α4β2 nicotinic acetylcholine receptor partial agonists with low intrinsic efficacy have antidepressant-like properties

Mineur, Yann S.; Einstein, Emily B.; Seymour, Patricia A.; Coe, Jotham W.; O’Neill, Brian T.; Rollema, Hans; Picciotto, Marina R.

doi:10.1097/fbp.0b013e328347546d

Cited by 45 publications

(34 citation statements)

References 41 publications

(74 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies show that both sazetidine-A and varenicline ameliorate cognitive withdrawal symptoms (Raybuck et al, 2008;Rezvani et al, 2011) and reduce nicotine self-administration (Levin et al, 2010;O'Connor et al, 2010;Rezvani et al, 2010). Furthermore, both varenicline and sazetidine-A have shown antidepressant efficacy in the forced swim test (Caldarone et al, 2011;Kozikowski et al, 2009;Mineur et al, 2011;Rollema et al, 2009;Turner et al, 2010). In contrast, in conflict anxiety paradigms like the NIH test, we have previously shown that chronic sazetidine-A has anxiolytic effects, while varenicline does not (Turner et al, 2010).…”

Section: Discussionmentioning

confidence: 91%

Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal

Turner

Wilkinson

Poole

et al. 2013

Neuropsychopharmacol

View full text Add to dashboard Cite

Smoking is the largest preventable cause of death in the United States. Furthermore, a recent study found that o10% of quit attempts resulted in continuous abstinence for 1 year. With the introduction of pharmacotherapies like Chantix (varenicline), a selective a4b2 nicotinic partial agonist, successful quit attempts have significantly increased. Therefore, novel subtype-specific nicotinic drugs, such as sazetidine-A, present a rich area for investigation of therapeutic potential in smoking cessation. The present studies examine the anxietyrelated behavioral and functional effects of the nicotinic partial agonists varenicline and sazetidine-A during withdrawal from chronic nicotine in mice. Our studies indicate that ventral hippocampal-specific infusions of sazetidine-A, but not varenicline, are efficacious in reducing nicotine withdrawal-related anxiety-like phenotypes in the novelty-induced hypophagia (NIH) paradigm. To further investigate functional differences between these partial agonists, we utilized voltage-sensitive dye imaging (VSDi) in ventral hippocampal slices to determine the effects of sazetidine-A and varenicline in animals chronically treated with saline, nicotine, or undergoing 24 h withdrawal. These studies demonstrate a functional dissociation of varenicline and sazetidine-A on hippocampal network activity, which is directly related to previous drug exposure. Furthermore, the effects of the nicotinic partial agonists in VSDi assays are significantly correlated with their behavioral effects in the NIH test. These findings highlight the importance of drug history in understanding the mechanisms through which nicotinic compounds may be aiding smoking cessation in individuals experiencing withdrawal-associated anxiety.

show abstract

Section: Discussionmentioning

confidence: 91%

Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal

Turner

Wilkinson

Poole

et al. 2013

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Mice were placed in clear glass beakers (18 cm in diameter) filled with 15 cm water (∼25°C). Videotapes were scored for time spent immobile over a 15-min period as described previously (42). Immobility was defined as the minimal amount of movement made by the mouse to stay afloat.…”

Section: Methodsmentioning

confidence: 99%

Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior

Mineur

Obayemi

Wigestrand

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

313

229

View full text Add to dashboard Cite

Symptoms of depression can be induced in humans through blockade of acetylcholinesterase (AChE) whereas antidepressant-like effects can be produced in animal models and some clinical trials by limiting activity of acetylcholine (ACh) receptors. Thus, ACh signaling could contribute to the etiology of mood regulation. To test this hypothesis, we administered the AChE inhibitor physostigmine to mice and demonstrated an increase in anxiety-and depression-like behaviors that was reversed by administration of nicotinic or muscarinic antagonists. The behavioral effects of physostigmine were also reversed by administration of the selective serotonin reuptake inhibitor fluoxetine. Administration of fluoxetine also increased AChE activity throughout the brain, with the greatest change in the hippocampus. To determine whether cholinergic signaling in the hippocampus could contribute to the systemic effects of cholinergic drugs, we infused physostigmine or virally delivered shRNAs targeting AChE into the hippocampus. Both pharmacological and molecular genetic decreases in hippocampal AChE activity increased anxietyand depression-like behaviors and decreased resilience to repeated stress in a social defeat paradigm. The behavioral changes due to shRNA-mediated knockdown of AChE were rescued by coinfusion of an shRNA-resistant AChE transgene into the hippocampus and reversed by systemic administration of fluoxetine. These data demonstrate that ACh signaling in the hippocampus promotes behaviors related to anxiety and depression. The sensitivity of these effects to fluoxetine suggests that shRNA-mediated knockdown of hippocampal AChE represents a model for anxiety-and depression-like phenotypes. Furthermore, abnormalities in the cholinergic system may be critical for the etiology of mood disorders and could represent an endophenotype of depression.psychosocial stress | affective disorders D epression affects one in six individuals worldwide, resulting in a substantial personal and economic burden. Although the precise etiology of depression is not known, a constellation of findings suggests that predisposing factors, including individual genetic makeup, interacting with stressful life events, can precipitate depressive disorders. Currently available antidepressants are effective at treating both depression and anxiety, but the therapeutic response remains variable. Only 30% of patients achieve remission during the first line of treatment with a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine, and many patients show only limited improvements. Thus, it is critical to identify the neurobiological factors that predispose individuals to stress susceptibility and depression to understand the etiology and develop therapeutics for the disorder.A recent human imaging study has suggested that acetylcholine (ACh) levels are elevated in patients who are actively depressed, as measured by occupancy of nicotinic receptors throughout the brain, and remain high in patients who have a history of depression (1). In addition, de...

show abstract

“…This could explain why nicotinic signaling has seemingly paradoxical effects: low dose chronic nicotine has a comparable effect to an antagonist of high affinity β2 subunit-containing (β2*) nAChRs in a conditioned emotional response task in mice (Anderson and Brunzell, 2012), and both nicotine and the nicotinic antagonist mecamylamine can increase serotonin release in the hippocampus (Kenny et al, 2000). Several pharmacological studies have confirmed that nicotinic blockers (antagonists or partial agonists) can alleviate depression-like behaviors in mice, either alone or in combination with monoaminergic drugs (Andreasen et al, 2009; Bacher et al, 2009; Mineur et al, 2009; Mineur et al, 2011; Rollema et al, 2009). Interestingly, commonly used antidepressants can also act as α4β2* nAChR antagonists in cell-based assays (Shytle et al, 2002; Slemmer et al, 2000), suggesting that these medications might also act in synergy with nAChR signaling to be fully effective.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

Self Cite

View full text Add to dashboard Cite

The co-morbidity between smoking and mood disorders is striking. Preclinical and clinical studies of nicotinic effects on mood, anxiety, aggression, and related behaviors, such as irritability and agitation, suggest that smokers may use the nicotine in tobacco products as an attempt to self-medicate symptoms of affective disorders. The role of nicotinic acetylcholine receptors (nAChRs) in circuits regulating mood and anxiety are beginning to be elucidated in animal models, but the mechanisms underlying the effects of nicotine on aggression-related behavioral states (ARBS) are still not understood. Clinical trials of nicotine or nicotinic medications for neurological and psychiatric disorders have often found effects of nicotinic medications on ARBS, but few trials have studied these outcomes systematically. Similarly, the increase in ARBS resulting from smoking cessation can be resolved by nicotinic agents, but the effects of nicotinic medications on these types of mental states and behaviors in non-smokers are less well understood. Here we review the literature on the role of nAChRs in regulating mood and anxiety, and subsequently on the closely related construct of ARBS. We suggest avenues for future study to identify how nAChRs and nicotinic agents may play a role in these clinically important areas.

show abstract

α4β2 nicotinic acetylcholine receptor partial agonists with low intrinsic efficacy have antidepressant-like properties

Cited by 45 publications

References 41 publications

Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal

Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal

Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior

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

Contact Info

Product

Resources

About