, Volume 236, Issue 1, pp 479–490 | Cite as

Attenuation of cocaine seeking in rats via enhancement of infralimbic cortical activity using stable step-function opsins

  • Victória A. Müller EwaldEmail author
  • Benjamin J. De Corte
  • Subhash C. Gupta
  • Katherine V. Lillis
  • Nandakumar S. Narayanan
  • John A. Wemmie
  • Ryan T. LaLumiere
Original Investigation



The infralimbic cortex (IL) and its downstream projection target the nucleus accumbens shell (NAshell) mediate the active suppression of cocaine-seeking behavior. Although an optogenetic approach would be beneficial for stimulating the IL and its efferents to study their role during reinstatement of cocaine seeking, the use of channelrhodopsin introduces significant difficulties, as optimal stimulation parameters are not known.


The present experiments utilized a stable step-function opsin (SSFO) to potentiate endogenous activity in the IL and in IL terminals in the NAshell during cocaine-seeking tests to determine how these manipulations affect cocaine-seeking behaviors.


Rats first underwent 6-h access cocaine self-administration followed by 21–27 days in the homecage. Rats then underwent cue-induced and cocaine-primed drug-seeking tests during which the optogenetic manipulation was given. The same rats then underwent extinction training, followed by cue-induced and cocaine-primed reinstatements.


Potentiation of endogenous IL activity did not significantly alter cue-induced or cocaine-primed drug seeking following the homecage period. However, following extinction training, enhancement of endogenous IL activity attenuated cue-induced reinstatement by 35% and cocaine-primed reinstatement by 53%. Stimulation of IL terminals in the NAshell did not consistently alter cocaine-seeking behavior.


These results suggest the utility of an SSFO-based approach for enhancing activity in a structure without driving specific patterns of neuronal firing. However, the utility of an SSFO-based approach for axon terminal stimulation remains unclear. Moreover, these results suggest that the ability of the IL to reduce cocaine seeking depends, at least in part, on rats first having undergone extinction training.


Optogenetics Channelrhodopsin Reinstatement Incubation of craving Cocaine seeking 



R.T.L was supported by National Institute of Health R01 DA034684. J.A.W. was supported by the Department of Veterans Affairs (Merit Award), National Institute on Drug Abuse R01 DA037216, National Heart, Lung and Blood Institute R01 HL113863, and the Carver Foundation. N.S.N. was supported by National Institute of Health R01 NS089470.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

Supplementary material

213_2018_4964_Fig5_ESM.png (234 kb)

(PNG 234 kb)

213_2018_4964_MOESM1_ESM.eps (1.2 mb)
High resolution image (EPS 1236 kb)
213_2018_4964_Fig6_ESM.png (107 kb)

(PNG 107 kb)

213_2018_4964_MOESM2_ESM.eps (1.1 mb)
High resolution image (EPS 1081 kb)
213_2018_4964_Fig7_ESM.png (108 kb)

(PNG 107 kb)

213_2018_4964_MOESM3_ESM.eps (1.1 mb)
High resolution image (EPS 1100 kb)
213_2018_4964_Fig8_ESM.png (112 kb)

(PNG 111 kb)

213_2018_4964_MOESM4_ESM.eps (1.1 mb)
High resolution image (EPS 1091 kb)
213_2018_4964_Fig9_ESM.png (145 kb)

(PNG 144 kb)

213_2018_4964_MOESM5_ESM.eps (1.1 mb)
High resolution image (EPS 1099 kb)
213_2018_4964_MOESM6_ESM.docx (63 kb)
ESM 6 (DOCX 63 kb)


  1. Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science (New York, NY) 282:298–300CrossRefGoogle Scholar
  2. Augur IF, Wyckoff AR, Aston-Jones G, Kalivas PW, Peters J (2016) Chemogenetic activation of an extinction neural circuit reduces cue-induced reinstatement of cocaine seeking. J Neurosci 36:10174–10180CrossRefGoogle Scholar
  3. Beshel J, Kopell N, Kay LM (2007) Olfactory bulb gamma oscillations are enhanced with task demands. J Neurosci 27:8358–8365CrossRefGoogle Scholar
  4. Di Chiara G (2002) Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res 137:75–114CrossRefGoogle Scholar
  5. Donnelly NA, Holtzman T, Rich PD, Nevado-Holgado AJ, Fernando AB, Van Dijck G, Holzhammer T, Paul O, Ruther P, Paulsen O, Robbins TW, Dalley JW (2014) Oscillatory activity in the medial prefrontal cortex and nucleus accumbens correlates with impulsivity and reward outcome. PLoS One 9:e111300CrossRefGoogle Scholar
  6. Fries P, Nikolic D, Singer W (2007) The gamma cycle. Trends Neurosci 30:309–316CrossRefGoogle Scholar
  7. Fries P, Reynolds JH, Rorie AE, Desimone R (2001) Modulation of oscillatory neuronal synchronization by selective visual attention. Science (New York, NY) 291:1560–1563CrossRefGoogle Scholar
  8. Gorelova N, Yang CR (1997) The course of neural projection from the prefrontal cortex to the nucleus accumbens in the rat. Neuroscience 76:689–706CrossRefGoogle Scholar
  9. Gutman AL, Nett KE, Cosme CV, Worth WR, Gupta SC, Wemmie JA, LaLumiere RT (2017) Extinction of cocaine seeking requires a window of infralimbic pyramidal neuron activity after unreinforced lever presses. J Neurosci 37:6075–6086CrossRefGoogle Scholar
  10. Huff ML, Emmons EB, Narayanan NS, LaLumiere RT (2016) Basolateral amygdala projections to ventral hippocampus modulate the consolidation of footshock, but not contextual, learning in rats. Learn Mem (Cold Spring Harbor, NY) 23: 51–60Google Scholar
  11. Huff ML, Miller RL, Deisseroth K, Moorman DE, LaLumiere RT (2013) Posttraining optogenetic manipulations of basolateral amygdala activity modulate consolidation of inhibitory avoidance memory in rats. Proc Natl Acad Sci U S A 110:3597–3602CrossRefGoogle Scholar
  12. Kelley AE (2004) Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning. Neurosci Biobehav Rev 27:765–776CrossRefGoogle Scholar
  13. LaLumiere RT, Niehoff KE, Kalivas PW (2010) The infralimbic cortex regulates the consolidation of extinction after cocaine self-administration. Learn Mem (Cold Spring Harbor, NY) 17:168–175CrossRefGoogle Scholar
  14. LaLumiere RT, Smith KC, Kalivas PW (2012) Neural circuit competition in cocaine-seeking: roles of the infralimbic cortex and nucleus accumbens shell. Eur J Neurosci 35:614–622CrossRefGoogle Scholar
  15. Lenoir M, Guillem K, Koob GF, Ahmed SH (2012) Drug specificity in extended access cocaine and heroin self-administration. Addict Biol 17:964–976CrossRefGoogle Scholar
  16. Liu Z, Wang Y, Cai L, Li Y, Chen B, Dong Y, Huang YH (2016) Prefrontal cortex to accumbens projections in sleep regulation of reward. J Neurosci 36:7897–7910CrossRefGoogle Scholar
  17. Ma YY, Lee BR, Wang X, Guo C, Liu L, Cui R, Lan Y, Balcita-Pedicino JJ, Wolf ME, Sesack SR, Shaham Y, Schluter OM, Huang YH, Dong Y (2014) Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections. Neuron 83:1453–1467CrossRefGoogle Scholar
  18. Muller Ewald VA, LaLumiere RT (2017) Neural systems mediating the inhibition of cocaine-seeking behaviors. Pharmacol Biochem BehavGoogle Scholar
  19. Pesaran B, Pezaris JS, Sahani M, Mitra PP, Andersen RA (2002) Temporal structure in neuronal activity during working memory in macaque parietal cortex. Nat Neurosci 5:805–811CrossRefGoogle Scholar
  20. Peters J, Kalivas PW, Quirk GJ (2009) Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem (Cold Spring Harbor, NY) 16: 279–288Google Scholar
  21. Peters J, LaLumiere RT, Kalivas PW (2008) Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J Neurosci 28:6046–6053CrossRefGoogle Scholar
  22. Pickens CL, Airavaara M, Theberge F, Fanous S, Hope BT, Shaham Y (2011) Neurobiology of the incubation of drug craving. Trends Neurosci 34:411–420CrossRefGoogle Scholar
  23. Tallon-Baudry C, Kreiter A, Bertrand O (1999) Sustained and transient oscillatory responses in the gamma and beta bands in a visual short-term memory task in humans. Vis Neurosci 16:449–459CrossRefGoogle Scholar
  24. Van den Oever MC, Rotaru DC, Heinsbroek JA, Gouwenberg Y, Deisseroth K, Stuber GD, Mansvelder HD, Smit AB (2013) Ventromedial prefrontal cortex pyramidal cells have a temporal dynamic role in recall and extinction of cocaine-associated memory. J Neurosci 33:18225–18233CrossRefGoogle Scholar
  25. Yizhar O, Fenno LE, Davidson TJ, Mogri M, Deisseroth K (2011a) Optogenetics in neural systems. Neuron 71:9–34CrossRefGoogle Scholar
  26. Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O'Shea DJ, Sohal VS, Goshen I, Finkelstein J, Paz JT, Stehfest K, Fudim R, Ramakrishnan C, Huguenard JR, Hegemann P, Deisseroth K (2011b) Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477:171–178CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Victória A. Müller Ewald
    • 1
    • 2
    Email author
  • Benjamin J. De Corte
    • 1
    • 3
  • Subhash C. Gupta
    • 4
  • Katherine V. Lillis
    • 2
  • Nandakumar S. Narayanan
    • 1
    • 3
    • 5
  • John A. Wemmie
    • 1
    • 4
    • 5
  • Ryan T. LaLumiere
    • 1
    • 2
    • 5
  1. 1.Interdisciplinary Neuroscience ProgramUniversity of IowaIowa CityUSA
  2. 2.W311 Seashore Hall, Department of Psychological and Brain SciencesUniversity of IowaIowa CityUSA
  3. 3.Department of NeurologyUniversity of IowaIowa CityUSA
  4. 4.Department of PsychiatryUniversity of IowaIowa CityUSA
  5. 5.Iowa Neuroscience InstituteUniversity of IowaIowa CityUSA

Personalised recommendations