Antidepressant effects of nicotine in an animal model of depression

“Animal studies have also shown that chronic nicotine administration can elicit antidepressant-like effects in rats both in the learned helplessness (Semba et al., 1998) and the forced swim (Djuric et al., 1999; Tizabi et al., 1999) paradigms.”

“In the forced swim model of depression, the antidepressant effect of nicotine was observed in the Flinders Sensitive Line (FSL) of rats, but was not seen in the Flinders Resistant Line (FRL) (Tizabi et al. 1999).”

“without a pretest in the Flinders Sensitive Line of rats, but not in the Flinders Resistant Line of rats (Tizabi et al. 1999).”

“In animal model studies, it is clear that nicotine reduces depressive-like symptoms such as helplessness and anhedonia (Djuric et al. 1999; Kalejaiye et al. 2011, 2012; Semba et al. 1998; Tizabi et al. 1999, 2000, 2009b, 2010).”

“Nicotine also has antidepressant-like effects in the forcedswim test (Tizabi et al. 1999; Tizabi et al. 2000) in Flinders-sensitive rats, a strain of rat that has been proposed as an animal model of depression (Overstreet 1995; Overstreet et al.”

“Nicotine treatment has antidepressant-like effects in several animal models of depression-like behavior, including the FST 152, 153 , the TST 154 and the olfactory bulbectomy model 155 .”

“…antidepressant effects of acute nicotine on learned helplessness (Semba et al. 1998) and other depression behaviors (Djuric et al. 1999; Tizabi et al. 1999), the effect of antidepressants such as bupropion as smoking cessation aids (Hurt et al. 1997) and that some antidepressants also…”

“…decreased immobility time in both the forced swim and tail suspension tests (Andreasen and Redrobe 2009b; Djuric et al. 1999; Semba et al. 1998; Tizabi et al. 1999), two laboratory paradigms that are frequently used to evaluate a candidate drug for potential antidepressant effects (Porsolt et…”

“Each frozen brain was later thawed on ice and hippocampus (bilateral) was dissected alternating between treatment groups as described previously (Tizabi et al. 1999, 2001).”

“Each frozen brain was later thawed on ice and hippocampus (bilateral) and frontal cortex up to the genu of corpus callosum was dissected as described previously [49].”

“…in agreement with basic and clinical studies showing that nicotine has antidepressant properties (Salin-Pascual et al, 1996; Suemaru et al, 2006; Tizabi et al, 1999; Vazquez-Palacios et al, 2004), the well-known effects of antidepressant treatment in the FST (Cryan et al, 2002), and with…”

“Animal studies have also shown that chronic nicotine administration can elicit antidepressantlike effects in rats both in the learned helplessness (Semba et al., 1998) and the forced swim (Djuric et al., 1999; Tizabi et al., 1999) paradigms.”

“Other studies from our laboratory [136,137] and from others [138,139] suggest interactions between antidepressants and some nAChR subtypes, but specific studies examining a6*-nAChRs have not yet been performed.”

“Nicotine also has antidepressant-like effects in the forced-swim test (Tizabi et al. 1999, 2000) in Flinders-sensitive rats, a strain of rat that has been proposed as an animal model of depression (Overstreet 1995; Overstreet et al. 1995).”

“Flinders sensitive rats are more immobile in the FST than their control counterparts, and both acute and chronic nicotine administration have an antidepressant-like effect in the FST in Flinders sensitive,but not control, rats (Tizabi et al. 1999).”

“Recent reports of differences in nicotinic mechanisms (Auta et al., 2000; Tizabi et al., 1999, 2000 ) have confirmed earlier reports of differences in nicotine sensitivity (Dilsaver et al., 1992; Schiller and Overstreet, 1993).”

“Furthermore, nicotine binds to neuronal nicotinic acetylcholine receptors (nAChRs) and partial agonists and antagonists of nAChRs including nicotine (14), mecamylamine and dihydro-betaerythroidine (DHβE) (15), cytisine (16) and varenicline (17), have antidepressant-like effects in preclinical studies.”

“In regard to depression, an antidepressant effect of nicotine has been well established by preclinical (Djuric et al., 1999; Kalejaiye et al., 2013; Semba et al., 1998; Tizabi et al., 2009; Tizabi et al., 2010; Tizabi et al., 1999; Tizabi et al., 2000), as well as few clinical studies (Cook et al.”

“This might be the reason for nicotine's antidepressant-like effects that have been reported, for instance, in genetic depressive rats of the Flinders Sensitive Line (Tizabi et al. 1999).”

“Animal studies support the role of nAChR systems in the pathophysiology of depression (Dursun and Kutcher 1999) as nicotine and nAChR agonists have demonstrated antidepressant effects in genetic (Djuric et al. 1999; Tizabi et al. 1999) and behavioral (Ferguson et al.”

“Interestingly, stimulation of cholinergic system by nicotine ameliorates depressive-like behaviors [59].”

“Indirect evidence for the involvement of nicotinic acetylcholine receptors in depression has been reported (Tizabi et al., 1999).”

“In rats, antidepressant-like effects are repeatedly reported with acute administration of nicotine (Tizabi et al., 1999, 2000, 2008; Vazquez-Palacios et al., 2004, 2005; Nowakowska et al., 2006) or subtype-selective nAChR agonists (Ferguson et al., 2000; Buckley et al., 2004; Pichat et al., 2007).”

“Nicotine is thought to have anti-depressant properties [25,26], as it is considered to increase the activity of the serotonergic system [27], acting in a similar manner to common antidepressants by targeting serotonin transmission.”

“Some studies suggest that even subtle changes in genetic makeup (different strains of rats) can alter sensitivity to drugs and the rewarding release of dopamine (see ‘‘Reward Pathway Activation’’ section: Cadoni et al. 2009).”

“, 1998] and the evidence that nicotine has antidepressant properties [Tizabi et al., 1999], the present findings also support the hypothesis that many of nicotine’s therapeutic effects may be attributed to its ability to induce the prolonged inactivation of various nAChRs following chronic administration [Lukas et al.”

“In these rats, which in drug-free state demonstrate an exaggerated immobility in the forced swimming test, acute or chronic administration of nicotine (0.4mgkg 1 s.c.) significantly improved the performance in the forced swimming test (Tizabi et al., 1999).”

“Similarly, acute and chronic treatment with nicotine, which has no antidepressant activity, both exhibit an antidepressant-like effect on the behaviour of FSL rats in the forced swim test [85]; this effect was blocked by prior treatment with the nicotinic receptor antagonist, mecamylamine [86].”

“For sample collection, frozen brains were thawed on ice and frontal cortex and hippocampus (bilateral) were dissected alternating between strains and treatment groups as described previously (Tizabi et al. 1999, 2000; Getachew et al. 2010).”

“However, as mentioned above, “antidepressant” effects for NC have also been reported clinically [11], and were also observed in some animal models [43-45].”

“However, some authors have observed decreased depression-like phenotypes in response to nicotine only in rat strains that display enhanced basal levels of depressive features, with contradictory effects depending on the post-injection time of the testing (311, 315, 318).”

“The data obtained from the OFT experiment further showed that the spontaneous activity and exploratory behavior were significantly enhanced by nicotine, suggesting that the anxiety symptoms were efficiently relieved by nicotine, which was mostly similar to a standard antidepressant drug, fluoxetine [8, 9].”

“Furthermore, nicotine has been reported to have antidepressant properties in depressed individuals (Glassman, 1993; Salin-Pascual and Drucker-Colin, 1998) and in animal models of depression (Tizabi et al., 1999).”

“…effect in the forced swim test (Andreasen & Redrobe, 2009; Suemaru et al., 2006; Tizabi, Getachew, Rezvani, Hauser, & Overstreet, 2009, Tizabi et al., 1999; Vázquez-Palacios, Bonilla-Jaime, & VelázquezMoctezuma, 2005), the chronic mild stress sucrose test (Andreasen, Henningsen, Bate,…”

“Thesefindings are in contrast to previous reports where an antidepressant-like effect of nicotine in other animal models of depression (e.g., FSL and FawnHooded rats) was observed regardless of such temporal consideration (Djuric et al., 1999; Tizabi et al., 1999, 2000, 2009).”

“In rats the more consistent finding is antidepressant-like effects for nicotine but not the nAChR antagonist mecamylamine, with nicotine being associated with decreased depressive behaviors after both acute and chronic administration of up to 2 weeks (Semba et al., 1998; Tizabi et al., 1999; Vázquez-Palacios et al., 2…”

“Pascual et al., 1996; Tizabi et al., 1999 .”

“1996) and animal (Tizabi et al. 1999; Vazquez-Palacios et al. 2004) studies is recognized, the underlying mechanism for this effect has not yet been carefully discovered.”

“The forced swim test has been reported to yield false positive results following acute administration of certain drugs that lack genuine antidepressant effects such as the motor stimulants caffeine, nicotine, and amphetamine (Porsolt et al. 1977, Detke et al. 1995,Tizabi et al. 1999).”

“effects in rats in learned helplessness (Semba et al., 1998; Ferguson et al., 2000) and forced swim models ( Tizabi et al., 1999 ) of depression.”

“ministration in a forced swim test (Tizabi et al., 1999).”

“observations: chronic administration of nicotine can elicit antidepressant-like effects in rats in various well-established paradigms (Semba, Mataki, Yamada, Nankai, & Toru, 1998; Djuric, Dunn, Overstreet, Dragomir, & Steiner, 1999; Tizabi et al., 1999).”

“In turn, the antidepressant effects of smoking and nicotine (Brody, 2006; Tizabi et al., 1999) reinforce cigarette use and increase the likelihood of future use.”

“A number of preclinical (Semba et al. 1998; Djuric et al. 1999; Tizabi et al. 1999, 2000, 2009, 2010; Kalejaiye et al. 2013) as well as a limited number of clinical studies (Pomerleau and Pomerleau 1992; Salin-Pascual et al. 1995; McClernon et al. 2006; Cook et al. 2007) have verified…”

“…et al. 2007; Rabenstein et al. 2006), rats tend to exhibit greater sensitivity to the antidepressant-like effect of agonists (e.g., nicotine) rather than antagonists (e.g., mecamylamine) (Djuric et al. 1999; Semba et al. 1998; Tizabi et al. 1999; Tizabi et al. 2000; Vieyra-Reyes et al. 2008).”

“In the rat forced swim test (rFST), antidepressant-like effects of nicotine have been observed after both acute and chronic administration (Djuric et al., 1999; Nowakowska et al., 2006; Tizabi et al., 1999, 2009; Vazquez-Palacios et al., 2005).”

“In agreement, nicotine has been shown to improve emotional responses in both humans and animals with signs of anhedonia (Tizabi et al., 1999; Cook et al., 2007; Spring et al., 2008), and the manifestations of anhedonia have been widely reported in CB1 knockout mice (Martin et al., 2002).”

“In rodents, several studies of nicotine administration have identified antidepressant-like effects during the forced swim test (FST) and tail suspension test (TST) [20–23], two preclinical models used to investigate potential antidepressant effects of candidate compounds [24, 25].”

“Preclinical data have shown that nicotine has antidepressant properties in different animal models of depression (Semba et al., 1998; Tizabi et al., 1999, 2000; Ferguson et al., 2000), and that knockout mice lacking the b2 subunit (b2 – / – ) are more prone to learned helplessness (Caldarone et…”

“In view of the premise that smoking is a form of self-medication for many people with affective disorders, it is not surprising that nicotine has been shown to have significant effects in several animal models of depression, including the learned helplessness paradigm [83] , the forced swim test [84] and the Flinders…”

“…behavioral testing, animals were sacrificed and their brains were removed and stored at −80 °C. Frozen brain tissues were thawed on ice and frontal cortex and hippocampus (bilateral) were dissected alternating between strains and treatment groups as described previously (Tizabi et al., 1999, 2001).”

“Nicotine in some strains of rats that do not manifest exaggerated immobility in the FST may decrease this immobility (Djuric et al.,, 1999).”

“As mentioned above, nicotinic agonists may have therapeutic potentials in various psychiatric disorders (Freedman et al. 1997; Sanberg et al. 1997; see also Tizabi et al. 1998, 1999 ).”

“…antidepressant-like effects in BALB/c and C57BL6/J mice (Andreasen and Redrobe, 2009a), supporting numerous rat studies (e.g. Semba et al., 1998; Tizabi et al., 1999, 2000, 2009; Vazquez-Palacios et al., 2004, 2005), as well as clinical reports of antidepressant effects of nicotine in human…”