, Nencini A, Scali C, Turlizzi E, Valacchi M (2012) Discovery of a novel alpha-7 nicotinic acetylcholine receptor agonist series and characterization of the potent, selective, and orally efficacious agonist 5-(4-acetyl[1,4]diazepan-1-yl)pentanoic acid [5-(4-methoxyphenyl)-1H-pyrazol-3-yl] amide (SEN15924, WAY-361789). J Med Chem 55(10):4806–4823

    Article  CAS  PubMed  Google Scholar 

  • Zoheir N, Lappin DF, Nile CJ (2012) Acetylcholine and the alpha 7 nicotinic receptor: a potential therapeutic target for the treatment of periodontal disease? Inflamm Res 61(9):915–926

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by FORUM Pharmaceuticals, Inc. The authors thank Dr. Karu Jayathilake at Vanderbilt University, Nashville, TN for his statistics support.

Conflicts of interest

Herbert Y. Meltzer is a stockholder of ACADIA and SureGene. He is, or has been, a consultant to ACADIA, Alkermes, Astellas, Boehringer Mannheim, Bristol Myers Squibb, BioLine Rx, Cephalon, Cypress, Dainippon Sumitomo, Eli Lilly, FORUM, Janssen, Lundbeck, Merck, Novartis, Ovation, Otsuka, Pfizer, Sunovion, Teva, and Valeant (BioVail); Dorothy G. Flood, Chaya Bhuvaneswaran, Dana Hilt, and Gerhard Koenig are employees of FORUM Pharmaceutical Inc.; Mei Huang and Anna R Felix do not have any conflicts of interests.

Author information

Author notes

  1. Mei Huang & Herbert Y. Meltzer

    Present address: Department of Psychiatry and Behavioral Science, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Ward Building 12-104, Chicago, IL, 60611, USA

Authors and Affiliations

  1. Division of Psychopharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37212, USA

    Mei Huang, Anna R. Felix & Herbert Y. Meltzer

  2. FORUM Pharmaceuticals Inc., Watertown, MA, 02472, USA

    Dorothy G. Flood, Chaya Bhuvaneswaran, Dana Hilt & Gerhard Koenig

Authors
  1. Mei Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna R. Felix
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dorothy G. Flood
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chaya Bhuvaneswaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dana Hilt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gerhard Koenig
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Herbert Y. Meltzer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Herbert Y. Meltzer.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, M., Felix, A.R., Flood, D.G. et al. The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens. Psychopharmacology 231, 4541–4551 (2014). https://doi.org/10.1007/s00213-014-3596-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-014-3596-0

Keywords

Search

Navigation