Thesis defense – Kevin Letort

Venue: BBS

Defense in french

Kévin Letort

Directed by : Karine Guillem

Teams : Choice, Addiction and Neurodysfunctions (Candy)

title

Escalation, Relapse, and Attention Deficits in a New Model of Nicotine Addiction in Rats: Role of Prefrontal’s Interneurons

Abstract

With more than 1.3 billion smokers worldwide, tobacco addiction, whose main addictive substance is nicotine, remains the most prevalent addiction and one of the leading causes of preventable death. Clinically, the diagnosis of this disorder relies on a set of criteria, among which the loss of control over consumption, notably characterized by an escalation of drug intake, plays a central role. However, this phenomenon of nicotine intake escalation has long remained difficult to model in animals.

To overcome this limitation, the laboratory recently developed an escalation model in rats, based on intravenous self-administration of increasing doses of nicotine, which induces escalated nicotine intake and heightened drug motivation compared to the standard model. The first part of this project consisted of evaluating the consequences of this escalation on two other key diagnostic criteria for addiction, namely abstinence and relapse, in male and female rats. This study demonstrated that rats having escalated their nicotine intake exhibit greater difficulty extinguishing drug-seeking behavior as well as increased vulnerability to nicotine-induced relapse, with no sex differences.

On a neurobiological level, drug intake and the control of drug seeking rely directly on the medial prefrontal cortex (mPFC), whose activity is finely regulated by local inhibitory interneurons. The second part of my work thus focused on the cellular consequences of this escalation on mPFC microcircuitry, and the causal role of interneurons in this phenomenon. The results revealed that nicotine intake escalation induces coordinated cellular alterations in pyramidal neurons and specific interneuron sub-populations, thereby fundamentally reshaping mPFC microcircuits.

Finally, while acute nicotine administration enhances attention, chronic smokers have impaired mPFC function alongside marked attentional deficits during withdrawal. In the last part of this project, we evaluated attentional performance during chronic intake and nicotine withdrawal, while chemogenetically manipulating mPFC interneurons activity. Our results i) confirm the key role played by mPFC interneurons in the pro-cognitive effects of nicotine, and ii) demonstrate that interneuron hyperactivity and abnormal gamma oscillations underlie the persistent attentional deficits observed during withdrawal following escalated nicotine intake.

Overall, this work reveals the complex role of prefrontal interneurons in the loss of control over nicotine intake and withdrawal-induced attentional deficits, paving the way for more targeted treatments for smoking cessation.

Key words

Nicotine, Addiction, Prefrontal Cortex, Interneurons

Jury

BESSON Morgane, CR, CNRS UMR 3571, Institut pasteur Paris                                   Rapporteuse

THIRIET Nathalie, PR, INSERM UMR-S 1084, Univ. Poitiers                                           Rapporteuse

DEGOULET Michael, CR, CNRS UMR 7289, Univ. Aix-Marseille                                   Examinateur

GEORGES François, DR, CNRS UMR 5293, Univ. Bordeaux                                            Examinateur

DEROCHE – GAMONET Véronique, DR, INSERM UMR 1215, Univ. Bordeaux       Examinatrice

GUILLEM Karine, DR, CNRS UMR 5287, Univ. Bordeaux                                                Directrice de thèse

• Place
  BBS
  
• Dates
  On 9 November 2026 at 14:30