Relapse is a two-component process consisting of a highly motivated drug-seeking phase that, if successful, is followed by a drug-using phase resulting in temporary satiation. In rodents, cue-induce drug seeking requires transient synaptic potentiation (t-SP) of cortical glutamatergic synapses on nucleus accumbens core medium spiny neurons, but it is unknown how achieving drug use affects this plasticity. We modeled the two phases of relapse after extinction from cocaine self-administration to assess how cocaine use affects t-SP associated with cue-induced drug seeking.
Photo credit: Rachel Poli.
In our manuscript, we describe a model of intravenous delta9-tetrahydrocannabinol plus cannabidiol self-administration and reinstatement in the rat. We show that this self-administration is CB1 receptor dependent as it can be blocked by rimonabant. We report that cue-induced reinstatement is inhibited by administration of drugs that have been shown to reduce relapse to other drugs of abuse (n-acetylcysteine, nNOS inhibitor, and matrix metalloproteinase 9 inhibitor). Finally, we report that THC self-administration and extinction results in enduring changes in structural and functional plasticity in the nucleus accumbens.
This is a comprehensive review of the role that glutamate signal transduction in the nucleus accembens plays in addiction-related behaviors. As a major input structure of the basal ganglia, the nucleus accumbens integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to drugs of abuse disrupts plasticity in this region producing adaptations that serve as the molecular basis for relapse vulnerability, allowing drug-associated cues to engender a pathologic motivation for drug seeking.
Recent Peer-Reviewed Publications
1. Spencer S*, Neuhofer D*, Chioma V, Garcia-Keller C, Schwartz D, Allen N, Scofield M, Ortiz T, Kalivas PW. (2018) A model of Δ9‐tetrahydrocannabinol (THC) self-administration and reinstatement that produces heroin-like synaptic plasticity in nucleus accumbens. Biological Psychiatry84(8):601-610. PMID: 29861097. PMCID: PMC6162175.
2. Spencer S and Kalivas PW. (2017) Glutamate transport: a new bench to bedside mechanism for treating substance abuse. International Journal of Neuropsychopharmacology20(10):797-812. PMID: 28605494. PMCID: 5632313.
3. Melis M, Frau R, Kalivas PW, Spencer S, Chioma V, Zamberletti E, Rubino T, Parolaro D. (2017) New vistas on cannabis use disorder. Neuropharmacology124:62-72. PMID: 28373077. PMCID: 5865400.
4. Smith AW, Scofield MD, Heinsbroek JA, Gipson CD, Neuhofer D, Roberts-Wolfe D, Spencer S,Stankeviciute N, Smith RJ, Allen A, Lorang M, Griffin III W, Boger HA, Kalivas PW. (2017) Accumbens nNOS interneurons regulate cocaine relapse. Journal of Neuroscience37(4):742-756. PMID: 28123012. PMCID: 5296777.
5. Spencer S, Garcia-Keller C, Roberts-Wolfe D, Heinsbroek JA, Mulvaney M, Sorrel A, Kalivas PW. (2017) Cocaine use reverses striatal plasticity produced during cocaine seeking. Biological Psychiatry81(7):616-624. PMID: 27837917. PMCID: 5346331.
>Featuredin“Early Career Investigator Commentary”article: Ferguson, D. (2017) Cocaine mediates the Cellular Mechanisms of Satiation.Biological Psychiatry81(7):e47-e48.
6. Brown RM, Kupchik YM, Spencer S, Garcia-Keller C, Spanswick DC, Lawrence AJ, Simonds SE, Schwartz DJ, Jordan KA, Jhou TC, Kalivas PW. (2017) Addiction-like synaptic impairments in diet-induced obesity. Biological Psychiatry81(9):797-806. PMID: 26826876. PMCID: 4889544.
7. Scofield MD, Heinsbroek JA, Gipson CD, Kupchik YM,Spencer S, Smith AW, Roberts-Wolfe D, Kalivas PW. (2016) The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacological Reviews68(3):816-71. PMID: 27363411. PMCID: 4931870.
8. Garcia-Keller C, Kupchik Y, Gipson C, Brown RM, Spencer S, Bollati F, Roberts-Wolfe D, Heinsbroek J, Cancela LM, Kalivas PW. (2015) Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration. Molecular Psychiatry21(8):1063-9. PMID: 26821978. PMCID: 4823171.
9. Sidor MM, Spencer SM, Dzirasa K, Parekh PK, Tye KM, Warden MR, Arey RN, Enwright JF III, Jacobsen JPR, Kumar S, Remillard EM, Caron MG, Deisseroth K, McClung CA. (2015) Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice. Molecular Psychiatry20(11):1406-19.PMID: 25560763. PMCID: 44929295.
10. Ozburn AR, Falcon E, Twaddle A, Nugent A, Gillman A, Spencer SM, Arey RN, Mukherjee S, Lyons-Weiler JF, Self DW, McClung CA. (2015) Direct regulation of diurnal Drd3 expression and cocaine reward by NPAS2. Biological Psychiatry77(5):425-433. PMID: 25444159. PMCID: 4315729.
11. Spencer S, Brown RM, Quintero GC, Kupchik YM, Thomas C, Reissner KJ, Kalivas PW. (2014) Alpha2delta-1 signaling in nucleus accumbens is necessary for cocaine-induced relapse. Journal of Neuroscience34(25):8605-8611. PMID: 24948814. PMCID: 4061396.
>Featuredin“Research Highlights”article: Bucci M. (2014) Your channels on Drugs. Nature Chemical Biology10(8):607.
12. Reissner KJ, Thomas CA, Brown RM, Spencer S, Tran PK,Kalivas PW. (2014) Chronic administration of the glial modulator propentofylline impairs cue-primed reinstatement to cocaine. Neuropsychopharmacology39(2):499-406. PMID: 23985782. PMCID: 3870775.