Skip to main content
    • Aa
    • Aa

Down-regulated striatal gene expression for synaptic plasticity-associated proteins in addiction and relapse vulnerable animals

  • Amanda L. Brown (a1), Jamie R. Flynn (a1), Doug W. Smith (a1) and Christopher V. Dayas (a1)
  • DOI:
  • Published online: 23 December 2010

Reducing the likelihood of relapse represents one of the greatest obstacles in the successful treatment of cocaine addiction. Dysregulation of the synaptic plasticity processes long-term potentiation (LTP) and long-term depression (LTD) is thought to be associated with protracted relapse risk. To improve our understanding of the molecular mechanisms contributing to relapse vulnerability we trained rats (n=52) to self-administer cocaine and phenotyped animals as relapse-vulnerable or relapse-resilient using procedures adapted from Deroche-Gamonet et al. (Science 2004, 305, 1014–1017). Gene expression analysis, targeted at synaptic plasticity-related genes, revealed significant transcript down-regulation in the ventral and dorsal striatum of relapse-vulnerable animals compared to relapse-resilient controls. This included reduced expression of genes encoding proteins implicated in the dendritic translation of synaptic plasticity-related transcripts, the dynamic regulation and trafficking of ionotropic glutamate receptors important for LTP and LTD, along with neuronal surface receptors that initiate downstream signalling pathways associated with synaptic plasticity. Together, our data are consistent with recent reports of an inability to evoke LTD in the striatum of addiction-vulnerable rats. To our knowledge, this is the first study to demonstrate down-regulated synaptic plasticity-associated gene expression not only in the ventral striatum, where the majority of addiction-related synaptic plasticity studies have been conducted, but also in the dorsal striatum of animals categorized as relapse-vulnerable. As these neural correlates were elucidated using an approach incorporating individual behavioural differences, they potentially provide more relevant insight into addiction and assist the development of novel pharmacotherapies to treat relapse.

Corresponding author
Address for correspondence: Dr C. V. Dayas, School of Biomedical Sciences and Pharmacy, Medical Sciences Building, University of Newcastle, Newcastle, NSW 2308, Australia. Tel.: +61249215618Fax: +61249 218667Email:
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.

SM Anderson , KR Famous , G Sadri-Vakili , V Kumaresan , (2008). CamkII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. Nature Neuroscience 11, 344353.

JC Anthony , LA Warner , RC Kessler (1994). Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the national comorbidity survey. Experimental and Clinical Psychopharmacology 2, 244268.

D Belin , E Balado , PV Piazza , V Deroche-Gamonet (2009). Pattern of intake and drug craving predict the development of cocaine addiction-like behavior in rats. Biological Psychiatry 65, 863868.

CR Bramham , MN Alme , M Bittins , SD Kuipers , (2010). The arc of synaptic memory. Experimental Brain Research 200, 125140.

CR Bramham , PF Worley , MJ Moore , JF Guzowski (2008). The immediate early gene arc/arg3.1: regulation, mechanisms, and function. Journal of Neuroscience 28, 1176011767.

SB Caine , GF Koob (1994). Effects of mesolimbic dopamine depletion on responding maintained by cocaine and food. Journal of the Experimental Analysis of Behavior 61, 213221.

D Centonze , B Picconi , P Gubellini , G Bernardi , (2001). Dopaminergic control of synaptic plasticity in the dorsal striatum. European Journal of Neuroscience 13, 10711077.

S Chowdhury , JD Shepherd , H Okuno , G Lyford , (2006). Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52, 445459.

KL Conrad , KY Tseng , JL Uejima , JM Reimers , (2008). Formation of accumbens Glur2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454, 118121.

A Contractor , SF Heinemann (2002). Glutamate receptor trafficking in synaptic plasticity. Science Signaling 2002, re14.

JW Dalley , TD Fryer , L Brichard , ES Robinson , (2007). Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315, 12671270.

V Deroche-Gamonet , D Belin , PV Piazza (2004). Evidence for addiction-like behavior in the rat. Science 305, 10141017.

DM Dietz , KC Dietz , EJ Nestler , SJ Russo (2009). Molecular mechanisms of psychostimulant-induced structural plasticity. Pharmacopsychiatry 42 (Suppl. 1), S69S78.

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

WM Freeman , KM Patel , RM Brucklacher , ME Lull , (2008). Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration. Neuropsychopharmacology 33, 18071817.

Y Fu , S Pollandt , J Liu , B Krishnan , (2007). Long-term potentiation (LTP) in the central amygdala (CEA) is enhanced after prolonged withdrawal from chronic cocaine and requires CRF1 receptors. Journal of Neurophysiology 97, 937941.

M Graziella De Montis , C Co , SI Dworkin , JE Smith (1998). Modifications of dopamine D1 receptor complex in rats self-administering cocaine. European Journal of Pharmacology 362, 915.

N Hay , N Sonenberg (2004). Upstream and downstream of mTOR. Genes & Development 18, 19261945.

MC Hearing , SW Miller , RE See , JF McGinty (2008 a). Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats. Psychopharmacology 198, 7791.

MC Hearing , RE See , JF McGinty (2008 b). Relapse to cocaine-seeking increases activity-regulated gene expression differentially in the striatum and cerebral cortex of rats following short or long periods of abstinence. Brain Structure and Function 213, 215227.

CA Hoeffer , E Klann (2010). mTOR signaling: at the crossroads of plasticity, memory and disease. Trends in Neurosciences 33, 6775.

SE Hyman (2005). Addiction: a disease of learning and memory. American Journal of Psychiatry 162, 14141422.

SE Hyman , RC Malenka , EJ Nestler (2006). Neural mechanisms of addiction: the role of reward-related learning and memory. Annual Reviews of Neuroscience 29, 565598.

E Izzo , R Martin-Fardon , GF Koob , F Weiss , (2002). Neural plasticity and addiction: PI3-kinase and cocaine behavioral sensitization. Nature Neuroscience 5, 12631264.

PW Kalivas (2009). The glutamate homeostasis hypothesis of addiction. Nature Reviews Neuroscience 10, 561572.

PW Kalivas , C O'Brien (2008). Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology 33, 166180.

F Kasanetz , V Deroche-Gamonet , N Berson , E Balado , (2010). Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science 328, 17091712.

S Kourrich , PE Rothwell , JR Klug , MJ Thomas (2007). Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens. Journal of Neuroscience 27, 79217928.

M Laplante , DM Sabatini (2009). mTOR signaling at a glance. Journal of Cell Science 122, 35893594.

C Luscher , KM Huber (2010). Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65, 445459.

P Luu , RC Malenka (2008). Spike timing-dependent long-term potentiation in ventral tegmental area dopamine cells requires PKC. Journal of Neurophysiology 100, 533538.

M Mameli , B Balland , R Lujan , C Luscher (2007). Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area. Science 317, 530533.

M Mameli , B Halbout , C Creton , D Engblom , (2009). Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAC. Nature Neuroscience 12, 10361041.

M Martin , BT Chen , FW Hopf , MS Bowers , (2006). Cocaine self-administration selectively abolishes LTD in the core of the nucleus accumbens. Nature Neuroscience 9, 868869.

R Martin-Fardon , MA Baptista , CV Dayas , F Weiss (2009). Dissociation of the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine] on conditioned reinstatement and reinforcement: comparison between cocaine and a conventional reinforcer. Journal of Pharmacology and Experimental Therapeutics 329, 10841090.

D Martinez , A Broft , RW Foltin , M Slifstein , (2004). Cocaine dependence and D2 receptor availability in the functional subdivisions of the striatum: relationship with cocaine-seeking behavior. Neuropsychopharmacology 29, 11901202.

RJ Moore , SL Vinsant , MA Nader , LJ Porrino , (1998). Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys. Synapse 30, 8896.

K Moussawi , A Pacchioni , M Moran , MF Olive , (2009). N-acetylcysteine reverses cocaine-induced metaplasticity. Nature Neuroscience 12, 182189.

MA Nader , JB Daunais , T Moore , SH Nader , (2002). Effects of cocaine self-administration on striatal dopamine systems in rhesus monkeys: initial and chronic exposure. Neuropsychopharmacology 27, 3546.

M Narita , H Akai , T Kita , Y Nagumo , (2005). Involvement of mitogen-stimulated p70-s6 kinase in the development of sensitization to the methamphetamine-induced rewarding effect in rats. Neuroscience 132, 553560.

G Page , FA Khidir , S Pain , L Barrier , (2006). Group I metabotropic glutamate receptors activate the p70s6 kinase via both mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK 1/2) signaling pathways in rat striatal and hippocampal synaptoneurosomes. Neurochemistry International 49, 413421.

RG Parsons , GM Gafford , FJ Helmstetter (2006). Translational control via the mammalian target of rapamycin pathway is critical for the formation and stability of long-term fear memory in amygdala neurons. Journal of Neuroscience 26, 1297712983.

JK Penberthy , N Ait-Daoud , M Vaughan , T Fanning (2010). Review of treatment for cocaine dependence. Current Drug Abuse Reviews 3, 4962.

RC Pierce , LJ Vanderschuren (2010). Kicking the habit: the neural basis of ingrained behaviors in cocaine addiction. Neuroscience Biobehavioral Reviews 35, 212219.

LJ Porrino , D Lyons , HR Smith , JB Daunais , (2004). Cocaine self-administration produces a progressive involvement of limbic, association, and sensorimotor striatal domains. Journal of Neuroscience 24, 35543562.

E Santini , M Heiman , P Greengard , E Valjent , (2009). Inhibition of mTOR signaling in parkinson's disease prevents L-dopa-induced dyskinesia. Science Signaling 2, ra36.

TD Schmittgen , KJ Livak (2008). Analyzing real-time PCR data by the comparative C(T) method. Nature Protocols 3, 11011108.

Y Serulle , S Zhang , I Ninan , D Puzzo , (2007). A GluR1-cGKII interaction regulates AMPA receptor trafficking. Neuron 56, 670688.

J Shi , W Jun , LY Zhao , YX Xue , (2009). Effect of rapamycin on cue-induced drug craving in abstinent heroin addicts. European Journal of Pharmacology 615, 108112.

L Slipczuk , P Bekinschtein , C Katche , M Cammarota , (2009). BDNF activates mTOR to regulate GluR1 expression required for memory formation. PLoS One 4, e6007.

MA Sutton , EF Schmidt , KH Choi , CA Schad , (2003). Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behavior. Nature 421, 7075.

MA Ungless , JL Whistler , RC Malenka , A Bonci (2001). Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411, 583587.

ND Volkow , JS Fowler , GJ Wang , R Hitzemann , (1993). Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14, 169177.

MW Waung , KM Huber (2009). Protein translation in synaptic plasticity: mGluRl-LTD, fragile X. Current Opinions in Neurobiology 19, 319326.

F Weiss (2005). Neurobiology of craving, conditioned reward and relapse. Current Opinions in Pharmacology 5, 919.

ME Wolf , CR Ferrario (2010). AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine. Neuroscience Biobehavioral Reviews 35, 185211.

AR Zavala , S Biswas , RE Harlan , JL Neisewander (2007). Fos and glutamate AMPA receptor subunit coexpression associated with cue-elicited cocaine-seeking behavior in abstinent rats. Neuroscience 145, 438452.

Recommend this journal

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

The 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? *


Type Description Title
Supplementary Materials

Brown Supplementary Material
Brown Supplementary Table and Figure Legend

 Unknown (47 KB)
47 KB
Supplementary Materials

Brown Supplementary Material
Brown Supplementary Figure 1

 Unknown (3.1 MB)
3.1 MB
Supplementary Materials

Brown Supplementary Material
Brown Supplementary Figure 2

 Unknown (7.3 MB)
7.3 MB
Supplementary Materials

Brown Supplementary Material
Brown Supplementary Figures 3 and 4

 Unknown (208 KB)
208 KB