Stress-mediated modulations in dopaminergic system and their subsequent impact on behavioral and oxidative alterations: An update

Abstract

Context: Stress-induced changes in the dopaminergic system and subsequent enhancement of oxidative load and behavior are associated with a wide range of central and peripheral nervous disorders. Dopamine acts as a key neurotransmitter in the brain plays an important role in the regulation of motor and limbic functions.

Objective: This article reviews the effect of stress on central dopaminergic system and its subsequent impact on the alterations in behavior and oxidative stress.

Methods: A literature survey in PubMed (Bethesda, MD), Scopus (Philadelphia, PA), SciFinder (Columbus, OH) and Google Scholar (PMV, CA) was performed to gather information regarding the role of stress on central dopaminergic system and its associated behavioral and oxidative alterations.

Results: Our collective data on behavioral studies and oxidative distress in stressful conditions show the functional reduction in dopaminergic neuronal system that could be one of the factors for the development of stress-induced motor suppression. Collectively, stress caused significant behavioral and oxidative alterations via suppression of neuronal functions of the central dopaminergic system.

Conclusions: This study provides an insight into the overall pathophysiological alterations in neuronal functions of the central dopaminergic system caused by acute and chronic unpredictable stress that, in our opinion, represent optimal utility as future therapeutic targets for neurodegenerative disorders.

• Behavior
• central dopaminergic system
• oxidative stress
• stress

Introduction: A short history of stress research

Stress is defined as a state of threatened homeostasis, which can be of physical and/or psychological nature. Different regulatory systems of the body are activated and orchestrated by various brain responses to improve the ability of the organism to adapt to internal or external challenges (Andrews et al., 2013; Armario, 2006; Mora et al., 2012). Stress is involved in psychopathology at all levels ranging from development, maintenance to relapse of disorders such as schizophrenia, Parkinson’s, addiction, depression, anxiety and cognitive disorders (Jahng et al., 2010; Jankord & Herman, 2008; Kalia, 2005; Nikiforuk, 2013; Tafet & Bernardini, 2003; Yang et al., 2013). The body responds to stress by way of allostasis, in which there is a continuous effort to maintain physiological functions within a certain range, variable to demand (McEwen, 2000). However, too much stress or inefficient management of allostasis leads to allostatic load leading to the development of various clinical disorders. Stress modulates the autonomic nervous system and hypothalamus–pituitary–adrenal (HPA)-axis that subsequently leads to behavioral, physiological and neurobiological changes (Joels et al., 2007; Sorensen et al., 2012). Glucocorticoids (GCs) are the final effectors of the HPA-axis and participate in the control of whole body homeostasis and the organism’s response to stress. They play a key regulatory role on the basal activity of the HPA-axis and on the termination of the stress response by acting at extrahypothalamic centers (frontal cortex and hippocampus), the hypothalamus and the pituitary gland (Andrews et al., 2013). The monoamines such as noradrenaline, dopamine (DA) and 5-hydroxytryptamine are widely distributed in the brain and play an important modulatory role during different stressful conditions (Carrasco & Van de Kar, 2003; Tsigos & Chrousos, 2002; Zalachoras et al., 2013). The frontal cortex and striatum have a high DA content (Miyazaki & Asanuma, 2008), while the hippocampus has a high concentration of GC receptors (Jankord & Herman, 2008). These brain regions are connected with each other through different neurotransmitter systems (Bekris et al., 2005; Noori et al., 2012). The involvement of DA, in relation to its modulatory role on behavioral, neuroendocrine and molecular changes in different brain regions under various stressful conditions is an emerging area in recent studies. DA in the central nervous system (CNS) plays an important role in behavior and physiological responses, and its dysfunctions have been reported in many neuropsychiatric disorders like depression, drug addiction, attention deficit hyperactivity disorder, schizophrenia, Parkinson’s and Alzheimer’s diseases (De Deyn et al., 2013; Espana & Jones, 2013; Hirano et al., 2012; Van Craenenbroeck et al., 2005). Effects of DA are mediated by dopaminergic receptors, which have been classified as D₁ and D₂ type. Based on transmembrane homology, D₁ and D₅ receptors have been grouped together as D₁ type receptors, whereas D₂, D₃ and D₄ receptors as D₂ type (LaHoste et al., 2000). Distribution of DA receptor subtypes in the brain regions and their functions in DA signaling and their associated behavior alterations are summarized in Table 1. Previous reports indicated that psycho-stimulants like cocaine activate HPA axis through the release of DA (Goeders, 2002). Furthermore, chronic stress conditions lead to the depletion of DA in brain, which can be related to dysregulation of HPA axis resulting in hypercortisolemia-like conditions as observed in depression, anxiety and drug abuse (del Rosario et al., 2002; Lucas et al., 2004). In addition, we also studied a differential involvement of DA system in different brain regions during acute stress (AS) and chronic unpredictable stress (CUS) conditions, our data showed that the levels of DA were modulated along with the changes mainly in D₁-like receptors (Rasheed et al., 2010a,b). Our results also suggest a functional reduction in locomotor behavior activity in both stress models. Furthermore, the neurochemical and behavioral effects of D₁ agonist pretreatment in our study allows us to provide insights in understanding the differential response of the DA system and the modulatory role of D₁ receptor under such stressful episodes (Rasheed et al., 2010a). During stress, the increased corticosterone level modulates monoaminergic and oxidative processes. Moreover, the central monoamine and antioxidant systems influence the functioning of each other during stressful conditions. Thus, the anti-stress activity of D₁ agonist could be related to an overall restoration of HPA axis activation and parallel alterations in the central monoamine and oxidative systems (Figure 1). AS significantly decreased the DA levels in the striatum and hippocampus, and D₁ agonist (A68930) pretreatment significantly reverted these changes. However, in the frontal cortex, significantly increased DA levels remain unchanged following D₁ agonist. CUS led to a decrease of DA levels in the frontal cortex, striatum and hippocampus, which were normalized by D₁ agonist (Rasheed et al., 2010a). AS enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the cortex and striatum, while CUS reduced the activities of SOD and catalase (CAT) in the cortex, striatum and hippocampus, when compared with no stress. Increased GSH-Px activity, with reduced glutathione (GSH) and increased lipid peroxidation, was observed in both AS and CUS in selected brain regions as compared to non-stress. Administration of D₁ agonist normalized the antioxidant enzyme activities, replenished GSH and decreased the extent of lipid peroxidation (Rasheed et al., 2011). All of these conclusions have been drawn from our previous studies (Rasheed & Alghasham, 2012; Rasheed et al., 2011, 2010a,b) and presented in Figure 1.

Figure 1. The schematic diagram summarizing the effects of dopamine D1 agonist on the central monoaminergic and oxidative systems under acute and chronic unpredictable stress. Acute stress (shows in upper panel of both antioxidant defense system and monoaminergic system) and chronic unpredictable stress (shows in lower panel of both antioxidant defense system and monoaminergic system). Solid line arrows signify the restoring effects of agonist (A68930) on stress (AS or CUS)-induced alterations, while dashed lines indicate the inability to revert these changes. Symbol

represents increase,

represents decrease, whereas

represents no change in the response. Abbreviations: AS, acute stress; CUS, chronic unpredictable stress; CORT, corticosterone; SOD, superoxide dismutase; CAT, catalase; GSH, glutathione; GSH-Px, glutathione peroxidase; MDA, malondialdehyde; DA, dopamine; HVA, homovanillic acid; DOPAC, 3,4-dihydroxyphenyl acetic acid.

Table 1. Distribution of dopamine receptors in the brain and their functions and their associated behavior alterations.

DA receptor subtype	Brain region (high expression)	Functions	Behavior alterations	References
D1	Striatum, NAc, OT, hypothalamus, thalamus and limbic system	Stimulate adenylate cyclase via Gs	Stereotypic motor response, repetitive behavior, impaired working memory, conditioned fear, rewards, locomotor activity, vigilance and hormonal homeostasis	Capper-Loup et al., 2002; Charntikov et al., 2011; Floresco & Magyar, 2006; Galistu & Daquila, 2013; Mansour et al., 1990; Neve et al., 2004
D5	Hippocampus (DG), thalamus, MN, CC, striatum, hippocampus, SN	Stimulate adenylate cyclase via Gs	Stereotypic, conditioned fear, locomotor activity, vigilance and hormonal homeostasis	Mansour et al., 1990; Neve et al., 2004
D2	Striatum, NAc, OT, CC, SR, amygdala, hippocampus (CA1, CA2, CA3 and DG) hypothalamus, SN and VTA	Negative coupling via Gi to adenylyl cyclase	Open field activity, stereotypic motor response, repetitive behavior, rewards, locomotor activity, vigilance, hormonal homeostasis and impaired working memory	Capper-Loup et al., 2002; Floresco & Magyar, 2006; Galistu & Daquila, 2013; Haghparast et al., 2013; Mansour et al., 1990; Neve et al., 2004
D3	Limbic region (NAc and OT), SN, VTA, hippocampus (CA1, CA2 and CA3)	Negative coupling via Gi to adenylyl cyclase	Locomotor activity, vigilance, hormonal homeostasis and rewards	Mansour et al., 1990; Neve et al., 2004
D4	FC, amygdala, hippocampus (CA1, CA2 and CA3) hypothalamus, mesencephalon, SN and thalamus	Negative coupling via Gi to adenylate cyclase	Locomotor activity, vigilance, hormonal homeostasis, rewards and impaired working memory	Floresco & Magyar, 2006; Mansour et al., 1990; Neve et al., 2004

Abbreviations: DA: dopamine; D: dopamine receptor type; OT: olfactory tubercle; DG: dentate gyrus; MN: mamillary nucleus; CC: cerebral cortex; SR: septal region; SN: substantia nigra; VTA: ventral tegmental area; NAc: nucleus accumbens; and FC: frontal cortex.

Cyr et al. (2001) established a direct relationship of GCs to DA receptors, indicating the importance of stressful conditions and related disorders like depression. These observations suggested that during stress, HPA axis deregulation is linked to receptor-mediated DA action, which is likely to involve D₁/D₂ receptors and DA transporter. Moreover, D₁-like receptors activate adenylatecyclase, whereas D₂-like receptors inhibit the same and activate potassium ion channels (Neve et al., 2004). Behavioral studies have also demonstrated a functional interaction between D₁ and D₂ receptors (Lex & Hauber, 2008). However, the interaction between D₁ and D₂ receptor subtypes in the development of the stress response lacks clarity. It can be hypothesized that the activation of D₁/D₂ receptors may contribute to the alteration in the HPA axis and in certain peripheral, central and behavioral changes during stressful conditions. The brain monoamine and antioxidant systems interact closely with the HPA axis and are implicated in the acquisition and maintenance of psychological and physical stress responses (Lucca et al., 2009; Perez-Nievas et al., 2007). It is well established that oxidative stress plays a fundamental role on the onset of various neurodegenerative diseases (Asanuma et al., 2003). Besides this, DA also has certain direct, non-receptor-mediated effects. DA can undergo auto-oxidation to produce free radicals, which are believed to mediate DA neurotoxicity (Asanuma et al., 2003, 2004). Similarly, reactive oxygen species (ROS) may also be produced during DA metabolism by the enzyme monoamine oxidase (MAO) (Hermida-Ameijeiras et al., 2004). In addition, DA depletes GSH levels in neurons by direct conjugation of oxidized DA with GSH or by generation of superoxide radical via DA receptors (Grima et al., 2003). Therefore, the receptor-independent ROS production by DA may have a direct bearing on altered body homeostasis during stressful conditions. Investigators have found alterations of central dopaminergic system during oxidative stress, and DA oxidation products are suggested to contribute in neurodegenerative diseases (Asanuma et al., 2003). This review will provide an update on DA activities in several stressful events that represent, in our opinion, optimal utility as future therapeutic targets for neurodegenerative disorders.

Role of stress and dopaminergic system in neurological disorders

Despite the power of modern molecular or pharmacological approaches and persisting investigative efforts, the complete interaction between the stress and dopaminergic system activation remains to be identified. DA is present in most of the parts of CNS but four particular neuronal pathways (nigrostriatal, mesolimbic, mesocortical and tuberoinfundibular) play an important role in dopaminergic signaling (Rasheed & Alghasham, 2012). In our previous studies, we evaluated the response of dopaminergic system in AS and CUS conditions by measuring DA levels, its receptor densities in the frontal cortex, striatum, hippocampus, amygdale and orbitofrontal cortex regions of brain (Rasheed et al., 2010a,b, 2011). Now, it is suggested that dopaminergic system is involved in the stress response, and the neural dopaminergic pathways involved in stress are important for current research. Therefore, in this study, we have summarized the precise relation of stress and altered dopaminergic system in neurological disorders (Table 2). Our literature survey suggests that dopaminergic system has received little attention in both clinical and preclinical research on stress, but the current research on this issue will definitely find out better ways of understanding the role of stress and dopaminergic system in neurological disorders.

Table 2. Role of stress and altered dopaminergic system in neurological disorders.

Type of stress	Altered DA pathways	DA alterations	Disorders	References
Acute stress	Nigrostriatal	DA ↓	Parkinson’s	Bozzi & Borrelli, 2006; Gandhi et al., 2012; Rasheed & Alghasham, 2012; Rasheed et al., 2010a; Snyder et al., 1985
			Huntington’s, ADHD	Bedard et al., 2011; Madras et al., 2005
	Mesocortical	DA ↑	Schizophrenia	Arnsten, 2011; Kambarova & Golubev, 2011; Rasheed et al., 2010a; Wood et al., 2013; Bozzi & Borrelli, 2006
			Tourette’s syndrome	Bozzi & Borrelli, 2006; Park et al., 2005
		DA ↓	Epilepsy, drug addiction	Bozzi et al., 2000
	Tuberoinfundibular	DA ↓	Pituitary tumors Abnormal lactation, menstrual cycle disturbance and sexual dysfunction	Benskey et al., 2012; Rasheed & Alghasham, 2012; Rasheed et al., 2010a; Van Craenenbroeck et al., 2005
CUS	Mesolimbic	DA ↓↓	Pituitary tumor	de Jong & deKloet, 2004; Mizoguchi et al., 2000; Rasheed & Alghasham, 2012
	Nigrostriatal	DA ↓↓	Parkinson’s	Rasheed & Alghasham, 2012; Shen et al., 2012; Snyder et al., 1985; Van Craenenbroeck et al., 2005
			Huntington’s, ADHD	Bedard et al., 2011; Madras et al., 2005
	Mesocortical	DA ↑↑	Schizophrenia Tourette’s syndrome	Bozzi & Borrelli, 2006; Rasheed & Alghasham, 2012; Wood et al., 2013
		DA ↓↓	Epilepsy, drug addiction	Bozzi et al., 2000; Bozzi & Borrelli, 2006
	Tuberoinfundibular	DA ↓↓	Pituitary tumors Abnormal lactation, menstrual cycle disturbance and sexual dysfunction	Mohankumar et al., 2011; Rasheed & Alghasham, 2012; Rasheed et al., 2010a; Van Craenenbroeck et al., 2005

Abbreviations: DA: dopamine; CUS: chronic unpredictable stress; ADHD: attention-deficit hyperactivity disorder. Symbols represent the following: ↓: decrease, ↓↓: severe decrease, ↑: increase and ↑↑: severe increase.

Behavioral modulations correlate with DA system and stress

Stress is linked with number of behavioral disorders including anxiety, mood and depression. However, the best-studied case of a stress axis interface with a psychiatric illness is that of major depressive disorders (Andrews et al., 2013; Harro & Oreland, 2001). Depressive disorders are common in humans and are believed to be influenced and/or induced by a wide variety of factors including biological, environmental and genetic ones. The pathophysiology of various neurodegenerative and behavioral disorders are also attributed to DA neurotransmission (Smith et al., 2008). Disorders involving DA neurons are manifested in movement disorders such as Parkinson’s and motivation disorders such as Schizophrenia and drug addiction. Various stress manipulations cause alterations in motor activity of animals, and dopaminergic pathways are crucial neural substrates for the control of locomotor activity (Benturquia et al., 2008). Thus, DA appears to play an essential role in locomotion via neural transmission (Salamone et al., 2005). DA has been implicated in the stress-related regulation of the HPA-axis, as well as in depression (Cabib & Puglisi-Allegra, 1996). There is evidence that central dopaminergic systems exert a positive control on the HPA-axis and the sympathetic nervous system, and reciprocally, GCs and catecholamines mediate stress-induced alterations. The dopaminergic mesolimbic and mesocortical pathways are activated by the nucleus locus coeruleus and the autonomous nervous system during stress. The mesolimbic pathway is involved in the processing and reinforcement of rewarding stimuli and in motivation of behavioral responses (Brooks & Berns, 2013; Obara et al., 2013). This system is believed to be involved in the activation of goal-directed behavior, and its inhibition may lead to emotional indifference and lack of initiative. This system has been shown to be highly sensitive to stress (Cabib & Puglisi, 2012). The mesocortical pathway is critical for cognitive functions such as judgment and planning of behavioral responses (Cabib & Puglisi-Allegra, 1996). Table 3 summaries the interplay between stress and DA alteration in various behavioral disorders. It is suggested that stressful experiences alter DA metabolism. Moreover, CUS may lead to different responsiveness to subsequent stressful experiences depending on the stressor, leading to different changes on mesolimbic function. Exposure to AS or CUS aversive experience may lead to inhibition of DA release in the NAC as well as to impaired response to both rewarding and aversive stimuli (Cabib & Puglisi-Allegra, 1996). The effects of stressful experiences on DA functioning in the mesocortical system can be very different or even opposite depending on the controllability of the situation, the genetic background of the organism and its life history (Cabib & Puglisi-Allegra, 1996). The dopaminergic system is involved in many behavioral and biological functions of the CNS including locomotor activity, emotional responses and neuroendocrine secretion (Nieullon & Coquerel, 2003) and has been the focus of research for many years. The pathophysiology of various neurodegenerative and behavioral disorders are also attributed to DA neurotransmission (Smith et al., 2008). Various stress manipulations cause alterations in motor activity of animals, and dopaminergic pathways are crucial neural substrates for the control of locomotor activity (Benturquia et al., 2008).

Table 3. Interplay of stress and altered dopaminergic system in behavioral disorders.

Altered DA pathways	Type of stress	DA alterations	Behavioral Disorders	References
Mesolimbic	AS	DA ↓	Depression, anxiety, mood, gold directed behavior and emotional indifference	Cabib & Puglisi-Allegra, 1996, 2012; Jahng et al., 2010; Pania & Gessab, 2002; Rasheed et al., 2010a,b; Yorgason et al., 2013
	CUS	DA ↓↓	MDDs, anxiety, mood, gold directed behavior and emotional indifference	Cabib & Puglisi-Allegra, 1996, 2012; Klimek et al., 2002; Moore et al., 2001; Pania & Gessab, 2002; Rasheed et al., 2010a,b; Tafet & Bernardini, 2003
Mesocortical	AS/CUS	DA↓ (AS) DA↓↓ (CUS)	Cognitive dysfunction, lacking of judgment and planning, anticipatory phenomena and focused attention	Joels et al., 2006; Moore et al., 2001; Nikiforuk, 2013; Tafet & Bernardini, 2003

Abbreviations: DA: dopamine; AS: acute stress; CUS: chronic unpredictable stress; MDD: major depressive disorders. Symbols represent the following: ↓: decrease, ↓↓: severe decrease, ↑: increase and ↑↑: severe increase.

In our study, we observed a decrease in behavioral locomotor activity when rats were subjected to acute and CUS as evaluated in terms of decreased horizontal activity, stereotypy counts and total distance traveled (Rasheed et al., 2010a) (Figure 2). In rodents, the mesostriatal and mesocorticolimbic dopaminergic pathways are known to modulate spontaneous and DA-induced motor activity (Benturquia et al., 2008; Ikemoto, 2007; Rasheed et al., 2010a; Rezvani et al., 2008). Thus, DA appears to play an essential role in locomotion via neural transmission (Salamone et al., 2005). The stress-induced adaptation of brain DA function involves DA receptors, and receptor densities are affected by altered extracellular DA levels (Floresco, 2007). Behavioral studies have also demonstrated a functional interaction between D₁ and D₂ receptors (Lex & Hauber, 2008). Furthermore, environmental or pharmacological manipulations of dopaminergic transmission are able to modify basic forms of behavior present in nature and linked to the survival of the individual and the species. Disruption of dopaminergic transmission will affect behavior, which is related to the ability to “feel” the environment and to take decisions based upon those sensations, which will affect the emotional status of the individual; that is, survival through the attribution of incentive salience to significant environmental stimuli and contextual reward/avoidance learning (Berridge, 2007; Bressan & Crippa, 2005). This unique ability has established DA, throughout evolution, as the principal neurotransmitter of motivated action, in the sense of physical and psychological movement toward “pleasure” or away from “pain” (Volkow et al., 2011). DA has been implicated in habituation, although no concerted effort has been made to attempt to differentiate its motor-activating effects from its effects on habituation. A few pharmacological studies have contributed to the understanding of the dopaminergic influences on habituation. Apomorphine, a D₂ agonist, decreases intrasession habituation in rats (Nadal, 2001; Rudzinska & Szczudlik, 2007). Chronic administration of D₁ receptor antagonist (SCH23390 or SRK-82958) results in increased locomotor activity during the habituation period (Charntikov et al., 2011). Administration of quinpirole, a D₂ antagonist, does not appear to affect intrasession habituation in general, although high doses can induce deficits in young (30-d old) rats. This corresponds well with the finding that D₂ receptor knockout mice display normal intersession habituation (Smith et al., 2002). It seems most likely that DA alters normal habituation by influencing other neurotransmitter systems that have been more clearly implicated in habituation. DA is known to play an important role in working memory and response sequencing in the PFC. In particular, DA acting on D₁ receptors has been shown to exert dual actions on these types of behaviors. Thus, D₁ agonist administration into the PFC of rats with poor performance on attentional function tasks significantly improved their performance, whereas impairing performance in rats that had higher baseline attentional skills (Granon et al., 2000). This is consistent with studies suggesting that optimal DA levels are required to maintain function in the PFC, with both too high and low D₁ stimulation leading to impaired working memory function (Floresco & Magyar, 2006). Several studies have shown that the DA system is activated by rewarding stimuli, such as food (Wise, 2013); however, it is becoming evident that DA is not the reward signal per se, but instead is necessary for the acquisition of reinforcing stimuli. Overall, studies support the suggestion that DA actions in the PFC may have a greater involvement in the regulation of novel circumstances, with the striatum involved more in expression of learned behaviors (Tofaris et al., 2006). This model is consistent with the physiologic studies show that DA can selectively activate circuits within the frontal cortex and striatal complex, potentially facilitating information flow along new pathways when a change occurs, but playing less of a role once a new stable steady state is achieved at which the internal representation is at equilibrium with the predicted external events. Full DA D1/5 receptor agonists A68930 and dihydrexidine produced marked inhibition of locomotor activity in rats. A68930 and dihydrexidine furthermore antagonized d-amphetamine-induced hyperactivity, a state of excess of brain DA activity. Analysis of c-fos expression in response to A68930 and dihydrexidine treatment suggested that such inhibitory actions of A68930 and dihydrexidine might be mediated by the activation of DA D1/5 receptors in the medial prefrontal cortex (Isacson et al., 2004). Together with previous work on hypofrontality and prefrontal DA D1/5 receptors in schizophrenia, as well as on the mechanisms of action of atypical antipsychotics, we suggest a beneficial role of DA D1/5 receptor agonism in schizophrenia.

Figure 2. Role of D1 receptor on behavior activities during stressful events. Involvement of D1 receptor was examined during acute stress (AS) and chronic unpredictable stress (CUS) events using D1 agonist (A68930). The saturation radio ligand binding assays revealed a significant decrease in the number of D₁-like receptors in the frontal cortex during CUS, which were further decreased by D1 agonist pretreatment. However, in the striatum and hippocampus, D1 agonist pretreatment reduced the CUS-induced increase in the number of D₁ like receptors. No significant changes were observed in the amygdala during AS and CUS, while D₂-like receptors were unchanged in all the brain regions studied. Behavior activities were significantly decreased in both the stress models, D1 agonist pretreatment significantly increased stereotypic counts and horizontal activity. Symbol

represents increase,

represents decrease, whereas

represents no change.

DA and oxidative stress

Many studies showed that exposure to different stressful conditions increases the production of ROS, and consequent oxidative damage, with a concomitant decline of in vivo antioxidant defense system (Schiavone et al., 2013). Stress exerts detrimental effects on several cell functions, through impairment of antioxidant defenses, leading to oxidative damage, which plays critical role in the pathophysiology of neurodegenerative diseases, neuropsychiatric disorders and stress-induced depression (Bilici et al., 2001; Torres et al., 2004). Oxidative stress induces many damaging processes in stress disorders such as mitochondrial dysfunction, dysregulation of calcium homeostasis (Amoroso et al., 2000), disruption of energy pathways (Ho et al., 2013), damage to neuronal precursors, impairment of neurogenesis (Li et al., 2012), induction of signaling events in apoptotic cell death (Cregan et al., 2002), ultimately leading to atrophy and morphological changes in the brain characteristic in stress-induced depression (Sapolsky, 2000). Furthermore, the brain is more vulnerable to oxidative damage compared to other organs for several reasons (Metodiewa & Koska, 2000). Brain consumes a higher rate of oxygen per unit mass of tissue, contains high levels of peroxidizable lipids, excitotoxic amino acids and low levels of antioxidants (Andersen, 2004; Metodiewa & Koska, 2000). Furthermore, stress leads to increased serum GC levels, which may alter antioxidant enzyme activities in brain (Zafir & Banu, 2009). Importantly, some studies indicate a link between the alterations in central monoaminergic system and increased oxidative load during physiological adverse conditions (Siraki & O’Brien, 2002). But the extent to which oxidation products contribute to the perturbed redox state during chronic stressful condition in the monoaminergic innervated regions warrants further study. A number of studies suggested a link between the alterations in central dopaminergic system and increased oxidative load during physiological adverse conditions (Siraki & O’Brien, 2002). DA oxidation products are postulated to contribute neurodegenerative disease process (Andersen, 2004). During stress, elevated catecholamine levels may undergo autoxidation, in which electrons are generated, which in turn can produce ROS (Carpagnano et al., 2003). DA forms ROS through DA metabolism by MAO and by autoxidation. DA also forms quinones and semiquinones, which can deplete GSH with simultaneous generation of ROS (Miyazaki & Asanuma, 2008). In order to neutralize ROS, the body uses enzymatic (SOD, CAT and GSH-Px) and non-enzymatic (GSH) antioxidant system. Under physiological conditions, DA is non-enzymatically oxidized by molecular oxygen to form hydrogen peroxide (H₂O₂) and the corresponding o-quinone (oQ). Then, the oQ undergoes an intramolecular cyclization, which is immediately followed by a cascade of oxidative reactions resulting in the final formation of a black, insoluble polymeric pigment known as neuromelanin (Aguilar Hernandez et al., 2003). In addition, DA is also enzymatically deaminated by MAO to form H₂O₂ and 3,4-dihydroxy phenyl acetaldehyde. This latter compound is then oxidized by aldehyde dehydrogenase to give 3,4-dihydroxyphenylacetic acid, which subsequently is methylated by catechol-O-methyltransferase to form homovanillic acid. Therefore, both the autoxidation and the MAO-mediated metabolism of DA involve the formation of H₂O₂, a compound that can easily be reduced in the presence of ferrous iron (Fe2+) to form, through the Fenton reaction, the hydroxyl radical (•OH), which is considered the most damaging free radical for living cells. Taking into account that the loss of dopaminergic neurons boosts both DA biosynthesis and turnover in the surviving neurons, it seems evident that the subsequent excessive autoxidation and metabolism of DA in these cells increases the oxidative stress, and thus contributes to the progressive loss of dopaminergic neurons observed with age and in Parkinson’s disease (Lev et al., 2013). Furthermore, these phenomena are enhanced by the presence of neuromelanin in dopaminergic neurons, due to its reported ability to accumulate iron (Andersen, 2004) and consequently may act by promoting the Fenton reaction. Furthermore, the pathogenicity of DA quinone formation has recently received attention as dopaminergic neuron-specific oxidative stress (Asanuma et al., 2003; Choi et al., 2005), in contrast to the general oxidative stress including the generation of ROS and reactive nitrogen species in the oxidation of DA. The DA as a neurotransmitter is usually stable within the synaptic vesicle. When the DA neurons are damaged, an excess amount of cytosolic DA or l-DOPA is spontaneously oxidized and produces DA quinones or DOPA quinones (Miyazaki & Asanuma, 2008). These quinones generated from DA or l-DOPA exerts cytotoxicity in or beside dopaminergic neurons by interacting with various bioactive molecules. Furthermore, the quinone formation is closely linked to other representative hypothesis such as mitochondrial dysfunction, inflammation, oxidative stress and dysfunction of the ubiquitin-proteasome system, in the pathogenesis of neuro-degenerative diseases. Based on our published studies (Ahmad et al., 2010; Rasheed et al., 2011, 2010a,b), we have also shown the stress-induced alterations in antioxidant mechanisms in different brain regions and their associated modulations in DA system (Figure 1). In short, oxidative stress is thought to play an important role in dopaminergic neurotoxicity, and pathogenic effects of the DA quinone have recently focused on dopaminergic neuron specific oxidative stress. Thus, we primarily review recent studies on the pathogenicity of quinone formation, in addition to several neuroprotective approaches against DA quinone induced dysfunction of dopaminergic neurons.

Final comments

We are only at the verge of understanding how acute or CUS can modulate the DA pathways in neurological and behavioral disorders and suggest that stress could be a cofactor in the pathogenesis and/or progress of disorders of the dopaminergic system possibly through oxidative mechanisms. DA-related and stress-related disorders are complex and multifactorial, both genetic and environmental factors play a role and it is not possible to attribute the cause of these disorders to a single event. There are some interesting studies in cultured cells, providing evidences for the interaction between DA and stress using stress marker hormone GCs (Van Craenenbroeck et al., 2005), but little is known about the physiological role in vivo or the relevance in neurological and behavioral disorders. Therefore, it would be of great value to study this into more detail in the future. One useful approach to expand our knowledge is to identify molecular factors or genes involved in neurological and behavioral disorders. This may be achieved by detailed studies using DA receptor knockouts (tissue-specific or inducible transgenes) or using GR transgenic mice in specific brain regions. More specifically, using brain area-specific transgenic of the DNA-binding defective DA receptor would even allow an assessment of which type of DA receptor-mediated gene regulation is involved, either by direct binding of DA onto DA receptors, or indirectly via protein–protein interactions with other transcription factors. Furthermore, vice versa, GR transgenic mice would provide useful information with regard to the role of DA signaling on GR function in the brain. Other ways to find out more about stress activities are post-mortem brain studies on the corticotrophin releasing hormone levels from the hypothalamus of patients, who suffered from neurological or behavioral disorders at various stages of the illness. In addition, molecular studies such as promoter analyses and signal transduction studies will allow unraveling of the mechanism of how activated stress marker GR can influence DA receptor regulation and dopaminergic signaling, and vice versa, how dopaminergic signalization can influence GR effects at the cellular levels. All these strategies surely open novel therapeutic approaches to understand more about the role of stress and dopaminergic system in neurological and behavioral disorders.

Conclusions

This review on behavioral studies and oxidative distress in stressful conditions suggest that a functional reduction in dopaminergic neuronal systems may be responsible for the development of stress-induced motor suppression, although the functional interaction of DA D1 and D2 receptors are still intact. In addition, this study also provides an insight into the overall pathophysiology of stress and implicating the importance of DA and stress as future therapeutic targets for neurological and behavioral disorders.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article. This work was supported, in part, by funds from College of Medicine, Qassim University.