Skip to main content
    • Aa
    • Aa
  • The International Journal of Neuropsychopharmacology, Volume 11, Issue 1
  • February 2008, pp. 63-70

Nicotine and clozapine effects on attentional performance impaired by the NMDA antagonist dizocilpine in female rats

  • Amir H. Rezvani (a1), Ehsan Kholdebarin (a1), Elizabeth Dawson (a1) and Edward D. Levin (a1)
  • DOI:
  • Published online: 13 February 2007

Cognitive impairment is very prevalent in schizophrenia and is currently undertreated in most patients. Attentional deficit is one of the hallmark symptoms of schizophrenia. Antipsychotic drugs, which can be quite effective in combating hallucinations are often ineffective in reducing cognitive impairment and can potentiate cognitive impairment. Previously, we found that the antipsychotic drug clozapine impaired, while nicotine improved, the accuracy of rats performing a visual signal detection attentional task in normal rats. For the current study, in a model of cognitive impairment of schizophrenia with the NMDA antagonist dizocilpine (0.05 mg/kg), we examined the effects of clozapine and nicotine on significantly impaired attentional hit accuracy. This dizocilpine-induced impairment was significantly (p<0.05) reversed by either clozapine (1.25 mg/kg) or nicotine (0.025 mg/kg). Interestingly, when clozapine and nicotine were given together, they blocked each other's beneficial effects. When the effective doses of 1.25 mg/kg clozapine and 0.025 mg/kg nicotine were given together the combination no longer significantly reversed the dizocilpine-induced hit-accuracy impairment. Given that the great majority of people with schizophrenia smoke, the potential beneficial effects of clozapine on attentional function may be largely blocked by self-administered nicotine. In addition, there are promising results concerning the development of nicotinic treatments to reverse cognitive deficits including attentional impairment. This is supported in the current study by the reversal of the dizocilpine-induced attentional impairment by nicotine. However, in schizophrenia the efficacy of nicotinic treatments may be limited by co-treatment with antipsychotic drugs like clozapine. It will be important to determine which of the complex effects of clozapine and nicotine are key in reversing attentional impairment and how they block each other's effects for the development of therapy to combat the attentional impairment of schizophrenia.

Corresponding author
Address for correspondence: A. H. Rezvani, Ph.D., Department of Psychiatry, Box 3412, Duke University Medical Center, Durham, NC 27710, USA. Tel.: (919) 668-1880Fax: (919) 681-3416E-mail:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

N Addy , ED Levin (2002). Nicotine interactions with haloperidol, clozapine and risperidone and working memory function in rats. Neuropsychopharmacology 27, 534541.

RM Bilder , RS Goldman , J Volavka , P Czobor , M Hoptman , B Sheitman , JP Lindenmayer , L Citrome , J McEvoy , M Kunz , (2002). Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. American Journal of Psychiatry 159, 10181028.

JD Brioni , DJ Kim , AB O'Neill , JE Williams , MW Decker (1994). Clozapine attenuates the discriminative stimulus properties of (-)-nicotine. Brain Research 643, 19.

P Bushnell (1998). Behavioral approaches to the assessment of attention in animals. Psychopharmacology 138, 231259.

PJ Bushnell , WM Oshiro , BK Padnos (1997). Detection of visual signals by rats: effects of chlordiazepoxide and cholinergic and adrenergic drugs on sustained attention. Psychopharmacology 134, 230241.

EF Domino , D Mirzoyan , H Tsukada (2004). N-methyl-d-aspartate antagonists as drug models of schizophrenia: a surprising link to tobacco smoking. Progress in Neuropsychopharmacology and Biological Psychiatry 28, 801811.

TP George , JC Vessicchio , A Termine , DM Sahady , CA Head , WT Pepper , TR Kosten , BE Wexler (2002). Effects of smoking abstinence on visuospatial working memory function in schizophrenia. Neuropsychopharmacology 26, 7585.

ED Levin , C Bettegowda , T Weaver , NC Christopher (1998). Nicotine-dizocilpine interactions and working and reference memory performance of rats in the radial-arm maze. Pharmacology, Biochemistry and Behavior 61, 335340.

ED Levin , L Icenogle , A Farzad (2005). Ketanserin interactions with nicotine and working memory function in rats. Pharmacology, Biochemistry and Behavior 82, 289292.

ED Levin , FJ McClernon , AH Rezvani (2006). Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology 184, 523539.

ED Levin , W Wilson , JE Rose , JP McEvoy (1996). Nicotine-haloperidol interactions and cognitive performance in schizophrenics. Neuropsychopharmacology 15, 429436.

JB Lohr , K Flynn (1992). Smoking and schizophrenia. Schizophrenia Research 8, 93102.

LF Martin , WR Kem , R Freedaman (2004). Alpha-7 nicotinic receptor agonists: Potential new candidates for the treatment of schizophrenia. Psychopharmacology 174, 5464.

JP McEvoy , O Freudenreich , WH Wilson (1999). Smoking and therapeutic response to clozapine in patients with schizophrenia. Biological Psychiatry 46, 125129.

J McGaughy , MW Decker , M Sarter (1999). Enhancement of sustained attention performance by the nicotinic acetylcholine receptor agonist abt-418 in intact but not basal forebrain-lesioned rats. Psychopharmacology 144, 175182.

J McGaughy , T Kaiser , M Sarter (1996). Behavioral vigilance following infusions of 192 IgG-Sapoin into the basal forebrain: selectivity of the behavioral impairment and relation to cortical ACH-positive fiber density. Behavioral Neuroscience 110, 247265.

NR Mirza , JL Bright (2001). Nicotine-induced enhancements in the five-choice serial reaction time task in rats are strain-dependent. Psychopharmacology 154, 812.

NR Mirza , Q Pei , IP Stolerman , TSC Zetterstrom (1996). The nicotinic receptor agonists (-)nicotine and isoarecolone differ in their effects on dopamine release in the nucleus accumbens. European Journal of Pharmacology 295, 207210.

S Miyamoto , G Duncan , D Goff , J Lieberman (2002). Therapeutics of schizophrenia. In: KL Davis , D Charney , JT Coyle , C Nemoroff (Eds.), Neuropsychopharmacology: The Fifth Generation of Progress (pp. 775807). New York: Raven Press.

AH Rezvani , PJ Bushnell , JM Burkholder , HB Glasgow , ED Levin (2001). Specificity of cognitive impairment from pfiesteria piscicida exposure in rats: attention and visual function vs. Behavioral plasticity. Neurotoxicology and Teratology 23, 609616.

AH Rezvani , PJ Bushnell , ED Levin (2002). Nicotine and mecamylamine effects on choice accuracy in an operant signal detection task. Psychopharmacology 164, 369375.

AH Rezvani , DP Caldwell , ED Levin (2004). Nicotine-antipsychotic drug interactions and attentional performance in female rats. European Journal of Pharmacology 486, 175182.

AH Rezvani , DP Caldwell , ED Levin (2005). Nicotinic-serotonergic drug interactions and attentional performance in rats. Psychopharmacology 179, 521528.

AH Rezvani , DP Caldwell , ED Levin (2006). Chronic nicotine interaction with clozapine and risperidone and attentional function in rats. Progress in Neuro-Psychopharmacology & Biological Psychiatry 30, 190197.

AH Rezvani , ED Levin (2003a). Nicotine interactions with the NMDA glutaminergic antagonist dizocilpine and attentional function. European Journal of Pharmacology 465, 8390.

AH Rezvani , ED Levin (2003b). Nicotine-alcohol interactions and attentional performance on an operant visual signal detection task in female rats. Pharmacology, Biochemistry and Behavior 76, 7583.

M Sarter , B Givens , JP Bruno (2001). The cognitive neuroscience of sustained attention: where top-down meets bottom-up. Brain Research. Brain Research Reviews 35, 146160.

GW Snedecor , WG Cochran (1967). Statistical Methods. Iowa State University Press, Ames, Iowa.

IP Stolerman , NR Mirza , B Hahn , M Shoaib (2000). Nicotine in an animal model of attention. European Journal of Pharmacology 393, 147154.

J Turchi , LA Holley , M Sarter (1995). Effects of nicotinic acetylcholine receptor ligands on behavioral vigilance in rats. Psychopharmacology 118, 195205.

HK White , ED Levin (1999). Chronic four week nicotine skin patch treatment effects on cognitive performance in Alzheimer's disease. Psychopharmacology 143, 158165.

HK White , ED Levin (2004). Chronic transdermal nicotine patch treatment effects on cognitive performance in age-associated memory impairment. Psychopharmacology 171, 465471.

S Wonnacott , J Irons , C Rapier , B Thorne , GG Lunt (1989). Presynaptic modulation of transmitter release by nicotinic receptors. In: A Nordberg , K Fuxe , B Holmstedt , A Sundwall (Eds.), Progress in Brain Research (pp. 157163). New York: Elsevier Science Publishers BV.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The International Journal of Neuropsychopharmacology
  • ISSN: 1461-1457
  • EISSN: 1469-5111
  • URL: /core/journals/the-international-journal-of-neuropsychopharmacology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *