In the public domain http://dx.doi.org/10.1037/bne0000021

Behavioral Neuroscience 2014, Vol. 128, No. 6, 713-721

Cotinine Reduces Depressive-Like Behavior and Hippocampal Vascular Endothelial Growth Factor Downregulation After Forced Swim Stress in Mice J. Alex Grizzell

Michelle Mullins

Bay Pines VA Healthcare System, Bay Pines, Florida, and University of South Florida

Bay Pines VA Healthcare System, Bay Pines, Florida

Alexandre Iarkov

Adeeb Rohani and Laura C. Charry

Bay Pines VA Healthcare System, Bay Pines, Florida, and Universidad Autonoma de Chile

Bay Pines VA Healthcare System, Bay Pines, Florida

Valentina Echeverria Bay Pines VA Healthcare System, Bay Pines, Florida, Tampa VA Healthcare System, Tampa, Florida, University of South Florida, and Universidad Autonoma de Chile Cotinine, the predominant metabolite of nicotine, appears to act as an antidepressant. We have previously shown that cotinine reduced immobile postures in Porsolt’s forced swim (FS) and tail suspension tests while preserving the synaptic density in the hippocampus as well as prefrontal and entorhinal cortices of mice subjected to chronic restraint stress. In this study, we investigated the effect of daily oral cotinine (5 mg/kg) on depressive-like behavior induced by repeated, FS stress for 6 consecutive days in adult, male C57BL/6J mice. The results support our previous report that cotinine administration reduces depressive-like behavior in mice subjected or not to high salience stress. In addition, cotinine enhanced the expression of the vascular endothelial growth factor (VEGF) in the hippocampus of mice subjected to repetitive FS stress. Altogether, the results suggest that cotinine may be an effective antidepressant positively influencing mood through a mechanism involving the preservation of brain homeostasis and the expression of critical growth factors such as VEGF. Keywords: depressive disorders, forced swim, neurogenesis, vascular endothelial growth factor

Depression is a mental disorder characterized by changes at the physiological, psychological, and behavioral levels. Highly prev­ alent, this disorder affects approximately 25% of women and 12% of men, and it is the leading cause of disability worldwide (Gelenberg, 2010; McIntyre, Liauw, & Taylor, 2011). Depression often manifests through multiple symptoms, including despair, guilt, anhedonia, psychomotor dysfunction, reduced positive af­ fect, and memory impairment (Nutt et al., 2007). High comorbidity

rates between depression and anxiety disorders as well as dementia have also been well described (Berger, Fratiglioni, Winblad, & Backman, 2005; Momartin, Silove, Manicavasagar, & Steel, 2004). The efficacy of treating depressive conditions is diminished by high rates of treatment resistance, and many fail to reach full remission (Philip, Carpenter, Tyrka, & Price, 2010b). Thus, a determined effort to identify and develop new therapies on the basis of validated disease mechanisms to treat depression is required.

This article was published Online First October 13, 2014. J. Alex Grizzell, Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System, Bay Pines, Florida and Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida; Michelle Mullins, Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System; Alexandre Iarkov, Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System and Universidad Autonoma de Chile, Facultad de Ciencias de la Salud; Adeeb Rohani and Laura C. Charry, Research and Development Service, Depart­ ment of Veterans Affairs, Bay Pines VA Healthcare System; Valentina Echeverria, Research and Development Service, Department of Veterans Affairs, Bay Pines VA Healthcare System, Research Service, Department of Veterans Affairs, Tampa VA Healthcare System, Tampa, Florida, De­

partment of Molecular Medicine, University of South Florida, and Univer­ sidad Autonoma de Chile, Facultad de Ciencias de la Salud. This material is the result of work supported with resources and the use of facilities at the Bay Pines VA Health Care System and the James A. Haley Veterans’ Hospital. The contents do not represent the views of the Department of Veterans Affairs or the U.S. Government. This work was also supported by the Bay Pines Foundation, Inc., and a grant obtained from the James and Esther King Biomedical Research Program 1KG03-33968 (to V.E.). We will be forever indebted to Ms. Rosalee Holmes, a member of our team that passed away before submission of this article. Correspondence concerning this article should be addressed to Valentina Echeverria, 10,000 Bay Pines Boulevard, Building 22, Room 123, Bay Pines, FL 33744. E-mail: [email protected]

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Experiencing physical or psychological stress is one of the more frequent external causes of depression (Bosch, Seifritz, & Wetter, 2012). The stimulation of the hypothalamic-pituitary-adrenal axis by chronic stress leads to increased inflammation and oxidative stress (Zunszain, Hepgul, & Pariante, 2013), which subsequently inhibit the expression of factors that contribute to the promotion of synaptic plasticity, neurogenesis, and neuronal survival (Dwivedi, 2009). Increasing evidence suggests that this cascade of events participates in the development and maintenance of depression (Kawahara, Croll, Wiegand, & Klatzo, 1997; Kim et al., 2007; Lee & Kim, 2009; Shi et al., 2010). In fact, proinflammatory mediators produced by activated immune cells induce many behavioral changes, including depression, anxiety, impaired cognitive func­ tion, diminished activity, and reduced appetite (Hart, 1988). Cho­ linergic compounds related to nicotine, such as anatabine, regulate cytokine production and display anti-inflammatory properties (Paris et al., 2013). Because neuroinflammation is a well-known phenomenon during depression, it is possible that the modulation of inflammation by these factors is key in mediating nicotinic modulators’ observed antidepressant effects. Cotinine, a component of tobacco leaves and the predominant metabolite of nicotine, is anti-inflammatory (Rehani et al., 2008) and facilitates serotonin (5-hydroxytryptamine; 5-HT) release in the brains of rats (Fuxe, Everitt, & Hokfelt, 1979). Cotinine treatment reduces anxiety in acute stress conditions (Zeitlin et al., 2012) and depressivelike behavior in mice subjected or not to prolonged restraint stress (Grizzell & Echevenia, 2014). These effects are accompanied by a cotinine-induced stimulation of the protein kinase B (Akt)/glycogen synthase 3(3 (GSK3(3) pathway (Echeverria et al., 2011; Grizzell & Echeverria, 2014). The activation of this pathway stimulates neuronal genesis and survival and decreases depressive-like behavior (Riadh et al., 2011; Wada, 2009). In fact, most currently prescribed antidepres­ sants, such as selective-serotonin reuptake inhibitors, monoamine oxidase (MAO) inhibitors, and tricyclic antidepressants, also activate this pathway (Beaulieu, Bainetdinov, & Caron, 2009; Echeverria et al., 2011) which, in turn, stimulates the expression of neurotrophic factors such as brain-derived neurotrophic factor (Beaulieu et al., 2009) and vascular endothelial growth factor (VEGF). Activation of this pathway also stimulates an upregulation of synaptic proteins such as synaptophysin (Bring, Anderson, Guernsey, & Jolivalt, 2013) and postsynaptic density protein-95 (PSD95; Xie et al., 2011). Indeed, cotinine treatment is also associated with an increased expression of synaptophysin (Grizzell & Echeverria, 2014; Grizzell et al., 2014) and PSD95 (Patel et al., 2014) in chronic stress and Alzheimer’s disease (AD) models, respectively. Here, we report the effect of cotinine on depressive-like behavior induced by repetitive, daily forced swim (FS) stress and provide some new insight about its potential mechanism(s) of action.

Method Animals Two-month-old male C57BL/6J mice (Jackson Laboratories, Bar Harbor, ME), weighing 25-30 g, were maintained on a 12-hr light/dark cycle (light on at 7:00 a.m.) with ad libitum access to food and water at a regulated temperature (25 ± 1 °C). Upon arrival, mice were group-housed and acclimated for 7 days before any intervention. After behavioral testing, euthanasia was per­

formed via cervical dislocation under anesthesia with isofluorane (4% induction, 2% for maintenance). Experiments were performed during the light period of the circadian cycle. All treatments and activities were conducted in accordance with the Guidelines for Animal Experiments issued by the Ethics Committee of the Bay Pines Veterans Affairs Healthcare System. These experiments also followed the National Institutes of Health standards and were approved by the Institutional Animal Care and Use Committee of Bay Pines Veterans Affairs Healthcare System.

Drugs and Route of Administration Cotinine ((5S)-l-methyl-5-(3-pyridyl) pyrrolidin-2-one; SigmaAldrich Corporation, St. Louis, MO) solutions were prepared by dissolving the powdered compound in sterile phosphate buffered saline. All mice were distributed in treatment groups per random assignment and then treated with vehicle or cotinine (5 mg/kg) via gavage. The gavage technique was performed by well-trained personnel and did not induce significant stress in the mice. All investigators were blind to treatment groups, and doses were chosen based on previously conducted studies (Grizzell & Echev­ erria, 2014; Zeitlin et al., 2012). Treatments were administered for 7 days before the induction of stress. For all animals, treatment continued from the onset of treatment until euthanasia.

Behavioral Procedures To induce depressive-like behavior, we used a broadly used model of stress in rodents, the repetitive FS stress paradigm (Furukawa-Hibi et al., 2011). FS mice were subjected to daily 6-min FS sessions for 6 days. After this time, all mice were tested for depressive-like behavior using Porsolt’s forced swim test (FST) (Bhatnagar Nowak, Babich, & Bok, 2004; Porsolt, Bertin, & Jalfre, 1977a, 1977b) and the tail suspension test (TST) (Cryan, Mombereau, & Vassout, 2005). Mice were monitored via closedcircuit video feed from an adjacent room, and all behavior was recorded for later quantification. FS stress. The FS stress test was performed as described (Furukawa-Hibi et al., 2011). Each mouse was placed in an ines­ capable transparent plastic cylinder (40 cm high X 20 cm in diameter) filled with water to a depth of 30 cm. Water was changed between each trial and its temperature maintained at 23-24 °C. In all cases, after exposure, animals were retrieved, dried with a hand towel, and returned to their home cages. Mice not exposed to stress (NES) serving as the control groups were removed from the animal housing facility and taken to the behavioral testing room during the same period of time as FS mice, but they remained in their home cages during the FS exposure period. Porsolt’s FST. The FST was performed as previously de­ scribed (Bhatnagar et al., 2004; Grizzell & Echeverria, 2014; Porsolt et al. 1977a, 1977b). The FST was developed based on the fact that rodents, when exposed to an inescapable stress, will engage in periods of fast movement followed by increasing periods of immobile posture, which is considered to be a measure of depressive-like behavior. Each mouse was placed in a transparent plastic cylinder filled with water at 23-24 °C as described in the previous section, and behavior was recorded for 5 min. Immobility times were scored by investigators blind to treatment levels. Im­ mobility was defined as the time spent floating, only making the movements necessary to maintain the head above the water.

COTININE IMPROVES MOOD AFTER FORCED SWIM STRESS

TST. The TST is a widely used instrument for quantifying depressive-like behavior in rodents (Cryan et al., 2005; Grizzell & Echeverria, 2014). This test is predicated upon the fact that ani­ mals subjected to the short-term unavoidable stress of being sus­ pended by their tail will develop an immobile posture and/or cessation of struggling behavior, which is considered analogous to depressive behavior. A strip of masking tape (20 cm X 1.9 cm) was positioned to encapsulate the tail of the mouse to prevent fall or injury. The end of the tape was adhered to a blunt hook suspended upside-down such that the tip of nose was approxi­ mately 6 in. from the floor of the TST chamber. Immobility, defined as the summation of time the animal does not struggle to escape, was measured during one 5-min trial and quantified sep­ arately by two investigators blind to treatment groups.

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Experimental Conditions Effect of cotinine on depressive-like behavior in mice. After 1 week of treatments, mice treated with vehicle or cotinine (5 mg/kg; n = 10/group) via gavage were exposed under continue treatment to 6-min FS stress for 6 consecutive days. Two additional control groups, NES mice, were treated with vehicle or cotinine via gavage (5 mg/kg; n = 10/group). Twenty-four and 48 h after the last FS session, mice in all groups were tested for depressive-like behavior using the TST and FST, respectively (Figure la). Western blot analysis of brain extracts. Western blot analy­ sis investigated the expression of VEGF (FS mice: n = 8/group; NES mice: n = 4-6/group). After euthanasia, mice were perfused with saline, and brain tissues were rapidly dissected and stored at —80 °C. Brain tissues were then disrupted by sonication in cold lyses buffer (Cell Signaling Technology, Danvers, MA) containing a complete protease inhibitor cocktail (Roche Molecular Biochemicals, Pleasan­ ton, CA). After sonication, brain extracts were incubated on ice for 30 min and centrifuged at 20,000 g for 30 min at 4 °C. Protein concen­ trations of supernatants were measured using the Bio-Rad protein assay (Bio-Rad, Hercules, CA). Equal amounts of protein were sep­ arated by gradient (4-20%) and sodium dodecyl sulfatepolyacrylamide gel electrophoresis, and they were then transferred to nitrocellulose membranes (BA83 0.2 p,m; Bio-Rad). The membranes were blocked in tris-buffered saline (TBS) with 0.1% Tween 20 (TBST) containing 5% dry skim milk for 1 hr. Membranes were incubated with primary antibodies in TBST overnight at 4 °C and with secondary antibodies for 1 hr at room temperature (RT) in a blocking buffer. Rabbit polyclonal antibodies directed against VEGF were obtained from Abeam (Cambridge, MA). A monoclonal anti­ body directed against p-tubulin (Promega Corporation, Madison, Wl) was used to control protein sample loading and transfer efficiency. Membranes were washed with TBST and incubated with LI-COR’s goat anti-mouse LRDye secondary antibodies (LI-COR Biosciences, Lincoln, NE) for 1 hr at RT and then washed with TBST and TBS. Images were acquired using an Odyssey Infrared Imaging System (LI-COR Biosciences) and analyzed using the National Institutes of Health Image J software.

Statistical Analysis To analyze the group and treatment effects, differences between group means in the behavioral analyses were assessed using a multifactorial, 2 (Treatment) X 2 (Stress) analysis of variance

Figure 1. Effect of cotinine on depressive-like behavior induced by repetitive FS stress in mice. A timeline (a) depicts mice were pretreated with 5 mg/kg of cotinine (Cot 5) or vehicle (Veh) daily for 1 week before 6 min daily for 6 days repetitive FS and continuously treated until eutha­ nized. Twenty-four and 48 hr after the cessation of FS exposure, depressive-like behaviors were assessed using the TST and Porsolt’s FST, respectively. FS exposure induced a significant increase in immobile postures, and cotinine significantly reduced these postures in the (b) TST and (c) FST. Tukey’s post hoc analyses revealed the reported differences between FS-exposed vehicle and cotinine-treated mice: **/> < .01; ****/? < .0001.

(ANOVA) and were followed by Tukey’s post hoc multiple com­ parisons tests. A one-way ANOVA was used to identify differ­ ences between groups in the analysis of VEGF protein expression between vehicle- and cotinine-treated FS mice and vehicle-treated NES mice. Student’s t test was use to compare protein expression data between NES mice treated with vehicle or cotinine because these were run on a separate gel. Statistical analyses were con­ ducted using statistical software packages (SPSS, Chicago, IL, and GraphPad Prism, San Diego, CA). For all comparisons, statistical significance was considered with a = .05. All error bars shown in figures represent the standard error of the mean (SEM).

Results Effect of Cotinine on Depressive-Like Behavior After Repetitive FS Stress To investigate whether continuous daily treatments with coti­ nine beginning 1 week before the induction of stress could prevent

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the increase in depressive-like behavior induced by 6 min/day for 6 days of FS stress, mice were subjected to the TST and FST 24 and 48 hr after the cessation of FS stress (Figure la). Results of a multifactorial, 2 (Treatment) X 2 (Stress) ANOVA of TST (Figure lb) revealed significant main effects of treatment (F(1>36) = 19.39, p < .0001) and stress (F(136) = 48.13, p < .0001). Results of a similar analysis on FST (Figure lc) also revealed significant main effects of treatment (F(1>36) = 29.54, p < .0001) and stress (Fd,36) = 204.30, p < .0001). Results of Tukey’s post hoc test revealed that in the TST (Figure lb), vehicle-treated FS mice displayed higher levels of immobility than NES mice (p < .0001) and cotinine-treated FS mice (p < .01). Tukey’s post hoc test also revealed that in Porsolt’s FST (Figure lc), vehicle-treated, stressed mice displayed significantly more immobility than NES (p < .0001) and cotinine-treated FS cohorts (p < .0001).

Analysis of the Protein Expression of VEGF in the Hippocampus of Mice After Repetitive FS Stress VEGF is a neurotrophin that modulates blood flow and angio­ genesis and is involved in neurogenesis (Cao et al., 2004; Fabel et al., 2003; Jin et al., 2002). In a pilot mRNA expression reverse transcriptase-polymerase chain reaction assay analysis, we found that the mRNA expression of VEGF-A was upregulated in the hippocampus of cotinine-treated FS mice when compared with vehicle-treated FS mice {p < .01; data not shown). Therefore, we investigated their associated protein expression levels in the hip­ pocampus of the same mice using Western blot analysis. The results show that the groups differed significantly from one an­ other (F(2 lg) = 14.93, p = .0002; Figure 2b), and Tukey-Kramer’s post hoc analyses revealed that vehicle-treated mice subjected to repetitive FS stress had a significant decrease in the expression of VEGF in the hippocampus (p < .001). On the other hand, FS mice treated with cotinine showed significantly higher levels of VEGF expression in the hippocampus than vehicle-treated FS mice (p < .05) to reach levels not significantly different than those of NES mice (p > .05; Figure 2b). Finally, in the absence of stress, a Student’s t test revealed that cotinine induced no changes in VEGF expression between cotinine and vehicle-treated mice, t = 0.2910, p = .7795 (Figure 2a).

Discussion We have previously shown that cotinine prevented depressivelike behavior in rodent models of mental health conditions (Grizzell & Echeverria, 2014; Patel et al., 2014). The present study investigated the molecular mechanisms of cotinine’s antidepres­ sant effects in a model of stress-induced impairment, the repetitive FS stress test. The behavioral tests showed that cotinine reduced depressive-like postures in the FST and TST, and neurochemical analysis revealed that cotinine prevented the stress-induced de­ crease of VEGF in the hippocampus of stress-exposed mice. The antidepressant properties of cotinine found in this study are in agreement with our recent reports showing that cotinine reduced depressive-like behavior in mice subjected to chronic restraint stress (Grizzell & Echeverria, 2014) as well as mice developing AD-like pathology (Patel et al., 2014). The antidepressant effect of cotinine in the restrained mice was accompanied by an increase in synaptic density in the CA1, CA3, and dentate gyrus of the

hippocampus as well as in the prefrontal and entorhinal cortices (Grizzell & Echeverria, 2014). Consistent with an effect of cotinine on synaptic function, cotinine’s positive effects on depressive-like behavior corresponded with an increase in the expression of PSD95 in the brain of AD mice (Patel et al., 2014). The TST and FST are highly regarded as valid and reliable tests of depressive-like behaviors, particularly in screening the efficacy of antidepressant compounds (Bourin & Hascoet, 2003; Ramos, 2008). In this study, both tests were included to control for indi­ vidual test limitations and to ensure a reliable antidepressant-like effect because some commonly prescribed antidepressants have only shown efficacy in one but not both. After 1 week of pretreat­ ment, we observed significant decreases in depressive-like behav­ ior in the TST and FST in the mice treated with cotinine. Because the interpretations of these tests are inherently reliant on sensori­ motor abilities, it would be plausible to attribute this effect to a cotinine-induced alteration of locomotor activity. However, based on previously reported evidence, the possibility that the observed decrease in immobility in these tests was due to a cotinine-induced decrease in locomotion is unlikely. A cotinine treatment regimen similar to that used in this study did not influence ambulation or sensorimotor abilities in the open field test either with or without exposure to an acute stressor (Zeitlin et al., 2012). In another study, cotinine-treatment did result in a marginal, although statis­ tically insignificant, reduction of ambulation in the open field; however, these same animals also displayed more escape-oriented behavior in the FST and TST (Grizzell & Echeverria, 2014). If cotinine were to influence locomotor behavior in a manner that would confound the interpretation of depressive-like behavioral tests, then one would expect to instead see an increase in immobile postures in the cotinine-treated groups, particularly in stressful conditions. Therefore, we conclude that the observed differences between cotinine- and vehicle-treated mice in the TST and FST reported here are not due to a cotinine-induced sensitization of locomotor activity. Although recent efforts have greatly advanced the pharmacoki­ netic and pharmacodynamic properties of cotinine, the mecha­ nism^) of action is still not completely understood. We have proposed that cotinine is a positive allosteric modulator of the homomeric a7-nicotinic acetylcholine receptors (nAChRs; Griz­ zell & Echeverria, 2014; Moran, 2012). Recent reports have shown in vivo evidence suggesting that cotinine’s effects are mediated by oil- and a4p2-nAChRs (de Aguiar, Parfitt, Jaboinski, & Barros, 2013; Wildeboer-Andrud, Zheng, Choo, & Stevens, 2014). Further pharmacological studies are required to determine whether these are the targets mediating cotinine’s antidepressant effects. The role of cotinine’s precursor, nicotine, in influencing depressive- and anxiety-like behavior in rodents appears to be somewhat equivocal (Fernandez, Grizzell, & Wecker, 2013; Philip, Carpenter, Tyrka, & Price, 2010a; Picciotto, Brunzell, & Caldarone, 2002). For exam­ ple, it has been reported that repetitive doses of nicotine reduced (Djuric, Dunn, Overstreet, Dragomir, & Steiner, 1999; Semba, Mataki, Yamada, Nankai, & Torn, 1998; Tizabi, Getachew, Rezvani, Hauser, & Overstreet, 2009) and induced (Hayase, 2007, 2008, 2013) depressive-like behavior. However, it has been sug­ gested that nicotine’s effects in the central nervous system may be due to complex relationships with its metabolites, most likely cotinine (Crooks & Dwoskin, 1997; Grizzell & Echeverria, 2014).

COTININE IMPROVES MOOD AFTER FORCED SWIM STRESS

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Figure 2. Cotinine treatment prevents the stress-induced decrease in the expression of VEGF in the hippocam­ pus of mice subjected to repetitive FS stress. The levels of VEGF and (3-tubulin in the hippocampus of mice were analyzed by Western blot (n = 5/group). The plots represent VEGF IRs in the hippocampus of mice, (a) Effect of cotinine on VEGF expression in NES mice, (b) Comparison of the expression of VEGF in vehicle-treated NES, vehicle-treated FS mice (FS + Veh), and cotinine-treated FS mice (FS + Cot 5). IRs were normalized to (3-tubulin and expressed as a percentage of the average value found in vehicle-treated NES mice. Western blot images are seen beneath each comparison, (c) Diagram representing potential molecular mechanisms underlying cotinine’s antidepressant effects. Cotinine, by positively modulating the a7nAChR or through other unidentified receptors, activates Akt, which stimulates CREB transcriptional activity and the expression of synaptic proteins such as PSD95, synaptophysin, and VEGF. CBP = CREB binding protein, CRE = cAMP-response element, CREB = CRE binding protein, ns = no significant difference, PI3K = phosphoinositide 3-kinase, IRs, immunoreactivity values. *** p < .001. See the online article for the color version of this figure.

There is consensus that the deleterious effects of stress result, at least in part, from a deregulation of the central monoamine sys­ tems. A decrease in MAO activity has been shown in the brains tobacco smokers (Fowler et al., 1996). Because MAO degrades dopamine, noradrenalin, and serotonin, it has been suggested that certain tobacco constituents, nicotine excluded, may acts as MAO inhibitors (Fowler et al., 1996). Cotinine has been shown to in­ crease the release and reduce the uptake of 5-HT in the brains of rats (Fuxe et ah, 1979). Thus, our results may be explained by an enhancement of the serotonergic system, which decreased the effect of stress, thereby reducing the engagement in depressivebehavior in the FS-exposed mice treated with cotinine. At the neurochemical level, we found that cotinine upregulated VEGF expression in the hippocampus of mice subjected to FS

stress. VEGF is a cytokine that plays an important role in modu­ lating neurogenesis and angiogenesis (Antequera et ah, 2012; Galvan, Greenberg, & Jin, 2006; Jin, Mao, & Greenberg, 2006; Schanzer et ah, 2004; Sun et ah, 2006). Stress reduces hippocam­ pal neurogenesis (Gould & Tanapat, 1999), and the enhancement of hippocampal neurogenesis buffers the stress response as well as associated depressive-like behaviors (Snyder, Soumier, Brewer, Pickel, & Cameron, 2011). VEGF is also neuroprotective (GoraKupilas & Josko, 2005). For example, increased VEGF levels prevent motor neuron degeneration induced by expression of a mutant form of the superoxide dismutase-1 (Lunn, Sakowski, Kim, Rosenberg, & Feldman, 2009). Furthermore, environmental en­ richment, considered of therapeutic value against depression (Han­ nan, 2014), enhances neurogenesis and hippocampal VEGF levels

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Figure 3. Diagram describing the postulated effects of stress and cotinine on depressive-like behavior and neuroplasticity. Stress decreases the ex­ pression of neurogenesis and neuroplasticity factors. Cotinine restores and/or preserves these cellular neuroplasticity processes and decreases stress-induced depressive-like behavior (Grizzell & Echeverria, 2014). See the online article for the color version of this figure.

(Cao et al., 2004). Moreover, increases in VEGF expression not only stimulate adult hippocampal neurogenesis, but they also con­ fer antidepressant-like effects in rodents (Fournier & Duman, 2012). Recent studies suggested that VEGF may be deregulated during depression (Fournier & Duman, 2012; Kahl et al., 2009), and the induction of its expression in the hippocampus is required for the effects of various antidepressants (Greene, Banasr, Lee, Wamer-Schmidt, & Duman, 2009; Wamer-Schmidt & Duman, 2007). This report provides novel evidence that cotinine prevents the decrease in the expression of VEGF in the hippocampus of mice exposed to high-salience stress. A modulation of VEGF expression by cotinine was previously suggested by an in vitro study using isolated carotid arteries that showed that cotinine and nicotine increased the mRNA and protein expression of VEGF in endothe­ lial cells (Conklin, Zhao, Zhong, & Chen, 2002). However, be­ cause cotinine did not induce any changes in VEGF expression in the control mice in this report, it is possible that cotinine is restoring VEGF expression by positively influencing molecular mechanisms of homeostasis only under conditions of stress. Taken together, we postulate that cotinine promotes restorative cerebral changes by stimulating signaling factors such as VEGF, which may, in turn, promote plasticity processes such as neurogenesis, and therefore enhanced stress resiliency and mood. These studies support the hypothesis that cotinine acts as an antidepressant, probably through a mechanism that involves the stimulation of synaptic plasticity processes such as neurogenesis and neuropro­ tection, by preserving the expression of neurogenesis factors such as VEGF. Outside of our laboratory, very little research has been con­ ducted investigating the influence of cotinine on symptoms asso­

ciated with depression. To our knowledge, no peer-reviewed lit­ erature has been reported documenting the investigation of cotinine on depressive-like behavior. Evidence of cotinine’s influ­ ence over mood at the clinical level has been reported (Keenan, Hatsukami, Pentel, Thompson, & Grillo, 1994). In this study, the authors conducted a randomized, double-blind, placebo-controlled, counterbalanced-order design experiment that investigated the effects of cotinine (30 mg base) given intravenously after 48 hr of absti­ nence from cigarette smoking. Serum cotinine concentrations increased to levels commonly achieved during daily cigarette smoking. Cotinine apparently produced subjective differences in self-reported ratings of restlessness, anxiety and tension, insomnia, sedation, and pleasantness when compared with placebo, although depression scores were unchanged from baseline. Not without controversy, the authors concluded that cotinine was behaviorally active in the setting of cigarette abstinence. However, almost 2 decades later, further clinical studies of the effect of cotinine on mood are almost nonexistent and no results are available on nonsmokers, stable smokers, or previous smokers outside of the withdrawal period. Aside from mood, cotinine has consistently been shown to elicit general memory enhancing effects (Buccafusco, Beach, & Terry, 2009; Buccafusco & Terry, 2009; Echeverria & Zeitlin, 2012; Echeverria et al. 2011; Grizzell & Echeverria, 2014) and these extend to conditions of prolonged stress (Grizzell & Echeverria, 2014). This said, one pilot clinical study did report an impairment of verbal recall on a long but not short list after cotinine treatment at doses up to 1.5 mg cotinine base/kg (Herzig et al., 1998). In the 16 individuals tested, there were also no reported changes in the profile of mood state scores after cotinine treatment (Herzig et al., 1998). However, because of the size of this study, its results must be taken with caution. In addition cotinine has been shown to reduce anxiety in abstaining cigarette smokers (Keenan et al., 1994) and anxiety-like behavior in rodents after acute-stress ex­ posure (Zeitlin et al., 2012). The consistency of cotinine in reducing depressive-like behavior with and without exposure to chronic stress conditions (Grizzell & Echeverria, 2014; Patel et al., 2014; Zeitlin et al., 2012) highlights the need to further investigate its ability to treat depression. This is particularly true when considering that cotinine has good pharma­ cokinetic properties (De Schepper, Van Hecken, Daenens, & Van Rossum, 1987) and a positive safety profile in humans, which includes no habit-forming properties or withdrawal effects, among others (Echeverria Moran, 2012; Hatsukami, Grillo, Pentel, Oncken, & Bliss, 1997; Hatsukami et al., 1998a; Hatsukami et al., 1998b). Therefore, further investigation of cotinine’s mechanistic role in modulating depressive-like states at the preclinical level as well as studies aimed at determining the therapeutic efficacy at the clinical level are warranted.

Conclusions Currently used antidepressants only effectively alleviate the symptoms in a portion of depressed patients and most have a delayed therapeutic onset. Neuroplasticity theories of depression have postulated that a failure of multiple aspects of plasticity processes underlie the etiology and maintenance of depression (Duman & Aghajanian, 2012). Accordingly, new antidepressant agents are in need of further investigation. Here, we provide

COTININE IMPROVES MOOD AFTER FORCED SWIM STRESS

evidence that cotinine prevents FS-induced depressive-like behav­ ior. Previous studies using repetitive FS as a stressor have shown that depressive-like behaviors were accompanied by decreased neurogenesis and synaptic plasticity in rodents (Wainwright & Galea, 2013). This study shows that cotinine’s antidepressant effects were accompanied by a restoration in the expression of hippocampal VEGF, a factor promoting adult neurogenesis. Coti­ nine benefits synaptic plasticity, learning, and memory, and it enhanced the expression of the neurogenesis factor VEGF under conditions of stress, which are effects similar to those of other antidepressants. Altogether, this evidence suggests that cotinine has the potential to be a new antidepressant agent and warrants clinical investigation.

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Received March 13, 2014 Revision received August 12, 2014 Accepted September 2, 2014 ■

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