The Impact of Adolescent Stress on Nicotine Use and Affective Disorders in Rodent Models

Abstract

Recent findings indicate that stress exposure during adolescence contributes to the development of both nicotine use and affective disorders, suggesting a potential shared biological pathway. One key system that may mediate the association between adolescent stress and nicotine or affective outcomes is the hypothalamic-pituitary-adrenal (HPA) axis. Here we reviewed evidence regarding the effects of adolescent stress on nicotine responses and affective phenotypes, and the role of the HPA-axis in these relationships. Literature indicates that stress, possibly via HPA-axis dysfunction, is a risk factor for both nicotine use and affective disorders. In rodent models, adolescent stress modulates behavioral responses to nicotine and increases the likelihood of affective disorders. The exact role that the HPA-axis plays in altering nicotine sensitivity and affective disorder development after adolescent stress remains unclear. However, it appears likely that adolescent stress-induced nicotine use and affective disorders are precipitated by repetitive activation of a hyperactive HPA-axis. Together, these preclinical studies indicate that adolescent stress is a risk factor for nicotine use and anxiety/depression phenotypes. The findings summarized here suggest that the HPA-axis mediates this relationship. Future studies that pharmacologically manipulate the HPA-axis during and after adolescent stress are critical to elucidate the exact role that the HPA-axis plays in the development of nicotine use and affective disorders following adolescent stress.

Graphical Abstract

This review examines the preclinical literature on how adolescent stress influences nicotine use and affective disorders. A model is proposed where adolescent stress initiates HPA-axis activation to enhance nicotine use/responding which in turn potentiates HPA-axis activation. This cyclical relationship ultimately leads to the development of affective disorders through heightened HPA-axis responding/sensitivity.

Introduction

Stress can be detrimental to both biological and behavioral processes (Bremner & Vermetten, 2001; McEwen, 2007). Although exposure to an acute stressor in a mature organism can play an adaptive role and promote survival, chronic exposure to stressors can have severe biobehavioral consequences (Vyas et al., 2004; Izquierdo et al., 2006). Initiation and regulation of the stress system, via the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system, is vital to maintain homeostasis. During adolescence, regions of the brain that regulate the HPA-axis undergo critical development (Giedd et al., 1999; Giedd, 2004; Lee et al., 2014; Keresztes et al., 2017). Also, during adolescence, HPA-axis reactivity is accentuated (i.e., greater glucocorticoid (GC) peak and/or longer glucocorticoid release following exposure to an acute stressor compared to weanlings and adults; Gunnar et al., 2009; Romeo, 2013). These findings suggest that exposure to stressors during the adolescent period may have lasting effects on behavioral and biological systems. In support, prospective clinical studies have shown that psychosocial stress exposure during adolescence are a risk factor for both initiation and progression of nicotine use and the development of anxiety and depression (Compas et al., 1993; Byrne et al., 1995; Koval et al., 2004; Finkelstein et al., 2006; Booker et al., 2008).

Given that adolescent psychosocial stressors increase the risk of both nicotine use and affective disorders (defined as anxiety and depression in this review), these two stress-exacerbated disorders may share a neurobiological mechanism. In addition, if such a common mechanism exists, this could facilitate their co-occurrence. The clinical manifestation of affective disorders among smokers is more severe than non-smokers (Farrell & White, 1998; Kessler et al., 2005; Fluharty et al., 2017). Moreover, adolescents with affective disorders begin using nicotine earlier than youths without these disorders (Rao & Chen, 2008). It is possible that this comorbidity stems from exposure to adolescent stressors that induce changes in HPA-axis physiology which may mediate long-term behavioral consequences. In this review, our definition of environmental stressors includes challenges that are frequently used in rodent models, both psychosocial (isolation, novel cage mates, and exposure to predator odor) and physical (restraint).

Here, we propose a model by which adolescent stressors plays a role in both nicotine use and affective disorder development. Specifically, stressor exposure during adolescence leads to HPA-axis activation, which can increase the likelihood of nicotine use, and this in turn facilitates the development of affective disorders (Figure1). We focus on the role of the HPA-axis in these responses, identify gaps within the existing literature, and conclude with suggestions for research to address these gaps.

Figure 1.

Proposed pathway for the development of nicotine use and affective disorders following adolescent stress. As depicted, adolescent stress initiates HPA-axis activation to enhance nicotine use/responding which in turn potentiates HPA-axis activation. This cyclical relationship ultimately leads to the development of affective disorders through heightened HPA-axis responding/sensitivity. Thicker lines represent connections with more supporting data. Thin lines represent connections with less supported data.

Adolescent stress may alter the relationship between nicotine use and affective disorders through HPA-axis activation – a proposed biological model.

Stressors impact a wide range of physiological systems across the lifespan, and these physiological stress responses during adolescence may have particularly strong maladaptive effects on the developing brain and behavior. In our proposed model (Figure 1), adolescent stress exposure activates a hyper-responsive HPA-axis, leading to altered behavioral responses to nicotine and facilitating development of affective disorders.

We hypothesize that initial exposure to stress in adolescence activates and regulates the HPA-axis (Fig. 1, arrow 1), leading to heightened nicotine responses (Fig. 1, arrow 2). This results in increased nicotine use, through enhanced sensitivity to nicotine reward. Together stressor and nicotine exposure have an additive effect on the HPA system (Fig. 1, arrow 3), ultimately increasing the probability of developing an affective disorder (Fig. 1, arrow 4). In the sections below, we provide evidence for each component of this model.

Adolescents have an enhanced HPA-axis response to stressors

Neurobiology of HPA-axis regulation

Stress response circuitry is well-characterized and previously reviewed (Gunnar & Quevedo, 2007; de Kloet et al., 2019). Briefly, when exposed to an acute stressor (i.e., any real or perceived threat to homeostasis), activation of the HPA-axis and the sympathetic nervous system promotes survival by shifting ongoing biological processes to increase energy availability. For this review, we focus on the HPA-axis component of the stress response. The HPA-axis response is initiated in the paraventricular nucleus of the hypothalamus (PVN), which receives excitatory and inhibitory signals from several stress-responsive brain regions including noradrenergic brainstem nuclei (e.g., the nucleus of the solitary tract) and corticolimbic regions such as the medial prefrontal cortex (mPFC), hippocampus, and amygdala (Ulrich-Lai & Herman, 2009). The PVN releases neuropeptides into the hypophyseal portal system, including corticotropin releasing factor (CRF). CRF stimulates anterior pituitary adrenocorticotropic hormone (ACTH) release into systemic circulation, which in turn, stimulates adrenal cortex synthesis and release of GCs; cortisol in primates and corticosterone in rodents (Antoni, 1986). Glucocorticoids mobilize energy stores, inhibit growth and reproductive processes, and enhance immune system function (Munck et al., 1984; Skorzewska et al., 2006; Peckett et al., 2011).

Although this physiological response to stressors is adaptive, repeated activation of this pathway can lead to maladaptive effects such as metabolic alterations, immune system suppression, psychiatric disorders, and altered responses to drugs of abuse (Munck et al., 1984; McEwen, 2007; de Kloet, 2014). To prevent aberrant GC-mediated physiological and behavioral outcomes, the HPA-axis has mechanisms to monitor and regulate further stress signaling (Herman et al., 2005). GC-dependent negative feedback is one prominent HPA-axis regulatory mechanism; circulating GCs inhibit the release of CRF and ACTH (Keller-Wood & Dallman, 1984; De Kloet, 2004; Herman et al., 2005). This negative feedback is mediated by activation of GC receptors in the pituitary, PVN, hippocampus, and mPFC (Keller-Wood & Dallman, 1984; Ulrich-Lai & Herman, 2009). Importantly, this negative feedback is highly plastic in that chronic stress can lead to increases in glucocorticoid receptor (GR) mRNA in the hippocampus but reductions of the same receptor in the mPFC (Mizoguchi et al., 2003). Both the hippocampus and mPFC play a role in the HPA-axis response to stress exposure; thus, this plasticity may support the organism’s response to changing environmental demands. However, alterations within the HPA-axis can manifest in behavioral and emotional consequences (i.e. increased risk of affective disorder development; Gillespie et al., 2009). That is, the activity of the HPA-axis can be molded by repetitive stress to meet environmental expectations, but in the process may produce maladaptive behaviors.

HPA-axis functionality: Developmental differences

The HPA-axis undergoes development throughout the lifespan that can influence the physiological response to a stressor (for review see Romeo et al., 2016). Despite being quiescent during the neonatal period, the HPA-axis is fully functional at this time but only responds to certain stressors (i.e., maternal separation or noxious insult; Kuhn et al., 1990; McCormick et al., 1998; Victoria et al., 2014; Mooney-Leber et al., 2018). During adolescence (approximately 35–63 days of age in rodents; McCutcheon & Marinelli, 2009), a more traditional stress response emerges, although adolescent animals have an enhanced and longer response compared to adults (Vazquez & Akil, 1993; Romeo et al., 2004; Romeo, 2013). For example, adolescent male rats exposed to a single 30-minute restraint stressor displayed an augmented corticosterone response compared to adult male rats exposed to the same stressor (Romeo et al., 2006). Similar results are observed in female rats (Romeo et al., 2004). These findings indicate that HPA-axis activity is altered by the maturation of an organism and that the adolescent period is marked by an enhanced physiological response to acute stress (arrow 1 – figure 1).

Although exposure to an acute stressor results in enhanced corticosterone levels in adolescent rodents inconsistencies in age-specific ACTH levels following an acute stressor exposure have been reported (Romeo et al., 2004; Foilb et al., 2011). These results suggest that the age-specific differences in stress-induced corticosterone responses may reflect adrenal maturation rather than development of upstream mechanisms (Foilb et al., 2011). In-line with this hypothesis, Romeo et al. (2014) found that stress-induced differences in corticosterone responses between adolescent and adult rats may result from changes in adrenal sensitivity to ACTH. They observed significantly higher basal Mc2r and stress evoked Marp expression in the adrenal cortex of adolescent vs. adult rats. Mc2R and Marp proteins aid in ACTH binding in the adrenal cortex, thus adolescent adrenal glands may be more sensitive to ACTH than adult adrenals. Collectively, these results suggest that enhanced adrenal sensitivity in adolescents likely contributes to the augmented HPA-axis reactivity observed in response to a stressor at this age.

Adolescent and adult animals also respond differently to chronic stress exposure. For instance, when rats were exposed to repeated 30-minute restraint stress for 7 days, adolescent male rats displayed a greater immediate corticosterone and ACTH response, but reduced circulating corticosterone levels 45-minutes after the final restraint stress exposure compared to adult rats. Similar findings with brain reactivity have been reported; both acute (single restraint session) and chronic (7-days of restraint) stressors significantly increase CRF/FOS immunoreactivity within the PVN, immediately and 45-minutes after stressor exposure in adolescent, but not adult, rats (Romeo et al., 2006). Another study conducted by Lui et al. (2012) examined the impact of different schedules of stressor exposure (acute vs. chronic homotypic – repeated restraint stress exposure for 8 days vs. chronic heterotypic – 7 days of cold stress exposure ending with 1 day of restraint stress exposure) on HPA-axis responses in adolescent (PND 30) and adult (PND 77) rats. They found that acute and chronic heterotypic stressors produced delayed recovery of plasma corticosterone concentrations after the final stress exposure in adolescent compared to adult rats. Alternatively, chronic homotypic stressors produced a greater initial corticosterone response immediately after stress exposure in adolescent compared to adult rats but did not impact recovery. These physiological changes may play a role in age-dependent differences in GC responses to stress.

As previously mentioned, brain regions involved in HPA-axis negative feedback undergo continued development during adolescence (Andersen & Teicher, 2008). Thus, repeated activation of the HPA-axis could lead to long-term changes in HPA-axis regulation. However, attempts to understand the consequences of repeated adolescent stressors on HPA-axis regulation have been inconclusive. Chronic adolescent stress exposure has led to both long-term augmented and blunted basal stress-induced HPA-axis function (Lepsch et al., 2005; Bourke & Neigh, 2011; Li et al., 2015; Caruso et al., 2017; Caruso et al., 2018a; Caruso et al., 2018b). Moreover, there are additional studies where no changes in HPA-axis functionality were observed following adolescent stress exposure (Wright et al., 2008; Cotella et al., 2019). Methodological differences between these studies (e.g. type and duration of stressor, age of stress exposure or outcome testing, sex, strain, and species) could account for these discrepancies in HPA-axis outcomes. For example, Isgor et al. (2004) reported that both chronic adolescent mixed physical (forced swim, restraint, loud noise, cold exposure & ether exposure) and social (isolation, novel environment, crowding, litter shifting, & subordination) stressors enhanced HPA-axis response to an acute stressor that was presented immediately after the chronic stressor in male rats. However, when exposed to the same acute stressor 3-weeks later, only rats exposed to the mixed physical stress displayed an enhanced HPA-axis response. It is possible that acute or repeated stress exposure during adolescence alters the development of neuronal systems downstream of the HPA-axis. In other words, long-term behavioral changes that are induced by adolescent stress may be initiated by abnormal HPA-axis hyperactivity that then impacts downstream neurobiological processes. This idea is discussed in further detail below.

Overall, there is evidence that the HPA-axis response to stress is different during the adolescent period compared to adulthood. Specifically, in response to a stressor, adolescent animals typically display prolonged GC release when compared to adult animals. This prolonged GC response suggests that adolescents exposed to external challenges are exposed to longer periods of elevated GC compared to adults. This extended period of GC response supports our proposed model (Fig. 1, arrow 1), that adolescent stress leads to augmented HPA-axis reactivity. Of note, there is less evidence that adolescent stress has a consistent long-term impact on HPA axis regulation. Nevertheless, continued experimentation comparing the impact of different type of stressors (physical, social, etc.) on long-term HPA-axis functioning would illuminate which HPA-axis sensitive adolescent stressors modulate long-term changes.

Adolescent stress enhances nicotine sensitivity and further HPA-axis activation

Nicotine and the HPA-axis

The HPA-axis is highly responsive to nicotine exposure. Among established human smokers, cigarette smoking or nicotine infusion rapidly increase levels of ACTH, and cortisol (Seyler et al., 1984; Pomerleau & Pomerleau, 1990; Kirschbaum et al., 1992; Stalke et al., 1992). Preclinical studies using rats and mice have reported similar findings: acute experimenter-administered nicotine that mimics plasma nicotine concentrations found in human smokers elevates circulating ACTH and cortisol (Balfour et al., 1975; Benwell & Balfour, 1979; Cam et al., 1979; Cam & Bassett, 1983; Lutfy et al., 2006; Lutfy et al., 2012). HPA axis activation, as indicated by elevated ACTH and corticosterone, is also observed when rats self-administer nicotine (Donny et al., 2000; Chen et al., 2008). Nicotine indirectly stimulates ACTH by binding and activating nicotinic acetylcholine receptors expressed on noradrenergic neurons of the NTS (Nucleus of the solitary tract; Matta et al., 1998). Upon nicotine binding, norepinephrine is released from NTS axon terminals in the PVN which, in turn, stimulates CRH secretion (Matta et al., 1998). Tolerance to nicotine’s HPA-axis stimulatory effects can develop in rats (Benwell & Balfour, 1979; Cam & Bassett, 1984; Chen et al., 2008), but may never fully develop in human smokers (Fuxe et al., 1989). These nicotine-induced fluctuations in HPA-axis activity have been proposed to mediate many of the physiological and behavioral effects of nicotine including its reinforcing properties (Fuxe et al., 1989; Pomerleau & Pomerleau, 1991; Pauly et al., 1992; Rohleder & Kirschbaum, 2006).

The relationship between nicotine and stress exposure may be additive as chronic stressor and chronic nicotine exposure both result in HPA-axis hyperactivity. For example, repeated nicotine exposure can alter subsequent HPA-axis responses to an acute stressor in rats (Benwell & Balfour, 1982; Chen et al., 2008). Further, in mice, chronic stress can augment ACTH and CORT responses to an acute nicotine injection (Lutfy et al., 2006). In clinical literature, a heightened HPA response to stress exposure is one indicator of vulnerability for the initiation and progression of nicotine use (de Wit et al., 2007; Richards et al., 2011). These findings suggest that the increased risk for initiation and progression of nicotine use among individuals exposed to stress may be related to HPA-axis hyperactivity.

Adolescent stress exposure, nicotine, & HPA-axis

Recent findings suggest that the reinforcing properties of nicotine are augmented by acute stress exposure during adolescence. For example, Brielmaier et al. (2012) examined the potentiating effect of adolescent stress on nicotine reward using a conditioned place preference (CPP) paradigm. They found that intermittent foot shock stress exposure 24-hours prior to nicotine CPP training shifted the potency of nicotine in adolescent rats. Specifically, adolescent rats exposed to stress before conditioning displayed a preference for the drug-paired side of the CPP arena at low doses, and this preference was not observed in non-stressed rats. Importantly, the stress-induced potentiation of nicotine reward was blocked when rats were systemically pretreated with a corticotrophin releasing factor receptor 1 (CRFR1) antagonist prior to foot shock exposure, suggesting that acute stress enhances sensitivity to nicotine through HPA-axis activation (Fig. 1, arrow 2). While Brielmaier et al. (2012) did not assess the impact of acute stress exposure during adulthood, other reports indicate that acute stress in adulthood enhances nicotine CPP (Smith et al., 2012; Javadi et al., 2017), suggesting that the impact of acute stress on nicotine reward may not be unique to a developmental period. However, to our knowledge this direct comparison, examining the impact of stress on nicotine CPP in adolescent and adult animals, has not been made. Moreover, an inherent challenge exists when making comparisons between adolescent and adult nicotine sensitivity as research has found nicotine preference in adolescent, but not adult, rats at similar nicotine doses (Belluzzi et al., 2004; Brielmaier et al., 2007). Even though stress increases nicotine reward in both age groups, a hyperresponsive stress system in adolescence might lead to a greater enhancing effect. Further examination of the relationship between stress exposure, age, and nicotine is needed. For instance, comparisons between adolescents and adults on stress thresholds required to induce nicotine preference could highlight unique age vulnerabilities. Nevertheless, Brielmaier et al. (2012) provides evidence that, during the adolescent period, HPA-axis activation in response to acute stress increases nicotine sensitivity.

An interaction between adolescent stress and nicotine has also been observed in several models of chronic social stress exposure. Two weeks of social instability reduced nicotine-evoked locomotor activity and locomotor sensitization in adolescent female, but not male, rats (McCormick & Ibrahim, 2007). Interestingly, this same stressor in adulthood led to enhanced nicotine-induced locomotor activity in female, but not male, rats (McCormick et al., 2004). Although these findings suggest that females may be more sensitive to the effects of adolescent chronic social stress on locomotor responses to nicotine, recent reports indicate that the impact of chronic adolescent stress on nicotine behaviors is influenced by multiple factors. For instance, male, but not female, BALB/cJ mice exposed to chronic variable social stress during adolescence had enhanced locomotor activity and increased serum corticosterone levels following acute nicotine administration (Caruso et al., 2018b). When these mice matured into adulthood, only male mice stressed during adolescence displayed a significant reduction in voluntary nicotine consumption. Interestingly, there were no observed differences in male or female C57BL/6J mice exposed to the same stress and nicotine procedures (Caruso et al., 2018a). Although published in two separate manuscripts, these data on BALB/cJ and C57BL/6J were collected at the same time. Thus, these results suggest genetic background can modulate the effects of adolescent chronic stressor on later nicotine responses (the effects of adolescent stressors on nicotine behavioral responses and HPA-axis outcomes are summarized in Table 1).

Table 1:

Behavioral response to nicotine following adolescent stress

Author	Species & strain	Age of stress exposure	Duration/type of stressor/and or pharmacological intervention; sex	Age of behavioral testing	Behavioral outcomes	HPA-axis outcomes
Brielmaier et al., 2012	Rat – Sprague-Dawley	PND 28	Foot shock ~20 times ♂	PND 29	↑ Nicotine sensitivity in CPP	N/A
		PND 28	Foot shock ~20 times & CRF1 antagonist ♂	PND 29	↔ Nicotine CPP	N/A
Zago et al., 2012	Rat – Wistar	PND 28	Nicotine and 2hr restraint stress ~ 7 days ♂	PND 37	↑ Nicotine locomotor compared to non-stressed nicotine group	N/A
		PND 60 (adult)	Nicotine and 2hr restraint stress ~ 7 days ♂	PND 69	↔ Nicotine locomotor response compared to non-stressed nicotine group	N/A
Cruz et al., 2008	Rat – Wistar	PND 28	2hr restraint stress ~ 7 days ♂	PND 37	↔ Nicotine locomotor response non-stressed nicotine group	↔ Nicotine induced CORT
		PND 60 (adult)	2hr restraint stress ~ 7 days ♂	PND 69	↔ Nicotine locomotor response compared to non-stressed nicotine group	↔ Nicotine induced CORT
McCormick & Ibrahim 2007	Rat – Long-Evans	PND30	1hour isolation + new cage partner ~ 16 days ♂	PND 45–46	↔ Nicotine locomotor response to repetitive nicotine and nicotine challenge	N/A
		PND30	1hour isolation + new cage partner ~ 16 days ♀	PND 45–46	↓ Nicotine locomotor response to repetitive nicotine and nicotine challenge	N/A
		PND30	1hour isolation ~ 16 days ♂	PND 45–46	↔ Nicotine locomotor response to repetitive nicotine and nicotine challenge	N/A
		PND30	1hour isolation ~ 16 days ♀	PND 45–46	↔ Nicotine locomotor response to repetitive nicotine and nicotine challenge	N/A
McCormick et al., 2004	Rat – Long-Evans	PND33	1hour isolation + new cage partner ~ 16 days ♂	PND72 ± 4	↔ Nicotine locomotor response to repetitive nicotine and nicotine challenge	↑ CORT response to acute stress after repetitive stress & nicotine compared to repetitive stress & single nicotine exposure
		PND33	1hour isolation + new cage partner ~ 16 days ♀	PND72 ± 4	↑ Nicotine locomotor response to repetitive nicotine and nicotine challenge	↑ CORT response to acute stress after repetitive stress & nicotine compared to repetitive stress & single nicotine exposure
Caruso et al., 2018b	Mouse – BALB/cJ	PND25	Repeated cycles of isolation & new cage mates ~ 34 days ♂	PND 56 −63 & 73–135	↑ Acute nicotine locomotor behavior ↓ Voluntary nicotine consumption at 200 ug/ml	↑ CORT response after 1.0mg/kg nicotine exposure
		PND25	Repeated cycles of isolation & new cage mates ~ 34 days ♀	PND 56 – 63 & 73–135	↔ Acute nicotine locomotor behavior ↔ Voluntary nicotine consumption	↔ CORT response to acute nicotine exposure
Caruso et al., 2018a	Mouse – C57BL/6J	PND25	Repeated cycles of isolation & new cage mates ~ 34 days ♂	PND 56 – 70 & 73 – 135	↔ Acute nicotine locomotor behavior ↔ Voluntary nicotine consumption	↔ CORT response to acute nicotine exposure
		PND25	Repeated cycles of isolation & new cage mates ~ 34 days ♀	PND 56 – 70 & 73 – 135	↔ Acute nicotine locomotor behavior ↔ Voluntary nicotine consumption	↔ CORT response to acute nicotine exposure
Cruz et al., 2005	Rat – Wistar	PND 28	Daily saline injections ~ 7 days & acute nicotine challenge 3 days later ♂	PND 37	↑ Nicotine induced locomotion	↑ Nicotine induced CORT
		PND 28	Daily nicotine injections ~ 7 days & acute nicotine challenge 3 days later ♂	PND 37	↑ Nicotine induced locomotion	↑ Nicotine induced CORT
		PND 90 (adult)	Daily saline injections ~ 7 days & acute nicotine challenge 3 days later ♂	PND 99	↔ Nicotine induced locomotion	↑ Nicotine induced CORT
		PND 90 (adult)	Daily nicotine injections ~ 7 days & acute nicotine challenge 3 days later ♂	PND 99	↑ Nicotine induced locomotion	↔ Nicotine induced CORT
Holliday et al., 2020	Mouse – C57BL/6J	PND 31	PND 29–31 shipping stress exposure & PND38–50 chronic nicotine exposure ♂	PND 50, 51, & 80	N/A	↑ Regional specific hippocampus GR & CRFR (PND50) ↓ Regional specific hippocampus GR & CRFR (PND51) ↑ Regional specific hippocampus GR & CRFR (PND80) & ↓ stress induced CORT

PD = Postnatal day; CRFR = Corticotrophin release factor receptor; GR = Glucocorticoid receptor; CPP = conditioned place preference; ↑ = Increased in comparison to control; ↓ = Decreased in comparison to control; ↔ = No change from control.

The co-occurrence of stress exposure plus nicotine may also lead to heightened HPA-axis responses. Zago et al. (2012) administered nicotine in conjunction with restraint stress exposure for 7 days. Following 7 nicotine/stressor pairings, adolescent, but not adult rats, displayed increased locomotor activity (a measure of drug sensitivity) in response to a nicotine challenge. Utilizing the same protocol Cruz et al. (2008) reported stress exposure alone for seven days failed to alter acute nicotine-induced locomotor activity in adolescent rats. Thus, co-exposure of nicotine and stress exposure may influence shared physiological pathways such as the HPA-axis, resulting in increased responses to nicotine. Supporting this idea, Pentkowski et al. (2011) found that nicotine co-exposure with social isolation in adolescent rats produced heightened corticosterone responses, compared to socially isolated adolescent rats given saline. Additionally, no change in corticosterone was observed in rats exposed to only nicotine. These results suggest a heightened HPA-axis response when nicotine and stress are experienced simultaneously.

Taken together, both acute and chronic stressors during adolescence appear to modulate behavioral responses to nicotine. That is, adolescent stress primes the brain to respond differently to nicotine. Currently, the mechanism(s) underlying these effects are unknown; however, research on stress and psychostimulants implicates changes in the HPA-axis (for review see Marinelli & Piazza, 2002). Recent studies demonstrate that the HPA-axis may play a role in the influence of stress on drug use as it is perturbed by both adolescent stress and nicotine exposure. For example, Holliday et al. (2020) reported that 2-day shipping stress exposure, followed by 12-days of nicotine exposure during adolescence in C57BL/6J mice produced acute and long-term changes in hippocampal CRFR1/2 and GR protein levels. While these changes were not accompanied by alterations in basal corticosterone levels, adolescent mice exposed to stress and nicotine had a blunted corticosterone response to 1 hour of restraint stress in adulthood (30 days after treatment) compared to saline-treated mice. Additionally, findings from McCormick and Ibrahim (2007) provide further support for physiological changes following adolescent stress and nicotine exposure. They report that repetitive, but not acute, adolescent nicotine exposure increased the number of Fos-labeled cells in the PVN compared to saline treated rats (Fos-ir was examined 2 h after the final saline or nicotine injection). Moreover, similar increases in Fos-labeled PVN cells were observed in male rats exposed to adolescent chronic social stress when compared to chronic isolation stress and non-stress exposed rats. No changes in female Fos-labeled PVN cells were observed following stress or nicotine exposure. These findings indicate that nicotine and stress interact to produce long-term changes in brain regions that mediate the HPA-axis response.

Nicotine administration alone is a potent modulator of hippocampus-dependent behavior and physiology (Gould, 2006), with some effects unique to the adolescent exposure. For example, multiple studies have found long-term cognitive impairments in hippocampus-dependent contextual fear conditioning following adolescent, but not adult, nicotine exposure (Spaeth et al., 2010; Portugal et al., 2012; Holliday et al., 2016; Gitik et al., 2018). Previous findings support a role of corticosterone in contextual fear memory (Cordero & Sandi, 1998). Specifically, adrenalectomized rats show diminished fear conditioning, which is reversed with corticosterone injections (Pugh et al., 1997). Moreover, Holiday et al., 2016 reported long-term reductions in hippocampal CA1 dendritic length following chronic adolescent nicotine exposure in C57BL/6J mice. This same effect has also been observed following chronic stress exposure in adult mice, albeit in an inconsistent fashion (for review see Conrad et al., 2017). It should be noted that the effect of adolescent nicotine withdrawal on dendritic spine changes could be due to alterations in cholinergic signaling and not the HPA-axis (Day & Greenfield, 2002; Nagy & Aubert, 2015). Given the unique impact of nicotine on adolescent hippocampal functioning, it is feasible that adolescent nicotine and stress exposure may alter hippocampus HPA-axis physiology leading to long-term disruptions in behavior.

Preclinical studies examining adolescent stress exposure and nicotine support two components of our proposed stress-nicotine-affective disorder development model. First, stress enhances nicotine sensitivity or reinforcement (figure 1 arrow 2). However, this area of research should be enhanced with additional studies directly comparing adolescent and adult animals. Specifically, there may be differences in terms of the amount of stress exposure required to induce changes in nicotine sensitivity between adults and adolescents. Further, it is unclear how the duration of stress or the interval between stress and nicotine exposure impacts drug sensitivity. Second, nicotine activates the HPA-axis (figure 1 arrow 3). Findings from Cruz et al. (2008) reported that acute nicotine exposure increases circulating corticosterone in male rats, a key components of HPA-activity. However, Cruz et al. (2005) demonstrated that repeated nicotine injections desensitized HPA-axis responding in adult, but not adolescent, male rats. That is, adolescent male rats continue to respond to nicotine exposure with heightened corticosterone even after repetitive exposure. Given that HPA-axis activation enhances the reinforcing properties of nicotine during adolescence, it is possible that HPA-axis activation following adolescent stress enhances nicotine reinforcement. In turn, continued nicotine use is facilitated through maintained HPA-axis activation by nicotine, producing an ongoing cyclical relationship.

Adolescent stress exposure increases the likelihood of affective disorder development

Affective outcomes following stress exposure

Anxiety and depression are associated with a myriad of symptoms, including feelings of guilt, worthlessness, sadness, fatigue, cognitive impairment, anhedonia, and heightened levels of irrational fear. Individuals suffering from these disorders have impaired day-to-day functioning and reduced quality of life. Anxiety disorders are first noted during adolescence, whereas mood disorders typically emerge in early adulthood (Kessler et al., 2005). Animal models can be used to determine the factors, including environment, age, and genetics, that contribute to anxiety- and depression-like behaviors (for review see Pryce et al., 2005; Neumann et al., 2011). Findings from rodent studies suggest that the onset of anxiety or depressive-like symptoms can be precipitated by acute or chronic (10 – 34 days) social or physical stress exposure during adolescence (Varlinskaya & Spear, 2012; Iniguez et al., 2016; Caruso et al., 2017; Caruso et al., 2018a; Caruso et al., 2018b). Here we discuss the role the HPA-axis plays in the development of affective disorders following adolescent stress exposure.

Adolescent stress, HPA-axis, and affective disorders

As discussed above, the HPA-axis response to an acute stressor differs based on age of exposure, with adolescent rodents typically displaying a more robust and longer-lasting response to a single stressor (Romeo et al., 2006; Foilb et al., 2011). In rodent studies, exposure to stress during this developmental period has been associated with acute and long-term biobehavioral modifications (for review see McCormick et al., 2010a). Regarding affective-like behaviors, the impact of adolescent stress appears to depend on the type of stress exposure. As summarized in McCormick and Green (2013), predator odor stressors during adolescences increases affective-like behaviors in male and female rats. Conversely, models of variable stressors and social defeat exposure during adolescence are less conclusive, with studies reporting increased and decreased anxiety-like behavior in adulthood. McCormick and Green (2013) address this discrepancy with the notation that it is not possible to determine the exact “stress-response” in terms of the biological response between study methods, thus differences in outcomes are expected. Nevertheless, a recent study utilizing chronic variable stressors (physical & social) reported long-term increases in immobility (depressive-like behavior) in the forced swim test and reduced amount of time spent in the open arms (anxiety-like behavior) during the elevated plus maze in male Wistar rats when stress exposure occurred during adolescence but not adulthood (Cotella et al., 2019). Moreover, Yorgason et al. (2013) reported that male rats exposed to a chronic social stressor that started during adolescence (i.e. social isolation from PND 28–74) reduced time spent in the open arms in the elevated plus maze when tested on PND 74 compared to group housed rats. Interestingly, when social stress was initiated in adulthood (PND 77– 174), there were no deficits in anxiety-like behavior on PND 174. Further, rats exposed to this stressor from adolescence through adulthood (PND 28–174) displayed increased anxiety-like behavior when tested on PND 174. These data indicate immediate and long-term anxiogenic effects of adolescent stress exposure. Additional evidence of adolescent chronic stress exposure precipitating affective behavioral deficits later in life have been reported elsewhere in both rat and mouse models (Vidal et al., 2007; Lukkes et al., 2009; Schmidt et al., 2010a; Schmidt et al., 2010b; Hong et al., 2012; Ros-Simo & Valverde, 2012; Scharf et al., 2013; Caruso et al., 2017; Gomes & Grace, 2017; Caruso et al., 2018a; Caruso et al., 2018b; Caruso et al., 2018c). Collectively, these findings indicate both acute and chronic stress exposure during adolescence modulates affective behavioral outcomes (the effects of adolescent stress exposure on affective behaviors and HPA-axis outcomes are summarized in Table 2).

Table 2:

Affective-like behavioral and HPA-axis outcomes following adolescent stress

Author	Species & strain	Age of stress exposure	Duration/type of stressor/and or pharmacological intervention; sex	Age of behavioral testing	Behavioral outcomes	HPA-axis outcomes
Caruso et al., 2017	Mouse – BALB/cJ	PND 22	Repeated cycles of isolation & new cage mates ~ 28 days ♂	PND 60– 69	↑ EPM ↔ Sucrose preference ↔ FST	↓ Basal fCORT ↓ Diurnal peak fCORT
		PND 22	Repeated cycles of isolation & new cage mates ~ 28 days ♀	PND 60– 69	↑ EPM ↑ Sucrose preference ↔ FST	↓ Diurnal peak fCORT ↔ Basal CORT
Caruso et al., 2018b	Mouse – BALB/cJ	PND 22	Repeated cycles of isolation & new cage mates ~ 28 days ♂	PND 60–69	↑ EPM ↔ FST ↔ Sucrose preference	↓ Basal CORT
		PND 22	Repeated cycles of isolation & new cage mates ~ 28 days ♀	PND 60–69	↑ EPM ↑ Sucrose preference ↔ FST	↓ Basal CORT
Caruso et al., 2018c	Mouse – C57Bl/6J	PND 25	Repeated cycles of isolation & new cage mates ~ 34 days ♂	PND 64–66	↑ EPM ↔ FST	N/A
		PND25	Repeated cycles of isolation & new cage mates ~ 34 days ♀	PND 64–66	↑ EPM ↔ FST	N/A
Caruso et al., 2018a	Mouse – C57BL/6J	PND25	Repeated cycles of isolation & new cage mates ~ 34 days ♂	PND 61–70	↑ EPM – replicated in both cohorts ↔ SAAT	↔ Basal CORT
		PND25	Repeated cycles of isolation & new cage mates ~ 34 days ♀	PND 61–70	↑ & ↔ EPM – varying results based on cohort ↔ SAAT	↔ Basal CORT
Iniguez et al., 2016	Mouse – C57BL/6	PND 35	Repeated social defeat ~ 10 days ♂	PND 45	↑ TST ↑ SI	N/A
Varlinskaya & Spear 2012	Rat – Sprague – Dawley	PND 35	Acute restraint stress ♂ & ♀	PND 35	↑ SI ↔ Play fighting	N/A
		PND 35	Acute social isolation ♂ & ♀	PND 35	↔ SI ↔ Play fighting	N/A
		PND 70 (adult)	Acute restraint stress ♂ & ♀	PND 70	↑ SI ↔ Play fighting	N/A
		PND 70 (adult)	Acute social isolation ♂ & ♀	PND 70	↔ SI ↔ Play fighting	N/A
Borodovitsyna et al., 2018	Rat – Sprague – Dawley	PND 42 – 49	Acute restraint & predatory odor exposure ♂	PND 42–49 & 49–56	↑ EPM ↑ OFT	N/A
Lovelock & Deak 2019	Rat – Sprague – Dawley	PND 29 – 30	Single session of 80 inescapable foot shocks ♂	PND 69–71 & 72–73	↑ LDB ↔ FST ↔ SI	↔ CRH gene expression
		PND 29 – 30	Single session of 80 inescapable foot shocks ♀	PND 69–71 & 72–73	↔ LDB ↔ FST ↔ SI	↔ CRH gene expression
Cotella et al., 2019	Rat – Wistar	PND 40	Chronic variable stress ~ 14 days ♂	PND 90 – 101	↑ EPM (total arm entries) ↑ FST	↔ ACTH & CORT following acute stress
		PND 60 (adult)	Chronic variable stress ~ 14 days ♂	PND 110 – 121	↔ EPM (total arm entries) ↔ FST	↑ ACTH & CORT following acute stress
Yorgason et al., 2013	Rat – Long-Evans	PND 28	Social isolation ~ 6 weeks ♂	PND 74	↑ EPM at both PND 74	N/A
		PND 28	Social isolation ~ 4 months ♂	PND 174	↑ EPM compared to animals exposed to social stress from PND 74–174	N/A
		PND 74 (adult)	Social isolation ~ 6 weeks ♂	PND 174	↔ EPM when compared to animals exposed to social stress from PND 28–174	N/A
Gomes & Grace 2017	Rat – Sprague – Dawley	PND 31	Foot sock 25 times daily ~ 10 days ♂	PND 65 – 69	↑ EPM	N/A
		PND 31	1-hour restraint stress daily ~ 10 days ♂	PND 65 – 69	↑ EPM	N/A
		PND 31	Foot shock & restraint stress combination daily ~ 10 days ♂	PND 65 – 69	↑ EPM	N/A
Schmidt et al., 2010a	Mouse – CD1	PND 29 – 31	Repetitive cycles of new cage mates ~ 7 weeks ♀	~ PND 78 – 82	↑ NSFT ↔ EPM ↔ Hippocampus GR gene expression	↑ Basal CORT ↔ Basal ACTH ↓ PNV CRH & GR gene expression ↓ Regional specific hippocampus MR gene expression
Schmidt et al., 2010b	Mouse – CD1	PND 29 – 31	Repetitive cycles of new cage mates ~ 7 weeks ♂ - Vulnerable animals based on high corticosterone values after stress exposure	~ PND 113 – 118	↑ OFT ↑ TST ↑ EPM	↑ Basal CORT immediate after chronic stress & 5 weeks later
		PND 29 – 31	Repetitive cycles of new cage mates ~ 7 weeks ♂ - Resilient animals based on low corticosterone values after stress exposure	~ PND 113 – 118	↔ OFT ↔ TST ↔ EPM	↔ Basal CORT 5 weeks later
Bourke & Neigh 2011	Rat – Wistar	PND 36	Mix modality stress (social defeat & restraint stress) ~ 2 weeks ♂	PND 48 – 57 & 96 – 104 (separate cohorts)	↔ Sucrose consumption ↔ FST ↔ EPM	↔ Stressed induced CORT
		PND 36	Mix modality stress (social defeat & restraint stress) ~ 2 weeks ♀	PND 48 – 57 & 96 – 104 (separate cohorts)	↑ Sucrose consumption ↑ FST ↑ EPM	↑ Stressed induced CORT
Yohn & Blendy 2017	Mouse – C57BL/6J Tac	PND 28	Chronic unpredictable stress ~ 12 days ♂	PND 40 (SPT) & PND 70 – 82 (other tests)	↑ Sucrose consumption ↑ MBT ↑ EZM ↑ FST	↔ CRF & CRFR1 in multiple brain regions ↑ CRFR2 in amygdala
		PND 28	Chronic unpredictable stress ~ 12 days ♀	PND 40 (SPT) & PND 70 – 82 (other tests)	↑ Sucrose consumption ↑ MBT ↑ EZM ↑ FST	↔ CRF, CRFR1, & CRFR2 in multiple brain regions
		PND 70 (adult)	Chronic unpredictable stress ~ 12 days ♂	PND 82 (SPT) & PND 112 – 126 (other tests)	↑ Sucrose consumption ↔ MBT ↔ EZM ↑ FST	↔ CRF, CRFR1, & CRFR2 in multiple brain regions
		PND 70 (adult)	Chronic unpredictable stress ~ 12 days ♀	PND 82 (SPT) & PND 112 – 126 (other tests)	↑ Sucrose consumption ↔ MBT ↔ EZM ↑ FST	↔ CRF, CRFR1, & CRFR2 in multiple brain regions
Iniguez et al., 2014	Mouse – C57BL/6	PND 35	Social defeat ~ 10 days ♂	PND 45	↑ SI ↑ FST ↑ Sucrose preference ↑ EPM	↑ CORT after final stress exposure
Bourke et al., 2014	Rat – Wistar	PND 28	Social isolation & daily social defeat ~ 23 days ♂	PND 52	↑ Sucrose preference ↑ FST (latency to immobility)	N/A
		PND 28	Social isolation & daily social defeat and CRF1 antagonist ~ 23 days ♂	PND 52	↔ Sucrose preference – Partial reversal of stress ↑ FST (latency to immobility)	N/A
Scharf et al., 2013	Mouse – CD1	PND 28	Chronic social stress – shifting cage mates ~ 7 weeks ♂	PND 112	↑ OFT ↔ EPM ↔ SI	↑ CORT after final stress exposure and 5 weeks later ↔ GR & CRH gene expression in hippocampus and PVN respectively
		PND 28	Chronic social stress – shifting cage mates ~ 7 weeks ♂	PND 450	↔ EPM	↔ Basal CORT ↓ CORT during CRH challenge test ↔ GR & MR gene expression in hippocampus and PVN ↓ CRH gene expression in PVN
Vidal et al., 2007	Rat – Wistar	PND 45	Social defeat ~ 5 stress exposure bouts ♂	PND 78	↑ SI	N/A
Ros-Simo & Valverde 2012	Mouse – CD1	PND 21	Social isolation ~ 7 weeks ♂	PND 71–75	↑ EPM ↑ TST ↑ LDB (compared to enriched environment animals)	↓ Basal CORT ↑ CORT to acute stressor when compared to basal response
Lukkes et al., 2009	Rat – Sprague-Dawley	PND 21	Social isolation ~ 3 weeks ♂	PND 56	↑ SI ↑ OFT	↔ Basal CORT ↔ Immediate CORT following acute stress ↓ CORT recovery from acute stress
Butler et al., 2014	Rat – Sprague-Dawley	PND 31	Social isolation ~ 3 weeks ♀	PND 85	↔ LDB ↔ EPM	N/A
Hong et al., 2012	Rat – Sprague-Dawley	PND 30	Social isolation ~ 3 weeks ♂	PND51 & 71	↔ FST ↔ Sucrose consumption	N/A
		PND 30	Social isolation ~ 3 weeks ♀	PND51 & 71	↑ FST ↓ Sucrose consumption	N/A

PND = Postnatal day; EPM = Elevated plus maze; FST = Forced swim test; SAAT = Social approach-avoidance test; TST = Tail suspension test; SI = Social interaction/investigation; LDB = Light dark box; NSFT = Novelty-induced suppression feeding test; EZM = Elevated zero maze; ↑ = enhanced affective-like or HPA-axis response; ↓= reduced affective-like or HPA-axis response; ↔ = No change from control.

Given that acute and repeated activation of the HPA-axis during adolescence does not necessarily result in long-term changes in HPA-axis physiology (for a thorough review see McCormick & Mathews, 2007), it is possible that development of affective disorders following adolescent stressors are the result of neurobiological systems influenced by the initial stress-evoked HPA-axis response. Therefore, affective behavioral differences that result from adolescent stress exposure may be initially produced by enhanced HPA-axis activity, but in the long-term, maintained through downstream biological mechanisms. Evidence for initial participation of the HPA-axis in development of affective-disorders was reported by Bourke et al. (2014). They found that administration of a CRFR1 antagonist via systemic injection during adolescent chronic social defeat stress exposure prevented stress-induced reductions in sucrose consumption (anhedonia) in male rats. However, CRFR1 antagonism during chronic adolescent stress had no effect on stress-induced changes in latency to immobility during the forced swim test. These data suggest that the CRFR1 system does not mediate all affective-like behaviors. Moreover, the role of CRF in motivated behaviors (such as sucrose consumption) is bidirectional. That is, stimulation of one brain region associated with CRF produces approach avoidance while another region produces approach motivation (Baumgartner, Schulkin, & Berridge, 2021), thus the mechanism by which CRF antagonism prevents the anhedonia phenotype remains unknown. Finally, it is unclear if antagonism of the HPA-axis during adolescent stress impacts future HPA-axis responding itself or associated neurobiological systems as this was not examined. Thus, it is possible that mechanisms outside of the HPA-axis facilitate changes in stress-induced depressive-like behavior.

Independent of the HPA-axis, chronic adolescent stress in rodents produced long-lasting reductions in hippocampal volume (Isgor et al., 2004). Similar decreases in hippocampal volume are observed in individuals suffering from depression (Bremner et al., 2000). Additionally, both acute and chronic adolescent stress exposure alter biological markers associated with neurogenesis, synaptogenesis, and cell survival in the hippocampus, such as BrdU and doublecortin (McCormick et al., 2010b; Sterlemann et al., 2010; Barha et al., 2011; McCormick et al., 2012; Uysal et al., 2012). Notably, changes in neurogenesis and cell survival are associated with depression in rodents and humans (Snyder et al., 2011; Duman & Li, 2012; Boldrini et al., 2013). Because stress modulates numerous systems within the brain (for example mPFC, amygdala, hippocampus), it is not surprising that brain regions outside of the HPA-axis are also impacted by adolescent stress (McEwen, 2007). The alterations in the hippocampus discussed here are just one example of such physiological change. The diversity of neural changes produced by stress presents a challenge in dissecting and linking various physiological changes to behavioral consequences.

The findings within this section lend support to our proposed model that adolescent stressors typically lead to increased anxiety- and depressive-like behaviors in rodents (Fig 1., arrow 4). Results from Bourke et al. (2014) indicate that changes in anhedonia produced by chronic adolescent stress exposure in male rats can be modulated by inhibition of the CRFR system. However, it is possible that affective behavioral consequences of adolescent stress are driven by biological systems outside of the HPA-axis, highlighting the weakest link in the proposed model. For example, results from the same study found that chronic selective serotonin reuptake inhibitors (SSRI) administration also attenuated anhedonia following adolescent stress exposure in male rats (Bourke et al., 2014). Interestingly, both inhibition of the CRFR system and serotonin reuptake failed to prevent adolescent stress-induced changes in the forced swim test, suggesting that certain behavioral consequences of adolescent stress are mediated through the HPA-axis system (i.e., anhedonia), whereas others (i.e., learned helplessness) are not. As highlighted in multiple sources (McCormick & Mathews, 2007; McCormick et al., 2010a; Romeo, 2010; Engel & Gunnar, 2020), adolescent rodents display a different HPA-axis response to acute and chronic stressors compared to adults, but the enduring effects of adolescent stress on HPA-axis responding are inconclusive. In our proposed model, the HPA-axis plays a role in development of the affective disorders (Fig. 1, arrow 4). However, adolescent stress may also alter downstream biological processes such as cell survival or neurogenesis.

Model recap/summary

Adolescent male and female rodents display elevated corticosterone levels after stress compared to adult animals (Romeo et al., 2004; Romeo et al., 2006). Regardless of age, stressors appear to have an agonistic effect on nicotine sensitivity; results from adolescent and adult rodent studies indicate that stress augments the rewarding properties of nicotine. One study found that stress exposure prior to nicotine exposure enhanced the rewarding properties of nicotine in adolescent mice, and this enhancement was prevented by HPA inhibition prior to stress exposure (Brielmaier et al., 2012). Moreover, after extinction of nicotine self-administration, adult rats exposed to intermittent foot shock exhibited greater reinstatement of nicotine self-administration than non-shocked controls (Buczek et al., 1999; Zislis et al., 2007). Further, blockade of the HPA-axis with a CRF antagonist prior to foot shock exposure weakened stress-induced reinstatement (Zislis et al., 2007). Although the latter two studies examined the interaction of stress and nicotine in adults, they provide support that HPA-axis activation increases the reinforcing properties of nicotine. Given the heightened HPA-axis response to stress during adolescence, it is likely that HPA-axis mediated increases in nicotine reinforcement will be exacerbated during adolescence.

In addition to enhancing initial responses to nicotine, the HPA-axis may play a role in continued nicotine use during adolescence. One study conducted by Cruz and colleagues (2005) found that repetitive nicotine exposure in adult rats, but not adolescents, led to a blunted corticosterone response to further nicotine. That is, repetitive nicotine exposure in adolescents continued to elicit an HPA-axis response regardless of previous nicotine exposure history. Based on the enhanced potency of nicotine reward following HPA-axis activation in adolescence (Brielmaier et al., 2012), adolescent stress could increase the likelihood of nicotine use. In this case, nicotine and the HPA-axis response would become cyclical, with the initial nicotine exposure resulting in HPA-axis activation, which itself would increase the likelihood of nicotine use. Again, it should be stressed that this hypothesis is built on limited findings and further examination is warranted.

As summarized by McCormick and Green (2013), there appears to be a relationship between adolescent stressors and the development of affective disorders. If this relationship is mediated by activation of the HPA-axis and subsequent increases in glucocorticoids, it could be argued that the additive effect of adolescent stress and nicotine use on corticosterone levels may facilitate the development of affective disorders.

Alternatively, it is possible that our proposed model could start with nicotine use. Nicotine activates the HPA-axis and increases corticosterone (Lutfy et al., 2006). Thus, it is feasible that initial nicotine use during adolescence stimulates HPA-axis activity and ultimately elicits changes in anxiety- and depressive-like behaviors independent of stress exposure (figure 1 arrow 5). Iniguez et al. (2009) reported that repeated nicotine exposure during adolescence led to increased anxiety- and depressive-like behavior in adulthood; an effect that was not seen with adult nicotine exposure. Similar long-term manifestations of depressive-like behavior in mice have been reported elsewhere (Holliday et al., 2016). Although not conclusive, this suggests that nicotine exposure during adolescence modulates affective behaviors, which may be driven by repetitive HPA-axis activation that is similar to that seen during repetitive stress exposure. However, adolescent nicotine effects on the HPA-axis remains understudied. It is worth noting that nicotine is capable of producing long-term changes in behavior that are unique to adolescent exposure (Spaeth et al., 2010; Portugal et al., 2012; Abreu-Villaca et al., 2015), supporting the idea that nicotine, independent of stress exposure, may modulate anxiety-like behavior during adolescence as well.

Implications of research/future directions/conclusions

Adolescence is marked by ongoing brain maturation (Andersen & Teicher, 2008). During this critical developmental period, the brain is vulnerable to external factors that can shape and predict future behavioral outcomes. Both human and rodent studies have highlighted a link between adolescent stress exposure and the development of nicotine use and affective disorders. There is evidence to suggest that the comorbidity of nicotine use and affective disorders following adolescent stress exposure is mediated, in part, by HPA-axis activation. However, the exact role the HPA-axis plays in this relationship needs further investigation. First, the role the HPA-axis plays in the development of affective disorders following adolescent stress exposure requires further examination. Studies that test if HPA-axis antagonism before or during adolescent stress abolishes affective outcomes would be valuable (Bourke et al., 2014). Second, since previous studies suggest that adolescent stressor-induced anxiety- and depressive-like behaviors are not maintained directly by the HPA-axis, it is important to examine the role of other neurobiological systems up-or-down-stream of the HPA-axis. For example, stress exposure modulates cholinergic signaling in the adult brain (Gilad, 1987; Mark et al., 1996), and this system has been associated with nicotine use/dependence and affective disorders (Saccone et al., 2007; Dagyte et al., 2011; Kamens et al., 2013; Kamens et al., 2015; Javadi et al., 2017). However, the impact of adolescent stress on cholinergic signaling remains understudied. Third, temporal differences in the impact of nicotine and/or stress exposure during adolescence needs further examination. It remains possible that short- and long-term impacts of adolescent nicotine and/or stress may be modulated by distinct substrates. Utilization of animal models that mimic adolescent nicotine and stress exposure would help map the timing of various biobehavioral consequences. Fourth, the field should move towards more defined/uniform terminology to clarify the consequences of certain “stressors”. That is, efforts to label specific stressors in both human and rodent studies (type and duration) may uncover relationships between specific stressors and biobehavioral outcomes. Finally, although beyond the scope of this review, continued examination of potential sources of stress during the adolescent period is paramount. Pinpointing and eliminating unnecessary activation of the HPA-axis, such as by nicotine or extreme stress, during vulnerable periods of development may ultimately aid in brain and behavioral development.

Abbreviations

ACTH

Adrenocorticotropic hormone

CPP

Conditioned place preference

CRF

Corticotrophin releasing factor

CRFR

Corticotrophin releasing factor receptor

CRFR1

Corticotrophin release factor receptor 1

GC

Glucocorticoid

GR

Glucocorticoid receptor

HPA

Hypothalamic-pituitary-adrenal

Marp

Melanocortin receptor accessory protein

Mc2r

Melanocortin 2 receptor

mPFC

Medial prefrontal cortex

NTS

Nucleus of the solitary tract

PND

Postnatal day

PVN

Paraventricular nucleus of the hypothalamus

SSRI

Selective serotonin reuptake inhibitor

Data Availability Statement

No original data are presented in this review.