Patterns of functional activity associated with cocaine self-administration in the rat change over time

Macey, Darrel J.; Rice, Wendy N.; Freedland, Cory S.; Whitlow, Christopher T.; Porrino, Linda J.

doi:10.1007/s00213-003-1676-7

Cited by 36 publications

(11 citation statements)

References 46 publications

(67 reference statements)

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“…Furthermore, 74 of the 90 genes (including the 32 genes that were significantly downregulated) displayed reduced expression levels in cocaine addicts. These findings were also highly consistent with previous brain imaging studies that have revealed negative effects of cocaine on brain glucose metabolism (London et al, 1990; Lyons, Friedman, Nader, & Porrino, 1996; Macey, Rice, Freedland, Whitlow, & Porrino, 2004; Thanos, Michaelides, Benveniste, Wang, & Volkow, 2008). Furthermore, alteration of certain genes encoding for mitochondrial components induced by cocaine (Lehrmann et al, 2003) and nicotine (Wang, Kim, Donovan, Becker, & Li, 2009) exposure had also been reported previously.…”

Section: Molecular Adaptations Accompanying Early Response and Lonsupporting

confidence: 91%

Gene Expression in the Addicted Brain

Zhou¹,

Enoch²,

Goldman³

2014

International Review of Neurobiology

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Addiction is due to changes in the structure and function of the brain, including neuronal networks and the cells that comprise them. Within cells, gene expression changes can track and help explain their altered function. Transcriptional changes induced by addictive agents are dynamic and divergent and range from signal pathway-specific perturbations to widespread molecular and cellular dysregulation that can be measured by “omic” methods and that can be used to identify new pathways. The molecular effects of addiction depend on timing of exposure or withdrawal, the stage of adaptation, the brain region, and the behavioral model, there being many models of addiction. However, the molecular neural adaptations across different drug exposures, conditions, and regions are to some extent shared and can reflect common actions on pathways relevant to addiction. Epigenetic studies of DNA methylation and histone modifications and studies of regulatory RNA networks have been informative for elucidating the mechanisms of transcriptional change in the addicted brain.

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Section: Molecular Adaptations Accompanying Early Response and Lonsupporting

confidence: 91%

Gene Expression in the Addicted Brain

Zhou¹,

Enoch²,

Goldman³

2014

International Review of Neurobiology

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“…Macey and colleagues [64] observed decreased glucose metabolism in the dorsolateral striatum after 60 hours of cocaine self-administration (2 hour daily sessions over 30 days). Similarly, a decrease was observed in dorsolateral striatum single neuron firing rates during instrumental movements over 28 hours of water self-administration (2 hour daily sessions over 14 days; [65]).…”

Section: Discussionmentioning

confidence: 99%

“…In the water-seeking experiment, animals acquired a habit, as evidenced by maintained operant movements despite prior satiation with water. In the cocaine-seeking experiment [64], although habit formation was not tested, neural activity of dorsolateral striatum neurons could be interpreted as a correlate of habit formation.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Habitual and Goal-Directed Behavior Following Devaluation of Cocaine: A Multifaceted Interpretation of Relapse

et al. 2009

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BackgroundCocaine addiction is characterized as a chronically relapsing disorder. It is believed that cues present during self-administration become learned and increase the probability that relapse will occur when they are confronted during abstinence. However, the way in which relapse-inducing cues are interpreted by the user has remained elusive. Recent theories of addiction posit that relapse-inducing cues cause relapse habitually or automatically, bypassing processing information related to the consequences of relapse. Alternatively, other theories hypothesize that relapse-inducing cues produce an expectation of the drug's consequences, designated as goal-directed relapse. Discrete discriminative stimuli signaling the availability of cocaine produce robust cue-induced responding after thirty days of abstinence. However, it is not known whether cue-induced responding is a goal-directed action or habit.Methodology/Principal FindingsWe tested whether cue-induced responding is a goal-directed action or habit by explicitly pairing or unpairing cocaine with LiCl-induced sickness (n = 7/group), thereby decreasing or not altering the value of cocaine, respectively. Following thirty days of abstinence, no difference in responding between groups was found when animals were reintroduced to the self-administration environment alone, indicating habitual behavior. However, upon discriminative stimulus presentations, cocaine-sickness paired animals exhibited decreased cue-induced responding relative to unpaired controls, indicating goal-directed behavior. In spite of the difference between groups revealed during abstinent testing, no differences were found between groups when animals were under the influence of cocaine.Conclusions/SignificanceUnexpectedly, both habitual and goal-directed responding occurred during abstinent testing. Furthermore, habitual or goal-directed responding may have been induced by cues that differed in their correlation with the cocaine infusion. Non-discriminative stimulus cues were weak correlates of the infusion, which failed to evoke a representation of the value of cocaine and led to habitual behavior. However, the discriminative stimulus–nearly perfectly correlated with the infusion–likely evoked a representation of the value of the infusion and led to goal-directed behavior. These data indicate that abstinent cue-induced responding is multifaceted, dynamically engendering habitual or goal-directed behavior. Moreover, since goal-directed behavior terminated habitual behavior during testing, therapeutic approaches aimed at reducing the perceived value of cocaine in addicted individuals may reduce the capacity of cues to induce relapse.

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“…Considerable evidence indicates that cortical activity decreases during cocaine withdrawal (e.g. humans: Volkow et al, 1992; Goldstein and Volkow, 2002; primates: Beveridge et al, 2006; Porrino et al, 2007; rats: Hammer et al, 1993; Macey et al, 2004; Sun & Rebec, 2006). A resultant decrease in the activity of glutamate projections to the NAc could lead to a synaptic scaling-mediated increase in AMPAR levels on MSN (see Sun and Wolf, 2009 for discussion).…”

Section: Ampar Transmission In the Nac During Incubationmentioning

confidence: 99%

Adaptations in AMPA receptor transmission in the nucleus accumbens contributing to incubation of cocaine craving

2014

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Cue-induced cocaine craving in rodents intensifies or “incubates” during the first months of withdrawal from long access cocaine self-administration. This incubation phenomenon is relevant to human users who achieve abstinence but exhibit persistent vulnerability to cue-induced relapse. It is well established that incubation of cocaine craving involves complex neuronal circuits. Here we will focus on neuroadaptations in the nucleus accumbens (NAc), a region of convergence for pathways that control cocaine seeking. A key adaptation is a delayed (~3–4 weeks) accumulation of Ca2+-permeable AMPAR receptors (CP-AMPARs) in synapses on medium spiny neurons (MSN) of the NAc. These CP-AMPARs mediate the expression of incubation after prolonged withdrawal, although different mechanisms must be responsible during the first weeks of withdrawal, prior to CP-AMPAR accumulation. The cascade of events leading to CP-AMPAR accumulation is still unclear. However, several candidate mechanisms have been identified. First, mGluR1 has been shown to negatively regulate CP-AMPAR levels in NAc synapses, and it is possible that a withdrawal-dependent decrease in this effect may help explain CP-AMPAR accumulation during incubation. Second, an increase in phosphorylation of GluA1 subunits (at the protein kinase A site) within extrasynaptic homomeric GluA1 receptors (CP-AMPARs) may promote their synaptic insertion and oppose their removal. Finally, elevation of brain-derived neurotrophic factor (BDNF) levels in the NAc may contribute to maintenance of incubation after months of withdrawal, although incubation-related increases in BDNF accumulation do not account for CP-AMPAR accumulation. Receptors and pathways that negatively regulate incubation, such as mGluR1, are promising targets for the development of therapeutic strategies to help recovering addicts maintain abstinence.

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Patterns of functional activity associated with cocaine self-administration in the rat change over time

Cited by 36 publications

References 46 publications

Gene Expression in the Addicted Brain

Gene Expression in the Addicted Brain

Evidence for Habitual and Goal-Directed Behavior Following Devaluation of Cocaine: A Multifaceted Interpretation of Relapse

Adaptations in AMPA receptor transmission in the nucleus accumbens contributing to incubation of cocaine craving

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