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

Figures & data

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.

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.

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.

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.

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