Vagus Nerve Stimulation (VNS) Modulates Synaptic Plasticity in the Infralimbic Cortex Via Trk-B Receptor Activation to Reduce Drug-Seeking in Male Rats

Overview

Journal J Neurosci

Specialty Neurology

Date 2024 May 8

PMID 38719446

Authors

Christopher M Driskill

Jessica E Childs

Aarron J Phensy

Sierra R Rodriguez

John T OBrien

Kathy L Lindquist

Aurian Naderi

Bogdan Bordieanu

Jacqueline F McGinty

Sven Kroener

Affiliations

Soon will be listed here.

Abstract

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in male rats trained to self-administer cocaine. Pairing 10 d of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay. Systemic blockade of tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in Layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates the extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.

References

Childress A, Hole A, Ehrman R, Robbins S, McLellan A, OBrien C . Cue reactivity and cue reactivity interventions in drug dependence. NIDA Res Monogr. 1993; 137:73-95. View

Mathew E, Tabet M, Robertson N, Hays S, Rennaker R, Kilgard M . Vagus nerve stimulation produces immediate dose-dependent anxiolytic effect in rats. J Affect Disord. 2019; 265:552-557. DOI: 10.1016/j.jad.2019.11.090. View

Dawson J, Liu C, Francisco G, Cramer S, Wolf S, Dixit A . Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial. Lancet. 2021; 397(10284):1545-1553. PMC: 8862193. DOI: 10.1016/S0140-6736(21)00475-X. View

Olsen L, Moore R, Bechmann N, Ethridge V, Gargas N, Cunningham S . Vagus nerve stimulation-induced cognitive enhancement: Hippocampal neuroplasticity in healthy male rats. Brain Stimul. 2022; 15(5):1101-1110. DOI: 10.1016/j.brs.2022.08.001. View

Follesa P, Biggio F, Gorini G, Caria S, Talani G, Dazzi L . Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain. Brain Res. 2007; 1179:28-34. DOI: 10.1016/j.brainres.2007.08.045. View

Taylor J, Olausson P, Quinn J, Torregrossa M . Targeting extinction and reconsolidation mechanisms to combat the impact of drug cues on addiction. Neuropharmacology. 2008; 56 Suppl 1:186-95. PMC: 2635342. DOI: 10.1016/j.neuropharm.2008.07.027. View

Nichols J, Nichols A, Smirnakis S, Engineer N, Kilgard M, Atzori M . Vagus nerve stimulation modulates cortical synchrony and excitability through the activation of muscarinic receptors. Neuroscience. 2011; 189:207-14. DOI: 10.1016/j.neuroscience.2011.05.024. View

Berglind W, See R, Fuchs R, Ghee S, Whitfield Jr T, Miller S . A BDNF infusion into the medial prefrontal cortex suppresses cocaine seeking in rats. Eur J Neurosci. 2007; 26(3):757-66. DOI: 10.1111/j.1460-9568.2007.05692.x. View

Kasanetz F, Lafourcade M, Deroche-Gamonet V, Revest J, Berson N, Balado E . Prefrontal synaptic markers of cocaine addiction-like behavior in rats. Mol Psychiatry. 2012; 18(6):729-37. DOI: 10.1038/mp.2012.59. View

10.

McDougle M, de Araujo A, Singh A, Yang M, Braga I, Paille V . Separate gut-brain circuits for fat and sugar reinforcement combine to promote overeating. Cell Metab. 2024; 36(2):393-407.e7. PMC: 11898112. DOI: 10.1016/j.cmet.2023.12.014. View

11.

Weiss F, Martin-Fardon R, Ciccocioppo R, Kerr T, Smith D, Ben-Shahar O . Enduring resistance to extinction of cocaine-seeking behavior induced by drug-related cues. Neuropsychopharmacology. 2001; 25(3):361-72. DOI: 10.1016/S0893-133X(01)00238-X. View

12.

Borland M, Engineer C, Vrana W, Moreno N, Engineer N, Vanneste S . The Interval Between VNS-Tone Pairings Determines the Extent of Cortical Map Plasticity. Neuroscience. 2017; 369:76-86. PMC: 5766390. DOI: 10.1016/j.neuroscience.2017.11.004. View

13.

Manta S, El Mansari M, Debonnel G, Blier P . Electrophysiological and neurochemical effects of long-term vagus nerve stimulation on the rat monoaminergic systems. Int J Neuropsychopharmacol. 2012; 16(2):459-70. DOI: 10.1017/S1461145712000387. View

14.

Hays S, Khodaparast N, Ruiz A, Sloan A, Hulsey D, Rennaker 2nd R . The timing and amount of vagus nerve stimulation during rehabilitative training affect poststroke recovery of forelimb strength. Neuroreport. 2014; 25(9):676-82. PMC: 4039714. DOI: 10.1097/WNR.0000000000000154. View

15.

Sun W, Zelek-Molik A, McGinty J . Short and long access to cocaine self-administration activates tyrosine phosphatase STEP and attenuates GluN expression but differentially regulates GluA expression in the prefrontal cortex. Psychopharmacology (Berl). 2013; 229(4):603-13. PMC: 3784626. DOI: 10.1007/s00213-013-3118-5. View

16.

Hastings M, Gauthier J, Mabry K, Tran A, Man H, Kantak K . Facilitative effects of environmental enrichment for cocaine relapse prevention are dependent on extinction training context and involve increased TrkB signaling in dorsal hippocampus and ventromedial prefrontal cortex. Behav Brain Res. 2020; 386:112596. PMC: 7430990. DOI: 10.1016/j.bbr.2020.112596. View

17.

Collins L, Boddington L, Steffan P, McCormick D . Vagus nerve stimulation induces widespread cortical and behavioral activation. Curr Biol. 2021; 31(10):2088-2098.e3. DOI: 10.1016/j.cub.2021.02.049. View

18.

Fumagalli F, Di Pasquale L, Caffino L, Racagni G, Riva M . Repeated exposure to cocaine differently modulates BDNF mRNA and protein levels in rat striatum and prefrontal cortex. Eur J Neurosci. 2007; 26(10):2756-63. DOI: 10.1111/j.1460-9568.2007.05918.x. View

19.

Dorr A, Debonnel G . Effect of vagus nerve stimulation on serotonergic and noradrenergic transmission. J Pharmacol Exp Ther. 2006; 318(2):890-8. DOI: 10.1124/jpet.106.104166. View

20.

Hammond S, Wagner J . The context dependency of extinction negates the effectiveness of cognitive enhancement to reduce cocaine-primed reinstatement. Behav Brain Res. 2013; 252:444-9. PMC: 3786700. DOI: 10.1016/j.bbr.2013.06.026. View