Elsevier

Biological Psychiatry

Volume 76, Issue 1, 1 July 2014, Pages 31-39
Biological Psychiatry

Archival Report
Escalation of Cocaine Intake and Incubation of Cocaine Seeking Are Correlated with Dissociable Neuronal Processes in Different Accumbens Subregions

https://doi.org/10.1016/j.biopsych.2013.08.032Get rights and content

Background

Cocaine addiction is characterized by a progressive increase in drug intake and a persistent craving for the drug during prolonged abstinence. Whether these two prominent features of cocaine addiction are related to each other and are mediated by similar or different neuronal processes is currently unknown.

Methods

Rats were first allowed to self-administer cocaine under long-access (6-hour) conditions to induce escalation of cocaine intake. Self-administration sessions were designed to measure both drug seeking and drug taking. After escalation, rats underwent a 1-month period of forced abstinence after which they were re-exposed to cocaine to induce re-escalation of cocaine intake. In vivo electrophysiologic recordings were conducted in the core and shell subregions of the nucleus accumbens (NAc) during cocaine intake escalation, after abstinence and during re-escalation.

Results

After abstinence, escalated levels of cocaine taking decreased toward pre-escalation levels, whereas cocaine seeking increased persistently. These opposite postabstinence changes were uncorrelated. At the neuronal level, the postabstinence decrease in cocaine taking was correlated with a normalization of depressed neuronal activity in the NAc shell that had developed during escalation of cocaine intake. In contrast, the incubation-like increase in cocaine seeking was selectively correlated with a persistent increase in the proportion of neurons in the NAc core that phasically fire during cocaine seeking.

Conclusions

These findings show that cocaine taking and cocaine seeking evolve differently during abstinence from extended drug use and depend on dissociable neuronal processes in different subregions of the nucleus accumbens.

Section snippets

Methods and Materials

See Supplement 1 for a more detailed description of the study methods.

Cocaine Taking Is Decreased While Cocaine Seeking Is Increased After Abstinence

Cocaine intake gradually increased from 40 to 78 infusions (F15,135 = 38.54; p < .001; Figure 1C) during long-access sessions of cocaine self-administration. After abstinence, however, escalated levels of cocaine intake decreased toward pre-escalation levels, confirming previous research (4). However, rats quickly re-escalated their intake of cocaine when re-exposed to the long-access regimen (F7,63 = 14.99; p < .001). As expected, whereas cocaine taking decreased after abstinence, cocaine

Discussion

This study demonstrates that cocaine seeking (i.e., latency to initiate and complete the first five nonreinforced responses of the session) and cocaine taking evolve in opposite direction and independently from each other during long-term abstinence from extended drug use. In addition, after it has undergone an incubation-like process, cocaine seeking persisted through re-escalation of cocaine intake after abstinence. The behavioral dissociation between cocaine taking and seeking is mediated by

References (49)

  • S. Wee et al.

    Alpha 1-noradrenergic system role in increased motivation for cocaine intake in rats with prolonged access

    Eur Neuropsychopharmacol

    (2008)
  • C.R. Ferrario et al.

    Alterations in AMPA receptor subunits and TARPs in the rat nucleus accumbens related to the formation of Ca(2)(+)-permeable AMPA receptors during the incubation of cocaine craving

    Neuropharmacology

    (2011)
  • C.A. Miller et al.

    Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory

    Neuron

    (2005)
  • Y.C. van Dongen et al.

    Anatomical evidence for direct connections between the shell and core subregions of the rat nucleus accumbens

    Neuroscience

    (2005)
  • D.S. Zahm

    An integrative neuroanatomical perspective on some subcortical substrates of adaptive responding with emphasis on the nucleus accumbens

    Neurosci Biobehav Rev

    (2000)
  • G.F. Koob et al.

    Drug abuse: Hedonic homeostatic dysregulation

    Science

    (1997)
  • S.H. Ahmed et al.

    Transition from moderate to excessive drug intake: Change in hedonic set point

    Science

    (1998)
  • J.W. Grimm et al.

    Neuroadaptation. Incubation of cocaine craving after withdrawal

    Nature

    (2001)
  • K.L. Conrad et al.

    Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving

    Nature

    (2008)
  • J.A. Hollander et al.

    Cocaine-associated stimuli increase cocaine seeking and activate accumbens core neurons after abstinence

    J Neurosci

    (2007)
  • P.W. Kalivas

    The glutamate homeostasis hypothesis of addiction

    Nat Rev Neurosci

    (2009)
  • J.Y. Chang et al.

    Electrophysiological and pharmacological evidence for the role of the nucleus accumbens in cocaine self-administration in freely moving rats

    J Neurosci

    (1994)
  • L.L. Peoples et al.

    Phasic firing of single neurons in the rat nucleus accumbens correlated with the timing of intravenous cocaine self-administration

    J Neurosci

    (1996)
  • U.E. Ghitza et al.

    Persistent cue-evoked activity of accumbens neurons after prolonged abstinence from self-administered cocaine

    J Neurosci

    (2003)
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    Authors SHA and LLP contributed equally to this work.

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