Skip to main content
    • Aa
    • Aa

Discrimination between cocaine-associated context and cue in a modified conditioned place preference paradigm: role of the nNOS gene in cue conditioning

  • Yossef Itzhak (a1) (a2), Concepción Roger-Sánchez (a3), Jonathan B. Kelley (a2) and Karen L. Anderson (a1)

The conditioned place preference (CPP) paradigm entails appetitive learning and is utilized to investigate the motivational effects of drug and natural reward in rodents. However, a typical CPP design does not allow dissociation between cue- and context-dependent appetitive learning. In humans, context and cues that had been associated with drug reward can elicit conditioned response and drug craving. Therefore, we investigated (a) methods by which to discriminate between cue- and context-dependent appetitive learning, and (b) the role of the neuronal nitric oxide synthase (nNOS) gene in appetitive learning. Wild-type (WT) and nNOS knockout (KO) mice were trained by cocaine (20 mg/kg) in a discrete context paired with a light cue (a compound context-cue stimulus). In test 1, approach behaviour to either the training context or to the cue in a novel context was determined. WT mice showed robust preference for both cocaine-associated context and cue. nNOS KO mice acquired approach behaviour for the cocaine-associated context but not cue. This finding suggests that the nNOS gene is required for cue-dependent appetitive learning. On the following day (test 2), mice were tested for approach behaviour to the compound context-cue stimulus. Context but not cue exposure in test 1 reduced approach behaviour to the compound context-cue stimulus in test 2, suggesting that repeated context but not cue exposures diminished the conditioned response. Hence, this modified CPP paradigm is useful for the investigation of approach behaviour for both drug-associated context and cue, and allows further investigation of mechanisms underlying cue- and context-dependent appetitive learning.

Corresponding author
Address for correspondence: Y. Itzhak, Ph.D., Department of Psychiatry and Behavioral Sciences, 1011 NW 15th Street, Gautier Building, Room 503, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Tel.: 305-243-4635Fax: 305-243-2989Email:
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.

O Arancio , I Antonova , S Gambaryan , SM Lohmann , (2001). Presynaptic role of cGMP-dependent protein kinase during long-lasting potentiation. Journal of Neuroscience 21, 143149.

HE Atallah , D Lopez-Paniagua , JW Rudy , RC O'Reilly (2007). Separate neural substrates for skill learning and performance in the ventral and dorsal striatum. Nature Neuroscience 10, 121136.

MA Balda , KL Anderson , Y Itzhak (2006). Adolescent and adult responsiveness to the incentive value of cocaine reward in mice: role of neuronal nitric oxide synthase (nNOS) gene. Neuropharmacology 51, 341349.

MA Balda , KL Anderson , Y Itzhak (2008). Differential role of the nNOS gene in the development of behavioral sensitization to cocaine in adolescent and adult B6;129S mice. Psychopharmacology 200, 509519.

MT Bardo , RA Bevins (2000). Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology 153, 3143.

D Belin , S Jonkman , A Dickinson , TW Robbins , (2009). Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction. Behavioral Brain Research 199, 89102.

RE Bernardi , KM Lattal , SP Berger (2006). Postretrieval propranolol disrupts a cocaine conditioned place preference. Neuroreport 17, 14431447.

ME Bouton (2004). Context and behavioral processes in extinction. Learning and Memory 11, 485494.

AR Childress , PD Mozley , W McElgin , J Fitzgerald , (1999). Limbic activation during cue-induced cocaine craving. American Journal of Psychiatry 156, 1118.

WL Chien , KC Liang , CM Teng , SC Kuo , (2003). Enhancement of long-term potentiation by a potent nitric oxide-guanylyl cyclase activator, 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole. Molecular Pharmacology 63, 13221328.

BJ Everitt , TW Robbins (2005). Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nature Neuroscience 8, 14811489.

PL Huang , TM Dawson , DS Bredt , SH Snyder , (1993). Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75, 12731286.

Y Itzhak (1997). Modulation of cocaine- and methamphetamine-induced behavioral sensitization by inhibition of brain nitric oxide synthase. Journal of Pharmacology and Experimental Therapeutics 282, 521527.

Y Itzhak , KL Anderson (2007). Memory reconsolidation of cocaine-associated context requires nitric oxide signaling. Synapse 61, 10021005.

Y Itzhak , KL Anderson (2008). Ethanol-induced behavioral sensitization in adolescent and adult mice: role of the nNOS gene. Alcoholism: Clinical and Experimental Research 32, 18391848.

Y Itzhak , JL Martin (2002). Cocaine-induced conditioned place preference in mice: induction, extinction and reinstatement by related psychostimulants. Neuropsychopharmacology 26, 130134.

Y Itzhak , JL Martin , MD Black , PL Huang (1998). The role of neuronal nitric oxide synthase in cocaine-induced conditioned place preference. Neuroreport 9, 24852488.

Y Itzhak , C Roger-Sanchez , KL Anderson (2009). Role of the nNOS gene in ethanol-induced conditioned place preference in mice. Alcohol 43, 285291.

JB Kelley , KL Anderson , Y Itzhak (2007). Long-term memory of cocaine-associated context: disruption and reinstatement. Neuroreport 18, 777780.

JB Kelley , MA Balda , KL Anderson , Y Itzhak (2009). Impairments in fear conditioning in mice lacking the nNOS gene. Learning and Memory 16, 371378.

Y Liu , B Le Foll , Y Liu , X Wang , (2008). Conditioned place preference induced by licit drugs: establishment, extinction, and reinstatement. Scientific World Journal 8, 12281245.

Y Matsumoto , S Unoki , H Aonuma , M Mizunami (2006). Critical role of nitric oxide-cGMP cascade in the formation of cAMP-dependent long-term memory. Learning and Memory 13, 3544.

MH Milekic , SD Brown , C Castellini , CM Alberini (2006). Persistent disruption of an established morphine conditioned place preference. Journal of Neuroscience 26, 30103020.

CA Miller , JF Marshall (2005). Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory. Neuron 47, 873884.

U Muller (2000). Prolonged activation of cAMP-dependent protein kinase during conditioning induces long-term memory in honeybees. Neuron 27, 159168.

DB Newlin (1992). A comparison of drug conditioning and craving for alcohol and cocaine. Recent Developments in Alcoholism 10, 147164.

JR Newton , C Ellsworth , T Miyakawa , S Tonegawa , (2004). Acceleration of visually cued conditioned fear through the auditory pathway. Nature Neuroscience 7, 968973.

D Puzzo , A Palmeri , O Arancio (2006). Involvement of the nitric oxide pathway in synaptic dysfunction following amyloid elevation in Alzheimer's disease. Reviews in the Neurosciences 17, 497523.

LB Resstel , FM Correa , FS Guimaraes (2008). The expression of contextual fear conditioning involves activation of an NMDA receptor-nitric oxide pathway in the medial prefrontal cortex. Cerebral Cortex 18, 20272035.

SJ Robbins , RN Ehrman , AR Childress , CP O'Brien (1999). Comparing levels of cocaine cue reactivity in male and female outpatients. Drug and Alcohol Dependence 53, 223230.

C Sanchis-Segura , R Spanagel (2006). Behavioural assessment of drug reinforcement and addictive features in rodents: an overview. Addiction Biology 11, 238.

GE Schafe , EP Bauer , S Rosis , CR Farb , (2005). Memory consolidation of Pavlovian fear conditioning requires nitric oxide signaling in the lateral amygdala. European Journal of Neuroscience 22, 201211.

TM Tzschentke (2007). Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addiction Biology 12, 227462.

E Valjent , AG Corbille , J Bertran-Gonzalez , D Herve , (2006). Inhibition of ERK pathway or protein synthesis during reexposure to drugs of abuse erases previously learned place preference. Proceedings of the National Academy of Sciences USA 103, 29322937.

NM White , GD Carr (1985). The conditioned place preference is affected by two independent reinforcement processes. Pharmacology, Biochemistry, and Behavior 23, 3742.

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? *