Expression of the 5-HT1A Serotonin Receptor in the Hippocampus Is Required for Social Stress Resilience and the Antidepressant-Like Effects Induced by the Nicotinic Partial Agonist Cytisine

Abstract

Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5-HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressantlike effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders.

Dipeptide tyrosyl-leucine exhibits antidepressant-like activity in mice

“…www.nature.com/scientificreports www.nature.com/scientificreports/ The antidepressant-like effect of YL was blocked by antagonists of 5-HT 1A , dopamine D 1 , and GABA A receptors. It was reported that 5-HT 1A and dopamine D 1 receptors in the hippocampus are involved in the antidepressant-like effect and hippocampal cell proliferation 28,36,37 . In the future, it will be necessary to elucidate how the monoamine system is directly and/or indirectly involved in the stress response and hippocampal cell proliferation.…”

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

“…Although both the nicotinic antagonist mecamylamine and the low efficacy partial agonist cytisine can decrease c-fos activity in the amygdala (Mineur et al, 2007), it is not known where in the brain nAChRs are required to alter behaviors relevant to stress and depression. Many brain areas that receive significant ACh innervation, including hippocampus, prefrontal cortex, habenuala, IPN, ventral tegmental area, and nucleus accumbens/striatum (Leao et al, 2015;Mineur et al, 2013Mineur et al, , 2015Picciotto and Mineur, 2014;Polter and Kauer, 2014;Zhao-Shea et al, 2013 could be involved in nAChR-related mood regulation. We demonstrate here that the non-selective nAChR antagonist mecamylamine can induce antidepressant-like effects when infused locally into the amygdala, suggesting that nAChR signaling is critical for baseline neuronal activity in this brain region, and that decreasing nAChR activity in amygdala is sufficient for an antidepressant-like response.…”

“…CD1 mice were selected for aggressive behavior as described previously (Mineur et al, 2013(Mineur et al, , 2015. On the initial defeat day, each C57BL/6J mouse was placed into a CD1 aggressor mouse home cage.…”

Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states

“…Further, as mentioned above, both chronic nicotine and the nicotinic antagonist mecamylamine can facilitate serotonin transmission in the hippocampus, while the effects of monoamine depletion can be partially reversed by nicotine administration and can lead to changes in anxiety-like behavior in the elevated plus maze (File et al, 2000a; File et al, 2000b; Fu et al, 1998; Kenny et al, 2000). We recently found that serotonin depletion could prevent antidepressant-like effects induced by the nicotinic partial agonist cytisine in the forced swim and the social defeat tests, while the effects of serotonergic drugs could be potentiated by this nicotinic compound (Mineur et al, 2014). Thus, changes in nAChR signaling, and more specifically, decreasing nAChR activity, can facilitate monoamine transmission and this may mediate the ability of nicotinic drugs to alter depression-like behaviors.…”