Abstract
Neuregulin 3 (NRG3) and ErbB4 have been linked to nicotine addiction; however, the neuronal mechanisms and behavioral consequences of NRG3-ErbB4 sensitivity to nicotine remain elusive. Recent literature suggests that relapse to smoking is due to a lack of impulsive control, which is thought to be due to altered functioning within the orbitofrontal cortex (OFC). Therefore, we examined circuitry changes within this structure following nicotine application. We report that nicotine controls synaptic plasticity in the OFC through NRG3/ErbB4-dependent regulation of GABAergic inhibition. We observed that both nicotine and NRG3 facilitated the conversion of long-term potentiation into long-term depression at cortical layer 3/5 synapses. Induction of long-term depression by nicotine relied on nicotinic receptor activation and key regulators of NRG3 signaling: (1) release of intracellular calcium, (2) activation of the BACE1 beta-secretase, and (3) ErbB4 receptor activation. Nicotine-induced synaptic plasticity was also associated with accumulation of intracellular GABA and was completely blocked by GABA A /GABA B antagonists. To test whether these mechanisms underlie OFC-dependent behavior, we evaluated the effects of nicotine in the go/no-go task. Nicotine-impaired stimulus discrimination in this task was rescued by pharmacologic disruption of the NRG3 receptor, ErbB4. Altogether, our data indicate that nicotine-induced synaptic plasticity in the OFC and cognitive changes depend on NRG3-ErbB4 signaling. We propose that nicotine activation of this pathway may contribute to nicotine addiction, particularly in individuals with genetic variation in NRG3.
Original language | English |
---|---|
Pages (from-to) | 1343-1354 |
Number of pages | 12 |
Journal | Neuropsychopharmacology |
Volume | 43 |
Issue number | 6 |
DOIs | |
State | Published - May 1 2018 |
Bibliographical note
Publisher Copyright:© 2018 American College of Neuropsychopharmacology. All rights reserved.
Funding
This work was supported by the National Institutes of Health Grants R00-DA-032681 (JRT), DA031747 (PIO), DA041632 (TJG), and DA037421 (VP). All authors declare no financial and non-financial competing interests. We thank Dr Andres Buonanno at NIH for generously providing of ErbB4 antibody. The authors declare no conflict of interest.
Funders | Funder number |
---|---|
National Institutes of Health (NIH) | DA041632, R00-DA-032681, DA037421 |
National Institute on Drug Abuse | K01DA031747 |
ASJC Scopus subject areas
- Pharmacology
- Psychiatry and Mental health