Role of ventral subiculum in context-induced relapse to alcohol seeking after punishment-imposed abstinence

Nathan J. Marchant, Erin J. Campbell, Leslie R. Whitaker, Brandon K. Harvey, Konstantin Kaganovsky, Sweta Adhikary, Bruce T. Hope, Robert C. Heins, Thomas E. Prisinzano, Eyal Vardy, Antonello Bonci, Jennifer M. Bossert, Yavin Shaham

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking.Werecently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub®NAc shell projection. Next, we reversibly inactivated the vSub withGABAreceptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory k opioid-receptor based DREADD (KORD) in vSub®NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub®NAc projection in this relapse.

Original languageEnglish
Pages (from-to)3281-3294
Number of pages14
JournalJournal of Neuroscience
Volume36
Issue number11
DOIs
Publication statusPublished - 16 Mar 2016

Cite this

Marchant, Nathan J. ; Campbell, Erin J. ; Whitaker, Leslie R. ; Harvey, Brandon K. ; Kaganovsky, Konstantin ; Adhikary, Sweta ; Hope, Bruce T. ; Heins, Robert C. ; Prisinzano, Thomas E. ; Vardy, Eyal ; Bonci, Antonello ; Bossert, Jennifer M. ; Shaham, Yavin. / Role of ventral subiculum in context-induced relapse to alcohol seeking after punishment-imposed abstinence. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 11. pp. 3281-3294.
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abstract = "In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking.Werecently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub{\circledR}NAc shell projection. Next, we reversibly inactivated the vSub withGABAreceptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory k opioid-receptor based DREADD (KORD) in vSub{\circledR}NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub{\circledR}NAc projection in this relapse.",
keywords = "Alcohol, Chemogenetics, Nucleus accumbens, Punishment, Relapse, Ventral subiculum",
author = "Marchant, {Nathan J.} and Campbell, {Erin J.} and Whitaker, {Leslie R.} and Harvey, {Brandon K.} and Konstantin Kaganovsky and Sweta Adhikary and Hope, {Bruce T.} and Heins, {Robert C.} and Prisinzano, {Thomas E.} and Eyal Vardy and Antonello Bonci and Bossert, {Jennifer M.} and Yavin Shaham",
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language = "English",
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Marchant, NJ, Campbell, EJ, Whitaker, LR, Harvey, BK, Kaganovsky, K, Adhikary, S, Hope, BT, Heins, RC, Prisinzano, TE, Vardy, E, Bonci, A, Bossert, JM & Shaham, Y 2016, 'Role of ventral subiculum in context-induced relapse to alcohol seeking after punishment-imposed abstinence' Journal of Neuroscience, vol. 36, no. 11, pp. 3281-3294. https://doi.org/10.1523/JNEUROSCI.4299-15.2016

Role of ventral subiculum in context-induced relapse to alcohol seeking after punishment-imposed abstinence. / Marchant, Nathan J.; Campbell, Erin J.; Whitaker, Leslie R.; Harvey, Brandon K.; Kaganovsky, Konstantin; Adhikary, Sweta; Hope, Bruce T.; Heins, Robert C.; Prisinzano, Thomas E.; Vardy, Eyal; Bonci, Antonello; Bossert, Jennifer M.; Shaham, Yavin.

In: Journal of Neuroscience, Vol. 36, No. 11, 16.03.2016, p. 3281-3294.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Role of ventral subiculum in context-induced relapse to alcohol seeking after punishment-imposed abstinence

AU - Marchant, Nathan J.

AU - Campbell, Erin J.

AU - Whitaker, Leslie R.

AU - Harvey, Brandon K.

AU - Kaganovsky, Konstantin

AU - Adhikary, Sweta

AU - Hope, Bruce T.

AU - Heins, Robert C.

AU - Prisinzano, Thomas E.

AU - Vardy, Eyal

AU - Bonci, Antonello

AU - Bossert, Jennifer M.

AU - Shaham, Yavin

PY - 2016/3/16

Y1 - 2016/3/16

N2 - In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking.Werecently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub®NAc shell projection. Next, we reversibly inactivated the vSub withGABAreceptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory k opioid-receptor based DREADD (KORD) in vSub®NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub®NAc projection in this relapse.

AB - In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking.Werecently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub®NAc shell projection. Next, we reversibly inactivated the vSub withGABAreceptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory k opioid-receptor based DREADD (KORD) in vSub®NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub®NAc projection in this relapse.

KW - Alcohol

KW - Chemogenetics

KW - Nucleus accumbens

KW - Punishment

KW - Relapse

KW - Ventral subiculum

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U2 - 10.1523/JNEUROSCI.4299-15.2016

DO - 10.1523/JNEUROSCI.4299-15.2016

M3 - Article

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SP - 3281

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JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 11

ER -