Elsevier

Biological Psychiatry

Volume 68, Issue 3, 1 August 2010, Pages 265-271
Biological Psychiatry

Archival Report
Granular Insular Cortex Inactivation as a Novel Therapeutic Strategy for Nicotine Addiction

https://doi.org/10.1016/j.biopsych.2010.01.029Get rights and content

Background

Nicotine is the principal component of tobacco smoke, resulting in addiction, and recent evidence suggests that damage to the insular cortex (insula) disrupts tobacco addiction in human smokers. However, the effect of an inactivation of this structure in an animal model of nicotine addiction has yet to be evaluated.

Methods

To study this question, we investigated the effects of reversible inactivation of the granular insula by local injection of a γ-aminobutyric acid agonists mixture (baclofen/muscimol) on nicotine self-administration (SA) under fixed and progressive ratio and on reinstatement of nicotine seeking induced by nicotine priming or nicotine-associated cues in rats. We also evaluated the effects of granular insula inactivation on food SA and relapse as a control.

Results

The inactivation of the granular insula decreased nicotine SA under both fixed and progressive ratios without affecting the SA of food under the same schedules of reinforcement. This inactivation also prevented the reinstatement, after extinction, of nicotine seeking induced by nicotine-associated cues or nicotine priming without modifying the reinstatement of food seeking.

Conclusions

Our study indicates that the integrity of the granular insula is necessary for exhibiting motivation to take nicotine and to relapse to nicotine seeking but not for consuming food pellets or to relapse for food seeking. Indeed, it might be interesting to study the effect of methods that are able to modulate the activity of the insula—such as repetitive transcranial magnetic stimulation or deep brain stimulation—on tobacco addiction and relapse in humans.

Section snippets

Animals

Male Long Evans rats (Charles River, Lachine, Quebec, Canada) experimentally naive at the start of the study and initially weighing 250–275 g were used for all experiments. All rats were individually housed in a temperature-controlled environment on a 12-hour reverse light/dark cycle (lights off from 7:00 am to 7:00 pm). Before any experimental manipulation, animals were given a minimum of 7 days to habituate to the colony room, during which they were weighed, handled, and received unlimited

Effect of GI Inactivation on Nicotine and Food SA Under the FR Schedule

The t test performed on the number of nicotine injections showed a significant effect of treatment [t(6) = 2.74, p < .05], indicating that the infusion of the Bac/Mus mix into the GI significantly reduced nicotine SA compared with vehicle administration in the GI (Figure 1A). The mean (± SEM) active lever presses after vehicle and Bac/Mus mix infusion were 143 ± 18 and 85 ± 22, respectively.

The t test performed on the number of food pellets indicated no significant effect of treatment [t(8) =

Discussion

We demonstrated in this study that reversible inactivation of the GI (by local infusion of a Bac/Mus mix) decreases nicotine SA under both FR and PR schedules of reinforcement and prevents the reinstatement of nicotine seeking induced by nicotine priming or nicotine-associated cue, without altering food SA or reinstatement of food seeking.

These findings are in line with the fact that human smokers with damage of the insula report a disruption of their addiction to tobacco but no modification in

References (56)

  • Z.H. Kiss et al.

    Neuronal response to local electrical stimulation in rat thalamusPhysiological implications for mechanisms of deep brain stimulation

    Neuroscience

    (2002)
  • B. Le Foll et al.

    Nicotine as a typical drug of abuse in experimental animals and humans

    Psychopharmacology

    (2006)
  • J.E. Rose et al.

    Nicotine self-administration in animals and humans: Similarities and differences

    Psychopharmacology

    (1997)
  • W.A. Corrigall et al.

    Nicotine maintains robust self-administration in rats on a limited-access schedule

    Psychopharmacology

    (1989)
  • A. Markou et al.

    The nicotinic antagonist methyllycaconitine has differential effects on nicotine self-administration and nicotine withdrawal in the rat

    Nicotine Tob Res

    (2001)
  • E.C. Donny et al.

    Nicotine self-administration in rats

    Psychopharmacology

    (1995)
  • S.R. Goldberg et al.

    Persistent behavior at high rates maintained by intravenous self-administration of nicotine

    Science

    (1981)
  • B. Le Foll et al.

    High reinforcing efficacy of nicotine in non-human primates

    PLoS ONE

    (2007)
  • M. Sofuoglu et al.

    Self-administration of intravenous nicotine in male and female cigarette smokers

    Neuropsychopharmacology

    (2008)
  • A.R. Damasio et al.

    Subcortical and cortical brain activity during the feeling of self-generated emotions

    Nat Neurosci

    (2000)
  • A.D. Craig

    How do you feel?Interoception: The sense of the physiological condition of the body

    Nat Rev Neurosci

    (2002)
  • S.G. Hardy

    Analgesia elicited by prefrontal stimulation

    Brain Res

    (1985)
  • T. Suhara et al.

    D1 dopamine receptor binding in mood disorders measured by positron emission tomography

    Psychopharmacology

    (1992)
  • M. Watanabe et al.

    Increase of extracellular dopamine in primate prefrontal cortex during a working memory task

    J Neurophysiol

    (1997)
  • P.S. Goldman-Rakic

    The cortical dopamine system: Role in memory and cognition

    Adv Pharmacol

    (1998)
  • A.L. Brody et al.

    Brain metabolic changes during cigarette craving

    Arch Gen Psychiatry

    (2002)
  • D. McBride et al.

    Effects of expectancy and abstinence on the neural response to smoking cues in cigarette smokersAn fMRI study

    Neuropsychopharmacology

    (2006)
  • T.R. Franklin et al.

    Limbic activation to cigarette smoking cues independent of nicotine withdrawalA perfusion fMRI study

    Neuropsychopharmacology

    (2007)
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