Nicotine modulates contextual fear extinction through changes in ventral hippocampal GABAergic function

Abstract

Numerous studies have attributed the psychopathology of anxiety and stress disorders to maladaptive behavioral responses such as an inability to extinguish fear. Therefore, understanding neural substrates of fear extinction is imperative for developing more effective therapies for anxiety and stress disorders. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs in the fear extinction process. In the present study, we first examined the involvement of several brain regions essential for fear extinction (i.e., dorsal and ventral hippocampus, dHPC and vHPC; infralimbic, IL, and prelimbic, PL of the medial prefrontal cortex, mPFC; basolateral nucleus of the amygdala, BLA) in the impairing effects of a nAChR agonist, nicotine, on contextual fear extinction in mice. Our results showed that systemic administration of nicotine during contextual fear extinction increased c-fos expression in the vHPC and BLA while not affecting dHPC, IL or PL. In line with these results, local nicotine infusions into the vHPC, but not dHPC, resulted in impaired contextual fear extinction. Interestingly, we found that local nicotine infusions into the PL also resulted in impairment of contextual fear extinction. Second, we measured the protein levels of the GABA synthesizing enzymes GAD65 and GAD67 in the dHPC and vHPC during contextual fear extinction. Our results showed that in the group that received acute nicotine, both GAD65 and GAD67 protein levels were downregulated in the vHPC, but not in dHPC. This effect was negatively correlated with the level of freezing response during fear extinction suggesting that the downregulated GAD65/67 levels were associated with disrupted fear extinction. Finally, using c-fos/GAD65/67 double immunofluorescence, we showed that nicotine mainly increased c-fos expression in non-GABAergic ventral hippocampal cells, indicating that acute nicotine increases vHPC excitability. Overall, our results suggest that acute nicotine’s impairing effects on fear extinction is associated with ventral hippocampal disinhibition. Therefore, these results further our understanding of the interaction between nicotine addiction and anxiety and stress disorders by describing novel neural mechanisms mediating fear extinction.

Long‐term molecular differences between resilient and susceptible mice after a single traumatic exposure

“…Furthermore, we measured an increase in mRNA for the CREB‐binding protein, an epigenetic regulator of transcription that is involved in various neuronal functions (Barrett et al, 2011; Valor et al, 2011) and whose deletion has shown to promote resilience (Manners et al, 2019) and neurogenesis in the hippocampus (Gundersen et al, 2013). Moreover, we observed increased levels in the PFC of R− mice of mRNA for the enzyme responsible for synthetizing GABA, glutamic acid decarboxylase 2 (GAD2), whose function is essential for proper neuronal communication and correct fear coping (Kutlu et al, 2018). Interestingly, mice lacking GAD2 (GAD2 −/− ) have shown increased susceptibility to stress (Qi et al, 2018), whereas heterozygous mice (GAD2 +/− ) showed increased resilience (Müller et al, 2014).…”

Resveratrol inhibits nicotine-induced conditioned place preference in mice

“…A literature survey indicates that NMDA antagonists demonstrate a decreasing effect on the acquisition of nicotine-induced CPP (Li et al, 2014;Yararbas et al, 2010). It was also indicated in a previous study that GABA receptor agonists, PPAR agonists and calcium channel blockers attenuate the reinstatement of nicotine-induced CPP (Aguilar, Rodríguez-Arias, Miñarro, 2009;Biala, Budzynska, 2008;Blanco-Gandía et al, 2018;Fattore et al, 2009;Jackson et al, 2017;Kutlu et al, 2018;Le Foll et al, 2013;Matheson, Le Foll, 2020;Panlilio, Justinova, Goldberg, 2013). Moreover, previous research illustrated that resveratrol diminishes morphine-induced CPP, morphine dependence, and methamphetamine-induced hyperactivity and dopamine overflow in rodents (Han et al, 2014;Miller et al, 2013;Rezaee et al, 2020).…”

“…Nicotine changes GABA activity in the brain by various mechanisms (D 'Souza, 2016). It was also found that GABA agonists decrease nicotine dependence, and reinstatement, and also accelerate the extinction of nicotine-conditioned place preference (Biala, Budzynska, 2008;Fattore et al, 2009;Kutlu et al, 2018;Li et al, 2012;Paterson, Froestl, Markou, 2004;Varani et al, 2014). Furthermore, a series of recent studies show that resveratrol stimulates GABA.…”

Nicotine Use and Metabotropic Glutamate Receptor 5 in Individuals With Major Depressive and Posttraumatic Stress Disorders

“…Prior preclinical studies have shown that nicotine may interfere with fear extinction (an important part of PTSD). 67 These effects may explain the observation of higher mGluR5 availability in smoking associated with PTSD.…”