Effects of social dominance and acute social stress on morphology of microglia and structural integrity of the medial prefrontal cortex.

Chronic stress increases activity of the brain's innate immune system and impairs function of the medial prefrontal cortex (mPFC). However, whether acute stress triggers similar neuroimmune mechanisms is poorly understood. Across four studies, we used a Syrian hamster model to investigate whether acute stress drives changes in mPFC microglia in a time-, subregion-, and social status-dependent manner. We found that acute social defeat increased expression of ionized calcium binding adapter molecule 1 (Iba1) in the infralimbic (IL) and prelimbic (PL) and altered the morphology Iba1+ cells 1, 2, and 7 days after social defeat. We also investigated whether acute defeat induced tissue degeneration and reductions of synaptic plasticity 2 days post-defeat. We found that while social defeat increased deposition of cellular debris and reduced synaptophysin immunoreactivity in the PL and IL, treatment with minocycline protected against these cellular changes. Finally, we tested whether a reduced conditioned defeat response in dominant compared to subordinate hamsters was associated with changes in microglia reactivity in the IL and PL. We found that while subordinate hamsters and those without an established dominance relationships showed defeat-induced changes in morphology of Iba1+ cells and cellular degeneration, dominant hamsters showed resistance to these effects of social defeat. Taken together, these findings indicate that acute social defeat alters microglial morphology, increases markers of tissue degradation, and impairs structural integrity in the IL and PL, and that experience winning competitive interactions can specifically protect the IL and reduce stress vulnerability.

Voluntary alcohol consumption during distinct phases of adolescence differentially alters adult fear acquisition, extinction and renewal in male and female rats.

Alcohol use during adolescence coincides with elevated risks of stress-related impairment in adults, particularly via disrupted developmental trajectories of vulnerable corticolimbic and mesolimbic systems involved in fear processing. Prior work has investigated the impact of binge-like alcohol consumption on adult fear and stress, but less is known about whether voluntarily consumed alcohol imparts differential effects based on adolescence phases and biological sex. Here, adolescent male and female Long Evans rats were granted daily access to alcohol (15%) during either early (Early-EtOH; P25-45) or late adolescence (Late-EtOH; P45-55) using a modified drinking-in-the-dark design. Upon adulthood (P75-80), rats were exposed to a three-context (ABC) fear renewal procedure. We found that male and female Early-EtOH rats showed faster acquisition of fear but less freezing during early phases of extinction and throughout fear renewal. In the extinction period specifically, Early-EtOH rats showed normal levels of freezing in the presence of fear-associated cues, but abnormally low freezing immediately after cue offset, suggesting a key disruption in contextual processing and/or novelty seeking brought by early adolescent binge consumption. While the effects of alcohol were most pronounced in the Early-EtOH rats (particularly in females), Late-EtOH rats displayed some changes in fear behavior including slower fear acquisition, faster extinction, and reduced renewal compared with controls, but primarily in males. Our results suggest that early adolescence in males and females and, to a lesser extent, late adolescence in males is a particularly vulnerable period wherein alcohol use can promote stress-related dysfunction in adulthood. Furthermore, our results provide multiple bases for future research focused on developmental correlates of alcohol mediated disruption in the brain.

Comparing the ontogeny, neurobiology, and function of social play in hamsters and rats.

Syrian hamsters show complex social play behavior and provide a valuable animal model for delineating the neurobiological mechanisms and functions of social play. In this review, we compare social play behavior of hamsters and rats and underlying neurobiological mechanisms. Juvenile rats play by competing for opportunities to pin one another and attack their partner's neck. A broad set of cortical, limbic, and striatal regions regulate the display of social play in rats. In hamsters, social play is characterized by attacks to the head in early puberty, which gradually transitions to the flanks in late puberty. The transition from juvenile social play to adult hamster aggression corresponds with engagement of neural ensembles controlling aggression. Play deprivation in rats and hamsters alters dendritic morphology in mPFC neurons and impairs flexible, context-dependent behavior in adulthood, which suggests these animals may have converged on a similar function for social play. Overall, dissecting the neurobiology of social play in hamsters and rats can provide a valuable comparative approach for evaluating the function of social play.

Gonadal steroid hormone receptors in the medial amygdala contribute to experience-dependent changes in stress vulnerability.

Social experience can generate neural plasticity that changes how individuals respond to stress. Winning aggressive encounters alters how animals respond to future challenges and leads to increased plasma testosterone concentrations and androgen receptor (AR) expression in the social behavior neural network. In this project, our aim was to identify neuroendocrine mechanisms that account for changes in stress-related behavior following the establishment of dominance relationships over a two-week period. We used a Syrian hamster model in which acute social defeat stress increases anxiety-like responses in a conditioned defeat test in males and in a social avoidance test in females. First, we administered flutamide, an AR antagonist, via intraperitoneal injections daily during the establishment of dominance relationships in male hamsters. We found that pharmacological blockade of AR prevented a reduction in conditioned defeat in dominant males and blocked an upregulation of AR in the posterior dorsal medial amygdala (MePD) and posterior ventral medial amygdala (MePV), but not in the ventral lateral septum. Next, we administered flutamide into the posterior aspects of the medial amygdala (MeP) prior to acute social defeat stress or prior to conditioned defeat testing in males. We found that pharmacological blockade of AR in the MeP prior to social defeat, but not prior to testing, increased the conditioned defeat response in dominant males and did not alter behavior in subordinates. Finally, we developed a procedure to establish dominance relationships in female hamsters and investigated status-dependent changes in plasma steroid hormone concentrations, estrogen receptor alpha (ERα) immunoreactivity, and defeat-induced social avoidance. We found that dominant female hamsters showed reduced social avoidance regardless of social defeat exposure as well as increased ERα expression in the MePD, but no status-dependent changes in the concentration of plasma steroid hormones. Overall, these findings suggest that achieving and maintaining stable social dominance leads to sex-specific neural plasticity in the MeP that underlies status-dependent changes in stress vulnerability.

Activity of a vmPFC-DRN Pathway Corresponds With Resistance to Acute Social Defeat Stress.

The ventromedial prefrontal cortex (vmPFC) plays a critical role in stress resilience through top-down inhibition of key stress-sensitive limbic and hindbrain structures, including the dorsal raphe nucleus (DRN). In a model of experience-dependent stress resistance, socially dominant Syrian hamsters display fewer signs of anxiety following acute social defeat when compared to subordinate or control counterparts. Further, dominants activate vmPFC neurons to a greater degree during stress than do subordinates and become stress-vulnerable following pharmacological inhibition of the vmPFC. Dominants also display fewer stress-activated DRN neurons than subordinates do, suggesting that dominance experience gates activation of vmPFC neurons that inhibit the DRN during social defeat stress. To test whether social dominance alters stress-induced activity of a vmPFC-DRN pathway, we injected a retrograde tracer, cholera toxin B (CTB), into the DRN of dominant, subordinate, and control hamsters and used a dual-label immunohistochemical approach to identify vmPFC neurons co-labeled with CTB and the defeat-induced expression of an immediate early gene, cFos. Results indicate that dominant hamsters display more cFos+ and dual-labeled cells in layers V/VI of infralimbic and prelimbic subregions of the vmPFC compared to other animals. Furthermore, vmPFC-DRN activation corresponded directly with proactive behavioral strategies during defeat, which is indicative of stress resilience. Together, results suggest that recruiting the vmPFC-DRN pathway during acute stress corresponds with resistance to the effects of social defeat in dominant hamsters. Overall, these findings indicate that a monosynaptic vmPFC-DRN pathway can be engaged in an experience-dependent manner, which has implications for behavioral interventions aimed at alleviating stress-related psychopathologies.

Chemogenetic activation of an infralimbic cortex to basolateral amygdala projection promotes resistance to acute social defeat stress.

Tremendous individual differences exist in stress responsivity and social defeat stress is a key approach for identifying cellular mechanisms of stress susceptibility and resilience. Syrian hamsters show reliable territorial aggression, but after social defeat they exhibit a conditioned defeat (CD) response characterized by increased submission and an absence of aggression in future social interactions. Hamsters that achieve social dominance prior to social defeat exhibit greater defeat-induced neural activity in infralimbic (IL) cortex neurons that project to the basolateral amygdala (BLA) and reduced CD response compared to subordinate hamsters. Here, we hypothesize that chemogenetic activation of an IL-to-BLA neural projection during acute social defeat will reduce the CD response in subordinate hamsters and thereby produce dominant-like behavior. We confirmed that clozapine-N-oxide (CNO) itself did not alter the CD response and validated a dual-virus, Cre-dependent, chemogenetic approach by showing that CNO treatment increased c-Fos expression in the IL and decreased it in the BLA. We found that CNO treatment during social defeat reduced the acquisition of CD in subordinate, but not dominant, hamsters. This project extends our understanding of the neural circuits underlying resistance to acute social stress, which is an important step toward delineating circuit-based approaches for the treatment of stress-related psychopathologies.

Strategies for the Treatment of Parkinson's Disease: Beyond Dopamine.

Parkinson's disease (PD) is the second-leading cause of dementia and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra alongside the presence of intraneuronal α-synuclein-positive inclusions. Therapies to date have been directed to the restoration of the dopaminergic system, and the prevention of dopaminergic neuronal cell death in the midbrain. This review discusses the physiological mechanisms involved in PD as well as new and prospective therapies for the disease. The current data suggest that prevention or early treatment of PD may be the most effective therapeutic strategy. New advances in the understanding of the underlying mechanisms of PD predict the development of more personalized and integral therapies in the years to come. Thus, the development of more reliable biomarkers at asymptomatic stages of the disease, and the use of genetic profiling of patients will surely permit a more effective treatment of PD.

Social Dominance Modulates Stress-induced Neural Activity in Medial Prefrontal Cortex Projections to the Basolateral Amygdala.

Stress is a contributing factor in the etiology of several mood and anxiety disorders, and social defeat models are used to investigate the biological basis of stress-related psychopathologies. Male Syrian hamsters are highly aggressive and territorial, but after social defeat they exhibit a conditioned defeat (CD) response which is characterized by increased submissive behavior and a failure to defend their home territory against a smaller, non-aggressive intruder. Hamsters with dominant social status show increased c-Fos expression in the infralimbic (IL) cortex following social defeat and display a reduced CD response at testing compared to subordinates and controls. In this study, we tested the prediction that dominants would show increased defeat-induced neural activity in IL, but not prelimbic (PL) or ventral hippocampus (vHPC), neurons that send efferent projections to the basolateral amygdala (BLA) compared to subordinates. We performed dual immunohistochemistry for c-Fos and cholera toxin B (CTB) and found that dominants display a significantly greater proportion of double-labeled c-Fos + CTB cells in both the IL and PL. Furthermore, dominants display more c-Fos-positive cells in both the IL and PL, but not vHPC, compared to subordinates. These findings suggest that dominant hamsters selectively activate IL and PL, but not vHPC, projections to the amygdala during social defeat, which may be responsible for their reduced CD response. This project extends our understanding of the neural circuits underlying resistance to social stress, which is an important step toward delineating a circuit-based approach for the prevention and treatment of stress-related psychopathologies.

Dominance relationships in Syrian hamsters modulate neuroendocrine and behavioral responses to social stress.

Stress is a well-known risk factor for psychopathology and rodent models of social defeat have strong face, etiological, construct and predictive validity for these conditions. Syrian hamsters are highly aggressive and territorial, but after an acute social defeat experience they become submissive and no longer defend their home territory, even from a smaller, non-aggressive intruder. This defeat-induced change in social behavior is called conditioned defeat (CD). We have shown that dominant hamsters show increased neural activity in the ventromedial prefrontal cortex (vmPFC) following social defeat stress and exhibit a reduced CD response at social interaction testing compared to subordinates. Although the vmPFC can inhibit the neuroendocrine stress response, it is unknown whether dominants and subordinates differ in stress-induced activity of the extended hypothalamic-pituitary-adrenal (HPA) axis. Here, we show that, following acute social defeat, dominants exhibit decreased submissive and defensive behavior compared to subordinates but do not differ from subordinates or social status controls (SSCs) in defeat-induced cortisol concentrations. Furthermore, both dominants and SSCs show greater corticotropin-releasing hormone (CRH) mRNA expression in the basolateral/central amygdala compared to subordinates, while there was no effect of social status on CRH mRNA expression in the paraventricular nucleus of the hypothalamus or bed nucleus of the stria terminalis. Overall, status-dependent differences in the CD response do not appear linked to changes in stress-induced cortisol concentrations or CRH gene expression, which is consistent with the view that stress resilience is not a lack of a physiological stress response but the addition of stress coping mechanisms. Lay summary Dominant hamsters show resistance to the behavioral effects of acute social defeat compared to subordinates, but it is unclear whether social status modulates the neuroendocrine stress response in Syrian hamsters. This study indicates that dominant social status does not alter stress-induced activity of the extended hypothalamic-pituitary-adrenal (HPA) axis, which suggests that the ability of dominants to cope with social defeat stress is not associated with changes in their neuroendocrine stress response.

Intranasal cotinine improves memory, and reduces depressive-like behavior, and GFAP+ cells loss induced by restraint stress in mice.

Posttraumatic stress disorder (PTSD), chronic psychological stress, and major depressive disorder have been found to be associated with a significant decrease in glial fibrillary acidic protein (GFAP) immunoreactivity in the hippocampus of rodents. Cotinine is an alkaloid that prevents memory impairment, depressive-like behavior and synaptic loss when co-administered during restraint stress, a model of PTSD and stress-induced depression, in mice. Here, we investigated the effects of post-treatment with intranasal cotinine on depressive- and anxiety-like behaviors, visual recognition memory as well as the number and morphology of GFAP+ immunoreactive cells, in the hippocampus and frontal cortex of mice subjected to prolonged restraint stress. The results revealed that in addition to the mood and cognitive impairments, restraint stress induced a significant decrease in the number and arborization of GFAP+ cells in the brain of mice. Intranasal cotinine prevented these stress-derived symptoms and the morphological abnormalities GFAP+ cells in both of these brain regions which are critical to resilience to stress. The significance of these findings for the therapy of PTSD and depression is discussed.

Dominance status alters restraint-induced neural activity in brain regions controlling stress vulnerability.

Understanding the cellular mechanisms that control resistance and vulnerability to stress is an important step toward identifying novel targets for the prevention and treatment of stress-related mental illness. In Syrian hamsters, dominant and subordinate animals exhibit different behavioral and physiological responses to social defeat stress, with dominants showing stress resistance and subordinates showing stress vulnerability. We previously found that dominant and subordinate hamsters show different levels of defeat-induced neural activity in brain regions that modulate coping with stress, although the extent to which status-dependent differences in stress vulnerability generalize to non-social stressors is unknown. In this study, dominant, subordinate, and control male Syrian hamsters were exposed to acute physical restraint for 30min and restraint-induced c-Fos immunoreactivity was quantified in select brain regions. Subordinate animals showed less restraint-induced c-Fos immunoreactivity in the infralimbic (IL), prelimbic (PL), and ventral medial amygdala (vMeA) compared to dominants, which is consistent with the status-dependent effects of social defeat stress. Subordinate animals did not show increased c-Fos immunoreactivity in the rostroventral dorsal raphe nucleus (rvDRN), which is in contrast to the effects of social defeat stress. These findings indicate that status-dependent changes in neural activity generalize from one stressor to another in a brain region-dependent manner. These findings further suggest that while some neural circuits may support a generalized form of stress resistance, others may provide resistance to specific stressors.

Cotinine improves visual recognition memory and decreases cortical Tau phosphorylation in the Tg6799 mice.

Alzheimer's disease (AD) is associated with the progressive aggregation of hyperphosphorylated forms of the microtubule associated protein Tau in the central nervous system. Cotinine, the main metabolite of nicotine, reduced working memory deficits, synaptic loss, and amyloid ß peptide aggregation into oligomers and plaques as well as inhibited the cerebral Tau kinase, glycogen synthase 3ß (GSK3ß) in the transgenic (Tg)6799 (5XFAD) mice. In this study, the effect of cotinine on visual recognition memory and cortical Tau phosphorylation at the GSK3ß sites Serine (Ser)-396/Ser-404 and phospho-CREB were investigated in the Tg6799 and non-transgenic (NT) littermate mice. Tg mice showed short-term visual recognition memory impairment in the novel object recognition test, and higher levels of Tau phosphorylation when compared to NT mice. Cotinine significantly improved visual recognition memory performance increased CREB phosphorylation and reduced cortical Tau phosphorylation. Potential mechanisms underlying theses beneficial effects are discussed.

Neuroinflammation: A Therapeutic Target of Cotinine for the Treatment of Psychiatric Disorders?

Neuroinflammation is a common characteristic of several mental health conditions such as major depression, bipolar disorder, post-traumatic stress disorder (PTSD) and schizophrenia (SCHZ). Inflammatory processes trigger and/or further deteriorate mental functions and are regarded as targets for therapeutic drug development. Cotinine is an alkaloid present in tobacco leaves and the main metabolite of nicotine. Cotinine is safe, non-addictive and has pharmacokinetic properties adequate for therapeutic use. Research has shown that cotinine has antipsychotic, anxiolytic, and antidepressant properties and modulates the serotonergic, cholinergic and dopaminergic systems. Consistent with the modulation of these neurotransmitter systems, cotinine behaves as a positive allosteric modulator of the nicotinic acetylcholine receptors (nAChRs) and has anti-inflammatory effects. The decrease in neuroinflammation induced by the stimulation of the cholinergic system seems to be a key element explaining the beneficial effects of cotinine in a diverse range of neurological and psychiatric conditions. This review discusses new evidence of the role of neuroinflammation as a key aspect in bipolar disorder, PTSD and major depression, as well as the potential use of cotinine to reduce neuroinflammation in those conditions.

New Insights into the Mechanisms of Action of Cotinine and its Distinctive Effects from Nicotine.

Tobacco consumption is far higher among a number of psychiatric and neurological diseases, supporting the notion that some component(s) of tobacco may underlie the oft-reported reduction in associated symptoms during tobacco use. Popular dogma holds that this component is nicotine. However, increasing evidence support theories that cotinine, the main metabolite of nicotine, may underlie at least some of nicotine's actions in the nervous system, apart from its adverse cardiovascular and habit forming effects. Though similarities exist, disparate and even antagonizing actions between cotinine and nicotine have been described both in terms of behavior and physiology, underscoring the need to further characterize this potentially therapeutic compound. Cotinine has been shown to be psychoactive in humans and animals, facilitating memory, cognition, executive function, and emotional responding. Furthermore, recent research shows that cotinine acts as an antidepressant and reduces cognitive-impairment associated with disease and stress-induced dysfunction. Despite these promising findings, continued focus on this potentially safe alternative to tobacco and nicotine use is lacking. Here, we review the effects of cotinine, including comparisons with nicotine, and discuss potential mechanisms of cotinine-specific actions in the central nervous system which are, to date, still being elucidated.

Cotinine reduces depressive-like behavior and hippocampal vascular endothelial growth factor downregulation after forced swim stress in mice.

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. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Cotinine halts the advance of Alzheimer's disease-like pathology and associated depressive-like behavior in Tg6799 mice.

Alzheimer's disease (AD) is associated with cognitive and non-cognitive symptoms for which there are currently no effective therapies. We have previously reported that cotinine, a natural product obtained from tobacco leaves, prevented memory loss and diminished amyloid-ß (Aß) plaque pathology in transgenic 6799 mice (Tg6799 mice) when treated prior to the development of the pathology. We have also shown that cotinine reduces depressive-like behavior in normal and chronically stressed C57BL/6 mice. Here, we extend our previous studies by investigating the effects of cotinine on the progression of AD-like pathology, depressive-like behavior, and the mechanisms underlying its beneficial effects in Tg6799 mice when left untreated until after a more advanced stage of the disease's development. The results show that vehicle-treated Tg6799 mice displayed an accentuated loss of working memory and an abundant Aß plaque pathology that were accompanied by higher levels of depressive-like behavior as compared to control littermates. By contrast, prolonged daily cotinine treatment to Tg6799 mice, withheld until after a mid-level progression of AD-like pathology, reduced Aß levels/plaques and depressive-like behavior. Moreover, this treatment paradigm dramatically improved working memory as compared to control littermates. The beneficial effects of cotinine were accompanied by an increase in the expression of the active form of protein kinase B and the postsynaptic density protein 95 in the hippocampi and frontal cortices of Tg6799 mice. This suggests that cotinine halts the progression of AD-like pathology while reducing depressive-like behavior by stimulating signaling pathways supporting synaptic plasticity in Tg6799 mice. The potential use of cotinine to treat cognitive and non-cognitive symptoms of AD is discussed.

Postpartum depression in rats: differences in swim test immobility, sucrose preference and nurturing behaviors.

Postpartum depression (PPD) is a common disorder affecting both mothers and their offspring. Studies of PPD in laboratory animals have typically assessed either immobility on forced swim testing or sucrose preference in ovariectomized rats following hormone supplementation and withdrawal or in stress models. To date, few studies have related these measures to maternal behaviors, a potential indicator of depressive-like activity postpartum. Because a single measure may be insufficient to characterize depression, the present study determined the distribution of depressive-like behaviors in Sprague-Dawley rats postpartum. Nurturing and non-nurturing behaviors exhibited by undisturbed dams were recorded during the first 12 days postpartum, and immobility in the forced swim test and sucrose preference were determined thereafter. A median-split analysis indicated that 19% of dams exhibited high sucrose preference and low immobility, 30% exhibited either only high immobility or only low sucrose preference, and 21% exhibited both high immobility and low preference. Dams exhibiting depressive-like activity on either or both tests displayed increased self-directed behaviors and decreased active nurturing during the dark phase of the diurnal cycle. This is the first study to characterize undisturbed nurturing and non-nurturing behaviors, and use both sucrose preference and immobility in the forced swim test, to classify PPD endophenotypes exhibited by rat dams following parturition. The present study underscores the idea that multiple tests should be used to characterize depressive-like behavior, which is highly heterogeneous in both the human and laboratory animal populations.

Cotinine reduces depressive-like behavior, working memory deficits, and synaptic loss associated with chronic stress in mice.

Chronic stress underlies and/or exacerbates many psychiatric conditions and often results in memory impairment as well as depressive symptoms. Such afflicted individuals use tobacco more than the general population and this has been suggested as a form of self-medication. Cotinine, the predominant metabolite of nicotine, may underlie such behavior as it has been shown to ameliorate anxiety and memory loss in animal models. In this study, we sought to investigate the effects of cotinine on working memory and depressive-like behavior in mice subjected to prolonged restraint. Cotinine-treated mice displayed better performance than vehicle-treated cohorts on the working memory task, the radial arm water maze test. In addition, with or without chronic stress exposure, cotinine-treated mice engaged in fewer depressive-like behaviors as assessed using the tail suspension and Porsolt's forced swim tests. These antidepressant and nootropic effects of cotinine were associated with an increase in the synaptophysin expression, a commonly used marker of synaptic density, in the hippocampus as well as the prefrontal and entorhinal cortices of restrained mice. The beneficial effects of cotinine in preventing various consequences of chronic stress were underscored by the inhibition of the glycogen synthase kinase 3 ß in the hippocampus and prefrontal cortex. Taken together, our results show for the first time that cotinine reduces the negative effects of stress on mood, memory, and the synapse.

The role of estrogen receptor ß and nicotinic cholinergic receptors in postpartum depression.

Postpartum depression (PPD) is a devastating disease occurring in approximately 20% of women. Women who suffer from PPD appear to be more sensitive to postpartum hormonal changes than women who do not experience this form of depression. Furthermore, women who quit smoking prior to or during pregnancy, and who develop PPD, are at an increased risk of smoking relapse. Unfortunately, the mechanistic relationship between the pathophysiology of PPD and smoking relapse is unknown. Here we review the roles of both estrogen receptor beta (ERß) and cholinergic nicotinic receptors (nAChRs) in the pathogenesis of depression and propose a mechanistic rationale to explain the high rate of smoking relapse exhibited by women who develop PPD.