High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation

Mecamylamine, sazetidine, and amitriptyline are ineffective in mice lacking the β2 nAChR subunit.

“Both the antagonist mecamylamine (Rabenstein et al. 2006) and the partial agonist sazetidine (Caldarone et al. 2011), as well as the classical antidepressant amitriptyline (Caldarone et al. 2004), are ineffective in mice lacking the β2 subunit”

Mecamylamine has antidepressant-like effects in mice.

“the nicotinic antagonist mecamylamine has antidepressantlike effects in mice (Caldarone et al. 2004;Rabenstein et al. 2006;Andreasen et al. 2009)”

KO mice lacking the β2* subunit show decreased depression-like behavior in the forced swim and tail suspension tests at baseline.

“at baseline, KO mice lacking the β2* subunit show decreased depression-like behavior in the forced swim and tail suspension tests at baseline, supporting the possibility that the β2 KO mimics the effect of nAChR blockade (Caldarone et al., 2004; Rabenstein et al., 2006).”

Amitriptyline has no effect in neurochemical and behavioral assays of antidepressant efficacy in KO mice lacking the β2 nAChR subunit, suggesting that β2* nAChRs are involved in this antidepressant response.

“the tricyclic antidepressant amitriptyline has no effect in neurochemical and behavioral assays of antidepressant efficacy in KO mice lacking the β2 nAChR subunit, strongly suggesting that β2* nAChRs are involved in this antidepressant response (Caldarone et al., 2004).”

Mecamylamine and DhβE have antidepressant-like properties in mice.

“Mecamylamine and the competitive nicotinic antagonist DhβE also have antidepressant-like properties in mice (Caldarone et al., 2004; Mineur et al., 2007; Rabenstein et al., 2006).”

A subthreshold dose of mecamylamine combined with amitriptyline results in antidepressant-like effects in mice, reinforcing that blockade of nAChRs yields antidepressant-like effects.

“a subthreshold dose of the nicotinic antagonist mecamylamine combined with the tricyclic antidepressant amitriptyline results in antidepressant-like effects in mice, reinforcing the idea that blockade of nAChRs yields antidepressant-like effects (Caldarone et al., 2004)”

Nicotinic agents can enhance antidepressant medication effects in preclinical tests that predict antidepressant response.

“In addition, in preclinical paradigms used to predict antidepressant response, the effects of AD medications can be augmented by administration of nicotinic drugs (Caldarone et al., 2004;Rollema et al., 2009a).”

In FST and TST, acute nicotinic antagonists like mecamylamine, unlike acute nicotine, yield antidepressant-like effects.

“Acute treatment with nicotinic antagonists, such as mecamylamine, but not acute nicotine, results in antidepressant-like effects in the forced swim test (FST) and the tail suspension test (TST) (Caldarone et al., 2004;Rabenstein et al., 2006).”

Antagonism of mAChRs or nAChRs, or blockade of ACh signaling through nAChRs with partial agonists, can decrease depression-like behavior in rodents.

“Consistent with an increase in ACh leading to symptoms of depression, antagonism of mAChRs or nAChRs, or blockade of ACh signaling through nAChRs with partial agonists, can decrease depression-like behavior in rodents (Caldarone et al., 2004; De Pablo et al., 1991; Mineur et al., 2007; Picciotto et al., 2002; Rabenstein et al., 2006).”

Mice lacking the β2-nAChR subunit are insensitive to the antidepressant-like effects of mecamylamine and amitriptyline.

“However, mice lacking the β2-nAChR subunit are insensitive to the antidepressant-like effects of mecamylamine (15) and amitriptyline (18).”

β2* nAChRs are required for antidepressant efficacy of at least one antidepressant medication.

“β2* nAChRs are required for antidepressant efficacy of at least one antidepressant medication (Caldarone et al., 2004)”

Preclinical studies in the forced swim test and tail suspension test have demonstrated antidepressant-like activity of mecamylamine and the selective α4β2 nicotinic acetylcholine receptor partial agonists cytisine and ispronicline.

“Preclinical studies in the forced swim test and the tail suspension test, established mouse models of antidepressant efficacy, have demonstrated antidepressant-like activity of the non-selective nicotinic acetylcholine receptor antagonist mecamylamine and the selective α4β2 nicotinic acetylcholine receptor partial agonists, cytisine (Caldarone et al., 2004; Rabenstein et al., 2006; Mineur et al.,”

The present results are in agreement with previous reports that both nicotinic acetylcholine receptor antagonists and partial agonists show antidepressant-like efficacy in animal depression models and can also increase antidepressant activity when co-administered with classic antidepressants such as SSRIs or tricyclic antidepressants.

“The present results are in agreement with previous reports that both nicotinic acetylcholine receptor antagonists and partial agonists show antidepressant-like efficacy in animal depression models and can also increase antidepressant activity when co-administered with classic antidepressants such as SSRIs or tricyclic antidepressants (Caldarone et al., 2004; Rabenstein et al., 2006; Mineur et al.,”

At 10 mg/kg, amitriptyline reduced immobility scores with greater efficacy than varenicline or sertraline when given alone in CD-1 mice.

“At 10 mg/kg, the tricyclic antidepressant amitriptyline, which consistently yields pronounced dose-dependency and near maximal efficacy in dose-response studies (data not shown; see e.g. Caldarone et al, 2004), reduced immobility scores with greater efficacy than varenicline or sertraline when given alone (Fig. 1B).”

Mecamylamine has antidepressant-like effects in the forced swim test and tail-suspension test in wild-type but not β2 knockout animals.

“mecamylamine, a nonselective nAChR antagonist, has similar antidepressant-like effects in the FST and tail-suspension test in wild-type but not in β2 KO animals (Andreasen, Nielsen, & Redrobe, 2009; Caldarone et al., 2004; Rabenstein, Caldarone, & Picciotto, 2006).”

Knockout mice lacking the β2 subunit of nAChRs show decreased baseline immobility in both the forced swim test and tail-suspension test compared to wild-type animals, indicating a reduced depression-like phenotype.

“KO mice that lack the β2 subunit of nAChRs show decreased amount of baseline immobility in both the FST and tail-suspension test, indication of reduced depression-like phenotype, compared to wild-type animals (Caldarone et al., 2004).”