Open access peer-reviewed chapter
Abstract
Anorexia nervosa (AN) is a psychiatric illness characterized by a lack of motivation and a taste for rewarding food consumption. Mood disorders such as depression and stress are frequently associated with this condition. Abnormalities in several neural systems have been identified in patients with AN, including serotonin, dopamine (DA), appetite-related neuropeptides, and other neurochemical systems. Moreover, the changes that occur between the mesolimbic dopaminergic pathway and the orexin neurons in the lateral hypothalamus (LH) in response to the reduction in food consumption are key in the development of AN. Several studies suggest a functional relationship between orexin and dopaminergic circuits. LH orexin neurons project dense fibers on dopaminergic neurons, potently activating these neurons. DA and orexin neurons regulate negative and positive motivational states, such as drug and food seeking behavior. For this reason, it is important to extend the study of the functional and emotional interactions that exist between both neuronal systems to design new drugs that act at a behavioral and molecular level to treat AN. This chapter provides an overview of the evidence from literature implicating dopamine-orexin systems in AN and discusses recent advances that have contributed to our current understanding of the mechanisms underlying the molecular bases of AN.
Keywords
- mesocorticolimbic system
- dopamine receptors
- reward
- mental illness
- orexin neurons
- motivation
- anxiety disorders
1. Introduction
Anorexia nervosa (AN) has been classified as a chronic psychiatric disease since this condition has a strong emotional component. AN belongs to a group of eating disorders and is characterized by extreme body weight loss. AN patients show combination of physical, psychological, and behavioral disturbances that usually have their onset during adolescence. AN is associated with high levels of psychiatric comorbidity including psychosis, hyperactivity, depression, and anxiety. In consequence, this illness has become a major focus of attention in terms of both the research community and the general public. The prevalence of AN is approximately 1% in women and less than 0.5% in men [1]. Patients with AN show a high degree of anhedonia (the reduced capacity to experience reward or pleasure) and have a disturbed body image and an intense fear of weight gain. Standardized mortality ratios show that the rate of death in AN is at least five times greater than that in the general population [2].
Little is known about the etiology and the intrinsic biological alterations of anorexia, but it appears to be the result of different factors, for example, low self-esteem, certain personality traits such as perfectionism, mental illnesses such as depression, anxiety, self-harm, difficulty to manage stress and cope with life. Feelings of obsession and compulsion are also related with AN. Society and communication media play a key role in this pathology, since through them we are constantly told that the image of the body is very important because it reflects our value, as people. While culture, society, and the media exert pressure on women to remain thin, now it is widely accepted that there is a biological basis for this psychiatric disorder. Henceforth, the complexity of AN has limited the development of neuroscience-based treatments, and no medication or other biological treatment has been approved for the disorder. Then, to understand the biology of pathological eating behavior is an important step in the development of appropriate pharmacotherapies that can be used to treat AN patients.
To date abnormalities in several neural systems have been identified in patients with AN, including serotonin and DA, appetite-related neuropeptides, and other neurochemical systems. This chapter will focus especially on the dopaminergic neurons of the ventral tegmental area (VTA) that project the nucleus accumbens (NAc) to form the mesocorticolimbic circuit; and in the orexin neurons localized exclusively in two subregions of the hypothalamus; the perifornical area (PFA) and the LH, where orexin peptide is expressing [3].
Previously, it was thought that the serotonin system was the only or most important neurotransmitter involved in AN, and all research was carried out around its neurotransmission. Subsequently, preclinic and clinic evidence propose that the dopaminergic system could be a key factor in the pathophysiology of eating disorders. The AN is characterized by a reduction in food intake (diet restriction) and hyperactivity. In this sense, decrease in DA content has been observed in hypothalamus, hippocampus, and the dorsal striatum after a restricted diet. Moreover, the motor activity is modulated mainly by dopaminergic circuits. These first data point out for the first time the possible contribution of dopaminergic transmission in anorexia.
The signals to eat or to stop eating are very complex and extend beyond the control of the homeostatic system that responds to metabolic and satiety signals from the gut. Recently, it has been proposed that mesocorticolimbic dopaminergic system also responds to features of food such as the sight, smell, and taste in addition to cues that predict food intake and override the ingestive behavior [4]. The motivation to eat is key in eating behavior and is regulated by several intrinsic and extrinsic factors. Neuronal and circulating peptides are released in response of internal states, such as hunger or satiety, to stimulate or repress food intake, respectively. Accumulating evidence has pointing out the orexin-containing neurons as central regulators of feeding behavior, energy balance modulation, and metabolic homeostasis.
2. Dopamine neurons
DA is a catecholamine and is a key neuromodulator involved in motivated behaviors. DA-containing neurons are characterized by the presence of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines, and are found throughout the mammalian central nervous system (CNS), including the ventral midbrain (VM) [5]. Midbrain DA-containing neurons are arranged principally in two nucleus: the substantia nigra pars compacta (SNc, also known as the A9 group) and the VTA, or A10 group [5, 6]. Different populations of DA-containing neurons project to distinct areas and control or modulate specific functions, according to their targets. We will emphasize in the VTA nucleus, which project to ventromedial striatum (NAc) and PFC, forming the mesocorticolimbic system. These DA-containing neurons regulate emotional behavior, natural motivation, reward and cognitive function, and are largely implicated in a range of psychiatric disorders [7, 8, 9].
DA acts primly through of two G protein-coupled DA D1 (D1R) and D2 (D2R) receptors [10]. D1R is a postsynaptic receptor that mediates more directly behavior, and the D2R is a presynaptic autoreceptor that regulates DA release in a negative feedback fashion; D1R increases, whereas D2R decreases adenylyl-cyclase activity, and both receptor types are distributed throughout the CNS [11]. A variety of studies indicate that an altered DA function in AN could be implicated. Patients with AN have shown low levels of homovanillic acid in their cerebrospinal fluid (CSF), the major DA metabolite [12]; in addition, a positron emission tomography (PET) study revealed an increase in D2R binding in the anteroventral striatum (NAc in rodents), in a mixed group of women recovered from both restricted-type anorexia nervosa and binge-eating/purging-type [13]. These data suggest that neuronal or synaptic DA may be reduced, but that DA receptors could be increased in number or sensitivity in a compensatory or negative feedback fashion [14]. Thus, a downregulation of receptor sensitivity might be an important therapeutic goal in AN, to compensate the low levels of DA.
Several hypotheses have been raised about the contribution of DA in AN. On one side, Bergh and Södersten [15] suggest that normal DA responses to hunger and exercise facilitate a progression into AN; in addition, O’Hara et al. [16] proposed that an anomaly in the reward system mediated by the DA leads to the development, maintenance, and resistance to the treatment of the AN.
2.1 Mesocorticolimbic dopamine neurons may facilitate the development of anorexia nervosa
According to Bergh and Södersten [15], dieting, along with high levels of exercise, leads to a stress response that increases cortisol and corticotrophin-releasing factor (CRF) [17, 18, 19, 20, 21, 22], which in turn promotes an increase in DA levels in the NAc [23, 24]. In such a way, DA facilitates rewarding behaviors such as diet and exercise to become habits similar to those associated with drug dependency or self-starvation by conditioning this type of reward to initially neutral stimuli [15, 25, 26, 27, 28]. In addition, the high CRF levels induced by diet restriction and exercise also facilitate to seek for food, while simultaneously suppressing food intake [29]. However, until now there is no clinical study that compares the DA levels in anorexic subjects before and after developing anorexia that shows chronically high levels of DA before the disease was declared.
2.2 Aberrant concept of starvation in anorexia nervosa
The mentalistic concept of AN assumes that it results from a mental illness. This concept describes this illness as a set of chronic and serious mental disorders with debilitating physical, cognitive, and socioemotional impairments such as anxiety, depression, obsessional traits, and pathological cognitions. Therefore, when the initial care of a patient with anorexia is focused only on cognitive therapies to treat psychological disorders do not usually give good long-time results. Moreover, symptoms such as anxiety and depression also emerge in healthy people during a starvation period [30]. There are many arguments against the hypothesis that an underlying mental disorder causes AN [31]. Recently, it was discovered that AN and anxiety have different genetic risk factors. Also, almost all mental disorder symptoms observed in anorexics disappear after normalization of eating behavior [31, 32].
O’Hara et al. [16] do not agree with the mentalist concept because this does not assume the normal functions of the neuroendocrine system, which is responsible for regulating the release of peptides that regulate food consumption. The mentalist concept does not take into account the physiological aspects in eating disorders, and this may be the reason why this approach to treating anorexia as a consequence of a mental illness has not led to an effective treatment. O’Hara et al. [16] proposed that an abnormality in the reward system mediated by DA leads to the development, maintenance, and resistance to treatment in the AN.
They suggest that the decrease in dopaminergic activity and the rejection of food intake are key in the development of anorexia. Therefore, they propose increasing DA levels to normalize the consumption of food to reduce the stress generated by starvation, which in turn reduces the release of CRF to gradually increase the consumption of food. However, recent studies suggest that changes in DA found in anorexic patients are due more to a normal characteristic of starvation than to a disease marker.
3. Hypothalamic orexin neurons modulate dopaminergic neurons
Orexin-A and orexin-B neuropeptides were initially identified as endogenous ligands for two orphan G protein-coupled receptors; the OX1R is coupled entirely to Gq, whereas OX2R is coupled to both Gi/o and Gq [33]. Both orexins are derived from proteolytic cleavage, of a precursor peptide (pre-pro-orexin), and are produced by a group of neurons in the LH and PFA, a region known as the feeding center (Figure 1). OX-A has the same affinity with both receptors, while OX-B has a greater affinity for OX2R than OX1R [33, 34]. These receptors are highly expressed throughout the brain including the “dopaminergic reward pathways” (Figure 1) [35, 36, 37, 38, 39]. Moreover, these peptides are also regarded as an important factor that regulates feeding behavior, owing to their localization within the lateral hypothalamic area, the classic “feeding center.”
Figure 1.
Schematic representation of the brain areas related to motivated and emotional behaviors. (A) Coronal section of the rat brain showing the lateral (LH) and perifornical area (PEA) of hypothalamus. (B) Representation of the main orexin projections and the expression of orexin receptors 1 and 2 (OX1R and OX2R) in these brain regions. The fear circuit comprising the hippocampus (Hypp), medial prefrontal cortex (mPFC), and amygdala (AMY). Areas implicated in anxiety: bed of the stria terminals (BNST), paraventricular thalamus (PVT), and septum. The paraventricular nucleus of the hypothalamus (PVN) regulates stress responses and the hypothalamic-pituitary-adrenal axis hormone cascade. The mesocorticolimbic system modulates the rewarding properties of food and drugs of abuse and comprising the ventral tegmental area (VTA) and nucleus accumbens (NAc). The locus coeruleus (LC) also has dense orexin innervations in concordance with its involvement in arousal and emotional memory. Abbreviation: LH, lateral hypothalamus.
Orexins were recognized as positive regulators of energy expenditure, thanks to the development of the orexin neuron-deficient mice. Studies conducted in these animals led to propose that orexins promote acute food consumption on one hand and on the other hand prevent the progress of obesity [40]. Since then, numerous pharmacological and genetic studies have supported that these peptides together with their receptors are key regulators of energy expenditure, thus influencing the energy balance.
The activation of the orexin system by means of the microinjection of orexin-A in the hypothalamus has shown that these peptides act as protectors in the development of obesity, by increasing energy expenditure. Also, orexin neurons increase energy expenditure by increasing thermogenesis in brown adipose tissue [40]. On the other hand, it has been observed that overexoression of pre-pro-orexin gene in an animal model promotes resistance to obesity induced by consumption of a high-fat diet [41]
The available anatomical, genetic, and pharmacological evidence supports that the behavioral consequences of the activity of the orexin system are due to parallel signaling to multiple brain regions and neurotransmitter systems such as DA. For example, the NAc is involved in hedonic and motivational aspects of feeding [42] and is an important brain region because endogenous orexin peptides act to modulate DA release [43], which act over hedonic processes associated with food evaluation and consumption. In addition, NAc is involved in the reward of natural behaviors, such as exercise, sex, and, of course food intake.
Orexins in the VTA, the major dopaminergic nucleus, have been implicated in drug and alcohol seeking and reinstatement. as well as food seeking, in highly salient circumstances, food seeking in highly salient circumstances, for example, during hunger, presentation of palatable foods or with exposure to food-related cues, but not in the consumption of regular food [44, 45]. An alternative mechanism by which orexins can stimulate the consumption of highly palatable food is via the paraventricular thalamic nucleus (PVT) because orexin neurons in the hypothalamus also send dense projections to the PVT [37], which in turn regulates DA efflux to the NAc via its glutamatergic projections [46, 47]. It has been reported that orexin actions in PVT promote DA efflux in the NAc, while the inhibition of its receptor OX1R in this region decreases hedonic intake of palatable foods [48]. Therefore, orexins not only can act directly in the VTA to increase DA [45, 49] but they also increase DA via action in the PVT to promote hedonic food intake [48]. In summary, the control that orexins exert over VTA-NAc circuit is key to modulate motivational behaviors and reward processes related to drug, alcohol, and food seeking.
Functional studies show the relationship between LH orexins and VTA-NAc circuit where orexins exert their actions on the dopaminergic neurons by increasing the firing frequency in VTA neurons in vitro and in vivo [50, 51]. These peptides induce an increase in DA release and its metabolites in both NAc and PFC [4, 49, 52, 53]. Electrical stimulation of the LH nucleus can increase both food intake and accumbal DA turnover [54, 55, 56]. In contrast, the inhibition of OX1R reduces DA cells firing [57], as well as significantly decrease in amphetamine, and cocaine-induced DA release in the NAc [57, 58]. On the other hand, the intracerebroventricular administration of OX-A leads to stress-related behavior like grooming, stereotypy, and hyperlocomotion [59], actions that were inhibited by DA D1 receptor (D1R) or DA D2 receptor (D2R) antagonists in rodents [59]. These data provide strong evidence that the orexin system contributes to DAergic neurons regulation in the mesocorticolimbic pathway and that the action of orexins in these neurons could involve a variety of behaviors that are known to be regulated by DA.
This framework suggests that understanding the function of the orexin requires studying them in a brain region-specific basis, as well as understanding the interactions between different brain regions that receive orexinergic input [40]
4. Anorexia nervosa and anxiety disorders: role of orexin and dopamine
4.1 Anorexia nervosa and anxiety disorders
AN is a very complex disease, characterized by a profound dysregulation in neurocircuits related to control eating behavior, anxiety, fear, and reward positive/negative reinforcers. AN is a serious motivated behavioral condition with high morbidity and mortality. Anorexic patients usually have a high comorbidity with severe anxiety disorders, such as obsessive-compulsive disorder (OCD) and social anxiety disorder (SAD) [60]. One characteristic that anorexics share with people suffering from SAD is their fear and concern about how other people perceive them. Elevated neuroticism and perfectionism as well as decreased novelty seeking are anxious personality traits observed in these disorders [60]. Therefore, anxiety disorders and AN are strongly correlated; in both disorders, the fear is organized around an irrational belief associated with heightened vigilance and pronounced anxiety. Another characteristic shared between AN and OCD is compulsivity: to engage in repetitive and stereotyped acts that have unwanted outcomes [61] and arises from a reduced ability to control inflexible yet maladaptive behavior as the starvation, which persists in the face of negative consequences, for example, interfering with academic/occupational/social interests in longer term and the behaviors promoting further, and potentially dangerous, weight loss.
Recently, Lloyd et al. [62] have proposed a central role for anxiety in the development of compulsive starvation; they suggest a dual mechanism by which anxiety could be motivating the initiation of AN and propose that the reinforcement effects of starvation cause excessive repetition of behaviors leading to the buildout of psychological symptoms of AN. They also suggest that starvation becomes compulsive until it has adverse implications for anxiety, which generates the symptoms of AN and which encourages the formation of a vicious circle that guarantees the persistence of an extreme dietary restriction. Stress and distress tolerance have been suggested as important factors in determining the onset and course of AN [61]. Stressful and traumatic events often precede eating diseases. Notably, high levels of anxiety tend to also precede the onset of addiction and OCD.
Dietary restriction has an anxiolytic effect, because women recovered from AN show elevated levels of serotonin (5-HT) metabolites [63], and gene variants linked to more active 5-HT and noradrenaline (NA) systems are implicated in AN [64, 65], supporting the involvement of these neurotransmitter systems in the heightened anxiety that precedes AN. Thus, dietary restriction relieves the anxiety (or negative reinforcement) provided by the dietary restriction that increases with anxiety.
Starvation is a compulsive behavior that over time becomes a habit with a dominant influence in individuals with AN. Surprisingly, in anorexics, there is an imperative need to keep starving [62]. However, this behavior puts your life at risk.
Subjects with AN show an extreme aversive state characterized by high levels of anxiety when eating, that is, when they do not carry out their compulsive behavior of starvation [61, 66]. This is also observed in addiction and OCD, where the execution of compulsions serves to temporarily relieve the negative effects [61, 67, 68, 69]. Several studies indicate that the levels of anxiety in anorexics are even higher than before the restriction of food and that this anxious behavior is partially mediated by an increased sensitivity of the 5-HT and NA systems, which results from the reduced consumption of tryptophan and tyrosine, respectively [70, 71].
When starvation becomes necessary to avoid an extremely anxious state, the desire to starve is enhanced given the poor emotion regulation abilities of individuals with AN, which limits the use of alternative strategies to overcome dysphoria [72, 73, 74].
Anxiety precedes and coincides with restrictive eating in AN [75, 76, 77, 78], which is not the case for individuals without the disorder [77]. Repeatedly engaging in dietary restriction in an anxious state facilitates anxiety to evoke restrictive eating habits, due to a pairing of emotion and behavior.
Thus, several mechanisms likely explain how anxiety promotes engagement in maladaptive dietary restriction habits that have developed during a compulsive illness.
4.2 Dopamine and orexins systems: evidence for an interconnection in anorexia nervosa
Stress and distress tolerance have been suggested as important factors in determining the onset and course of AN. Stressful and traumatic events often precede eating diseases. AN comprises a hyperactivation of the HPA axis [79]. Patients with AN present significantly elevated concentration of plasma cortisol, increased central CRF, and significantly less cortisol suppression after dexamethasone administration than controls [80, 81]. Moreover, hormonal changes also do not seem to be specific for AN and are found in other diseases or in healthy subjects as a consequence of malnutrition and starvation [82]. In general, these data show the need to study other molecules as possible indicators of HPA-axis hyperactivity on the one hand and that regulate emotional states on the other hand. DA and orexins share diverse characteristics at the physiological, psychological, and psychiatric levels, such as the ability to modulate the HPA axis activity, induce drug and food seeking behavior, increase the motivation to obtain food, and regulate emotional states, such as depression and anxiety.
At first it was thought that orexins participated in the consumption of food because orexin central administration produces food seeking, and food deprivation increases orexin mRNA [83, 84]. In addition, orexin neurons are excited by peripheral signals of nutrient needs (e.g., ghrelin), inhibited by satiety signals (e.g., glucose) and interact with feeding peptides to promote food consumption and seeking [85, 86, 87, 88, 89]. Notably, orexin neurons are active during hunger and help to translate peripheral hunger signals into increased appetitive responding for food and cues associated to consumption of food. Thus, orexins facilitate food seeking especially in motivationally charged circumstances.
Orexins orchestrate various aspects of stress responses. For example, acute (but not chronic and predictable) stress is associated with orexin neuron activation [90]. The orexins help to organize the response to stress, but only when it assumes a motivated and adaptable behavior to cope with stress, that is, when you can escape the stressor. In contrast, when a stressor is chronic, predictable, and impossible to escape, the activity of orexin system decreases, and this hypoactivity can produce motivational symptoms similar to depression.
In the case of DA, it is involved in motivational but not consummatory aspects of feeding. The blocking of mesocorticolimbic dopaminergic system decreases the response for motivational tasks associated with obtaining food [91]. DA depletion or administration of DA receptor antagonists in NAc reduces the motivation to consumption high palatable food [92, 93, 94, 95]. The motivation to eat is a key factor to maintain a normal feeding behavior.
Dysfunction of the OXs and DA systems may contribute to the pathology of anxiety and addiction to food and drugs of abuse, which is commonly associated with anxiety and/or defective fear processing, depression, and cognitive impairment as well as other comorbid conditions. Increase in orexin mRNA levels has been observed in animals exposed to different stressors such as immobilization [96], cold stress [96], or hypoglycemia [84], while that both acute and chronic stress promote major changes in DA signaling in the mesocorticolimbic pathway such as increases in DA release in the striatum, NAc, and PFC [97, 98, 99]. D2R receptor knockout mice display anxiety and depression-like behaviors upon chronic stress [100]. Repeated restrain stress produces increases and decreases in DA receptor densities within the mesoaccumbens and nigrostriatal systems in two different strains of mice [101]. So, these results suggested that stressful conditions could be augmented the vulnerability to develop psychiatric illnesses as AN. So, any decline in the transmission of DA and orexins can generate a lack of motivation to consume food. However, there are few studies about the participation of DA receptors in the PFA/HL areas on the control of food drinking. Studies suggest that ethanol intake and excessive food consumption could be similarly affected by DA in the PFA/HL areas, with increases in both ethanol and food intake after D1 receptor activation and decrease in both consumptions after the activation of D2 [100].
Considering that the anxiety induces specific reduction of the D2R in the NAc and that DA attenuates several addictive behaviors in animals [100], it is difficult not to think that DA may act as an anxiolytic agent through the D2R activation. On the other hand, the decreased release of orexins could promote low food consumption, that is, the dysfunction of the orexin system could be accentuating the lack of motivation for the search and consumption of food in anorexics. In this way, the stimulation of orexin receptors together with DA could reduce the stress generated by starvation and, at the same time, increase the motivation for food consumption.
5. Conclusion
Considering on the one hand that AN is a compulsive disorder, and on the other hand that starvation is the result of a negative reinforcement, it is suggested that the dysfunction of DA and orexins in the mesocorticolimbic system is key to the successful treatment of AN. The model can justify the use of existing and planned prevention and treatment programs but may also guide the development of novel interventions to favorably affect the incidence and recovery rates of a life-threatening condition.
Acknowledgments
To the Consejo Nacional de Ciencia y Tecnología (CONACyT 241216) and Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz (IC16033.0).
References
- 1.
Zipfel S, Giel KE, Bulik CM, Hay P, Schmidt U. Anorexia nervosa: Aetiology, assessment, and treatment. Lancet Psychiatry. Dec 2015; 2 (12):1099-1111. DOI: 10.1016/S2215-0366(15)00356-9 - 2.
Arcelus J, Mitchell AJ, Wales J, Nielsen S. Mortality rates in patients with anorexia nervosa and other eating disorders. A meta-analysis of 36 studies. Archives of General Psychiatry. Jul 2011; 68 (7):724-731. DOI: 10.1001/archgenpsychiatry.2011.74 - 3.
Yoshida K, McCormack S, España RA, Crocker A, Scammell TE. Afferents to the orexin neurons of the rat brain. Journal of Comparative Neurology. 2006; 494 :845-861. DOI: 10.1002/cne.20859 - 4.
Palmiter RD. Is dopamine a physiologically relevant mediator of feeding behavior? Trends in Neurosciences. 2007; 30 :375-381. DOI: 10.1016/j.tins.2007.06.004 - 5.
Björklund A, Hökfelt T. Handbook of Chemical Neuroanatomy. Elsevier: Amsterdam; New York; 1983 - 6.
Dahlström A, Fuxe K. Localization of monoamines in the lower brain stem. Experientia. 1964; 20 :398-399 - 7.
Carlsson ML. On the role of prefrontal cortex glutamate for the antithetical phenomenology of obsessive compulsive disorder and attention deficit hyperactivity disorder. Progress in Neuropsychopharmacology & Biological Psychiatry. 2001; 25 :5-26. DOI: 10.1016/S0278-5846(00)00146-9 - 8.
Chao J, Nestler EJ. Molecular neurobiology of drug addiction. Annual Review of Medicine. 2004; 55 :113-132. DOI: 10.1146/annurev.med.55.091902.103730 - 9.
Hornykiewicz O. Psychopharmacological implications of dopamine and dopamine antagonists: A critical evaluation of current evidence. Neuroscience. 1978; 3 :773-783. DOI: 10.1016/0306-4522(78)90030-1 - 10.
Asakawa A, Inui A, Momose K, Ueno N, Fujino MA, Kasuga M. Endomorphins have orexigenic and anxiolytic activities in mice. Neuroreport. 1998; 9 :2265-2267 - 11.
Cooper JR, Bloom FE, Roth RH. The Biochemical Basis of Neuropharmacology. 8th ed. Oxford: Oxford University Press; 2003. 518 p. DOI: 10.1093/ageing/afw180 - 12.
Kaye WH, Ebert MH, Raleigh M, Lake R. Abnormalities in CNS monoamine metabolism in anorexia nervosa. Archives of General Psychiatry. 1984; 41 :350-355. DOI: 10.1176/ajp.141.12.1598 - 13.
Frank GK, Bailer UF, Henry SE, Drevets W, Meltzer CC, Price JC, et al. Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomographyand [11c]raclopride. Biological Psychiatry. 2005; 58 :908-912. DOI: 10.1016/j.biopsych.2005.05.003 - 14.
Karson CN. Spontaneous eye-blink rates and dopaminergic systems. Brain. 1983; 106 :643-653 - 15.
Bergh C, Södersten P. Anorexia nervosa, self-starvation and the reward of stress. Nature Medicine. 1996; 2 :21-22 - 16.
O’Hara CB, Campbell IC, Schmidt U. A reward-centred model of anorexia nervosa: A focussed narrative review of the neurological and psychophysiological literature. Neuroscience & Biobehavioral. Reviews. 2015; 52 :131-152. DOI: 10.1016/j.neubiorev.2015.02.012 - 17.
Hotta M, Shibasaki T, Masuda A, Imaki T, Demura H, Ling N, et al. The responses of plasma adrenocorticotropin and cortisol to corticotropin-releasing hormone (CRH) and cerebrospinal fluid immunoreactive CRH in anorexia nervosa patients. Journal of Clinical Endocrinology and Metabolism. 1986; 62 :319-324. DOI: 10.1210/jcem-62-2-319 - 18.
Rojo L, Conesa L, Bermudez O, Livianos L. Influence of stress in the onset of eating disorders: Data from a two-stage epidemiologic controlled study. Psychosomatic Medicine. 2006; 68 :628-635. DOI: 10.1097/01.psy.0000227749.58726.41 - 19.
Estour B, Germain N, Diconne E, Frere D, Cottet-Emard J-M, Carrot G, et al. Hormonal profile heterogeneity and short-term physical risk in restrictive anorexia nervosa. Journal of Clinical Endocrinology & Metabolism. 2010; 95 :2203-2210. DOI: 10.1210/jc.2009-2608 - 20.
Gwirtsman HE, Kaye WH, George DT, Jimerson DC, Ebert MH, Gold PW. Central and peripheral ACTH and cortisol levels in anorexia nervosa and bulimia. Archives of General Psychiatry. 1989; 46 :61-69. DOI: 10.1001/archpsyc.1989.01810010063009 - 21.
Schorr M, Lawson EA, Dichtel LE, Klibanski A, Miller KK. Cortisol measures across the weight spectrum. Journal of Clinical Endocrinology & Metabolism. 2015; 100 :3313-3321. DOI: 10.1210/JC.2015-2078 - 22.
Shibuya I, Nagamitsu S, Okamura H, Komatsu H, Ozono S, Yamashita Y, et al. Changes in salivary cortisol levels as a prognostic predictor in children with anorexia nervosa. International Journal of Psychophysiology. Nov 2011; 82 (2):196-201. DOI: 10.1016/j.ijpsycho.2011.08.008 - 23.
Holly EN, DeBold JF, Miczek KA. Increased mesocorticolimbic dopamine during acute and repeated social defeat stress: Modulation by corticotropin releasing factor receptors in the ventral tegmental area. Psychopharmacology. 2015; 232 :4469-4479. DOI: 10.1007/s00213-015-4082-z - 24.
Wanat MJ, Hopf FW, Stuber GD, Phillips PE, Bonci A. Corticotropin-releasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C-dependent enhancement of Ih. Journal of Physiology. 2008; 586 (8):2157-2170. DOI: 10.1113/jphysiol.2007 - 25.
Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: From actions to habits to compulsion. Nature Neuroscience. 2005; 8 :1481-1489. DOI: 10.1038/nn1579 - 26.
Jansen A. A learning model of binge eating: Cue reactivity and cue exposure. Behaviour Research and Therapy. 1998; 36 :257-272. DOI: 10.1016/S0005-7967(98)00055-2 - 27.
Méquinion M, Chauveau C, Viltart O. The use of animal models to decipher physiological and neurobiological alterations of anorexia nervosa patients. Frontiers in Endocrinology (Lausanne). 2015; 6 :68. DOI: 10.3389/fendo.2015.00068 - 28.
Södersten P, Nergårdh R, Bergh C, Zandian M, Scheurink A. Behavioral neuroendocrinology and treatment of anorexia nervosa. Frontiers in Neuroendocrinology. 2008; 29 :445-462. DOI: 10.1016/j.yfrne.2008.06.001 - 29.
Stengel A, Taché Y. CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress. Frontiers in Neuroscience. 2014; 8 :52. DOI: 10.3389/fnins.2014.00052 - 30.
Keys A, Brozek J, Henschel A, Mickelsen O, Taylor HL. The Biology of Human Starvation. Minneapolis, MN: University of Minnesota Press; 1950 - 31.
Bergh C, Callmar M, Danemar S, Hölcke M, Isberg S, Leon M, et al. Effective treatment of eating disorders: Results at multiple sites. Behavioral Neuroscience. 2013; 127 :878-889. DOI: 10.1037/a0034921 - 32.
Bergh C, Brodin U, Lindberg G, Södersten P. Randomized controlled trial of a treatment for anorexia and bulimia nervosa. Proceedings of the National Academy of Sciences of the United States of America. 2002; 99 :9486-9491. DOI: 10.1073/pnas.142284799 - 33.
Zhu Y, Miwa Y, Yamanaka A, Yada T, Shibahara M, Abe Y, et al. Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and –insensitive G-proteins. Journal of Pharmaceutical Sciences. 2003; 92 :259-266. DOI: 10.1254/jphs.92.259 - 34.
Suzuki M, Beuckmann CT, Shikata K, Ogura H, Sawai T. Orexin-A (hipocretins-1) is possibly involved in generation of anxiety-like behavior. Brain Research. 2005; 1044 :116-121. DOI: 10.1016/j.brainres.2005.03.002 - 35.
Carelli RM. Nucleus accumbens cell firing during goal-directed behaviors for cocaine vs. 'natural' reinforcement. Physiology & Behavior. 2002; 76 :379-387. DOI: 10.1016/S0031-9384(02)00760-6 - 36.
Koob GF, Bloom FE. Cellular and molecular mechanisms of drug dependence. Science. 1988; 242 :715-723. DOI: 10.1126/science.2903550 - 37.
Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. Journal of Neuroscience. 1998; 18 :9996-10015. DOI: 10.1523/JNEUROSCI.18-23-09996 - 38.
Sutcliffe JG, de Lecea L. The hypocretins: Setting the arousal threshold. Nature Review Neuroscience. 2002; 3 :339-349. DOI: 10.1038/nrn808 - 39.
Wise RA, Rompre PP. Brain dopamine and reward. Annual Review of Psychology. 1989; 40 :191-225. DOI: 10.1146/annurev.ps.40.020189.001203 - 40.
Perez-Leighton1 CE, Butterick-Peterson TA, Billington CJ, Kotz CM. Role of orexin receptors in obesity: From cellular to behavioral evidence. International Journal of Obesity. 2013; 37 :167-174. DOI: 10.1038/ijo.2012.30 - 41.
Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T, et al. Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metabolism. 2009; 9 :64-76. DOI: 10.1016/j.cmet.2008.10.010 - 42.
Wise RA. Role of brain dopamine in food reward and reinforcement. Philosophical Transactions of the Royal Society London B: Biological Sciences. 2006; 361 :1149-1158. DOI: 10.1098/rstb.2006.1854 - 43.
Narita M, Nagumo Y, Miyatake M, Ikegami D, Kurahashi K, Suzuki T. Implication of protein kinase C in the orexin-induced elevation of extracellular dopamine levels and its rewarding effect. European Journal of Neuroscience. 2007; 25 :1537-1545. DOI: 10.1111/j.1460-9568.2007.05403.x - 44.
Borgland SL, Chang S-J, Bowers MS, Thompson JL, Vittoz N, Floresco SB, et al. Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers. Journal of Neuroscience. 2009; 29 :11215-11225. DOI: 10.1523/JNEUROSCI.6096-08.2009 - 45.
España RA, Oleson EB, Locke JL, Brookshire BR, Roberts DC, Jones SR. The hypocretin–orexin system regulates cocaine self-administration via actions on the mesolimbic dopamine system. European Journal of Neuroscience. 2010; 31 :336-348. DOI: 10.1111/j.1460-9568.2009.07065.x - 46.
Jones MW, Kilpatrick IC, Phillipson OT. Regulation of dopamine function in the nucleus accumbens of the rat by the thalamic paraventricular nucleus and adjacent midline nuclei. Experimentral Brain Research. 1989; 76 :572-580 - 47.
Parsons MP, Li S, Kirouac GJ. Functional and anatomical connection between the paraventricular nucleus of the thalamus and dopamine fibers of the nucleus accumbens. Journal of Comparative Neurology. 2007; 500 :1050-1063. DOI: 10.1002/cne.21224 - 48.
Choi DL, Davis JF, Magrisso IJ, Fitzgerald ME, Lipton JW, Benoit SC. Orexin signaling in the paraventricular thalamic nucleus modulates mesolimbic dopamine and hedonic feeding in the rat. Neuroscience. 2012; 210 :243-248. DOI: 10.1016/j.neuroscience.2012.02.036 - 49.
Vittoz NM, Berridge CW. Hypocretin/orexin selectively increases dopamine efflux within the prefrontal cortex: Involvement of the ventral tegmental area. Neuropsychopharmacology. 2006; 31 :384-395. DOI: 10.1038/sj.npp.1300807 - 50.
Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE. Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. Journal of Neuroscience. 2003; 23 :7-11. DOI: 10.1523/JNEUROSCI.23-01-00007.2003 - 51.
Muschamp JW, Dominguez JM, Sato SM, Shen RY, Hull EM. A role for hypocretin (orexin) in male sexual behavior. Journal of Neuroscience. 2007; 27 :2837-2845. DOI: 10.1523/JNEUROSCI.4121-06.2007 - 52.
España RA, Melchior JR, Roberts DC, Jones SR. Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration. Psychopharmacology. 2011; 214 :415-426. DOI: 10.1007/s00213-010-2048-8 - 53.
Vittoz NM, Schmeichel B, Berridge CW. Hypocretin/orexin preferentially actives caudomedial ventral tegmental areas dopamine neurons. European Journal of Neuroscience. 2008; 28 :1629-1640. DOI: 10.1111/j.1460-9568.2008.06453.x - 54.
Hernandez L, Hoebel BG. Feeding and hypothalamic stimulation increase dopamine turnover in the accumbens. Physiology & Behavior. 1988; 44 :599-606. DOI: 10.1016/0031-9384(88)90324-1 - 55.
Hoebel BG, Hernandez L, Schwartz DH, Mark GP, Hunter GA. Microdialysis studies of brain norepinephrine, serotonin, and dopamine release during ingestive behavior. Theoretical and clinical implications. Annals of the New York Academy of Sciences. 1989; 575 :171-193. DOI: 10.1111/j.1749-6632.1989.tb53242.x - 56.
Moorman DE, Aston-Jones G. Orexin/hypocretin modulates response of ventral tegmental dopamine neurons to prefrontal activation: Diurnal influences. Journal of Neuroscience. 2010; 30 :15585-15599. DOI: 10.1523/JNEUROSCI.2871-10.2010 - 57.
Prince CD, Rau AR, Yorgason JT, España RA. Hypocretin/orexin regulation of dopamine signaling and cocaine self-administration is mediated predominantly by hypocretin receptor 1. ACS Chemical Neuroscience. 2015; 21 :138-146. DOI: 10.1021/cn500246j - 58.
Quarta D, Valerio E, Hutchenson DM, Hedou G, Heidbreder C. The orexin-1 receptor antagonists SB-334867 reduce amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization. Neurochemistry International. 2010; 56 :11-15. DOI: 10.1016/j.neuint.2009.08.012 - 59.
Nakamura T, Uramura K, Nambu T, Yada T, Goto K, Yanagisawa M, et al. Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system. Brain Research. 2000; 873 :181-187. DOI: 10.1016/S0006-8993(00)02555-5 - 60.
Guarda AS, Schreyer CC, Boersma GJ, Tamashiro KL, Moran TH. Anorexia nervosa as a motivated behavior: Relevance of anxiety, stress, fear and learning. Physiology & Behavior. 2015; 152 :466-472. DOI: 10.1016/j.physbeh.2015.04.007 - 61.
Fineberg NA, Menchon JM, Zohar J, Veltman DJ. Compulsivity—A new trans-diagnostic research domain for the roadmap for mental Health Research in Europe (ROAMER) and research domain criteria (RDoC) initiatives. European Neuropsychopharmacology. 2016; 26 :797-799. DOI: 10.1016/j.euroneuro.2016.04.001 - 62.
Lloyd EC, Frampton I, Verplanken B, Haase AM. How extreme dieting becomes compulsive: A novel hypothesis for the role of anxiety in the development and maintenance of anorexia nervosa. Medical Hypotheses. 2017; 108 :144-150. DOI: 10.1016/j.mehy.2017.09.001 - 63.
Kaye WH, Fudge JL, Paulus M. New insights into symptoms and neurocircuit function of anorexia nervosa. Nature Review Neuroscience. 2009; 10 :573-584. DOI: 10.1038/nrn2682 - 64.
Nunn K, Frampton I, Lask B. Anorexia nervosa—A noradrenergic dysregulation hypothesis. Medical Hypotheses. 2012; 78 :580-584. DOI: 10.1016/j.mehy.2012.01.033 - 65.
Calati R, De Ronchi D, Bellini M, Serretti A. The 5-HTTLPR polymorphism and eating disorders: A meta-analysis. International Journal of Eating Disorders. 2011; 44 :191-199. DOI: 10.1002/eat.20811 - 66.
Godier LR, Park RJ. Compulsivity in anorexia nervosa: A transdiagnostic concept. Frontiers in Psychology. 2014; 5 :778. DOI: 10.3389/fpsyg.2014.00778 - 67.
Figee M, Vink M, de Geus F, Vulink N, Veltman DJ, Westenberg H, et al. Dysfunctional reward circuitry in obsessive-compulsive disorder. Biological Psychiatry. 2011; 69 :867-874. DOI: 10.1016/j.biopsych.2010.12.003 - 68.
Fontenelle LF, Oostermeijer S, Harrison BJ, Pantelis C, Yücel M. Obsessive-compulsive disorder, impulse control disorders and drug addiction: Common features and potential treatments. Drugs. 2011; 71 :827-840. DOI: 10.2165/11591790-000000000-00000 - 69.
Chamberlain SR, Lochner C, Stein DJ, Goudriaan AE, van Holst RJ, Zohar J, et al. Behavioural addiction—A rising tide? European Neuropsychopharmacology. 2016; 26 :841-855. DOI: 10.1016/j.euroneuro.2015.08.013 - 70.
Hart M, Wilcken B, Williams LT, Sibbritt D, Nunn KP. Tyrosine supplementation as an adjunct treatment in anorexia nervosa—A noradrenergic repletion hypothesis. Advanced Eating Disorder. 2013; 1 :161-168 - 71.
Haleem DJ. Serotonin neurotransmission in anorexia nervosa. Behavioural Pharmacology. 2012; 23 :478-495. DOI: 10.1097/FBP.0b013e328357440d - 72.
Atkinson MJ, Wade TD. Mindfulness-based prevention for eating disorders: A school-based cluster randomized controlled study. International Journal of Eating Disorders. 2015; 48 :1024:37. DOI: 10.1002/eat.22416 - 73.
Spindler A, Milos G. Links between eating disorder symptom severity and psychiatric comorbidity. Eating Behaviors. 2007; 8 :364-373. DOI: 10.1016/j.eatbeh.2006.11.012 - 74.
Sternheim L, Startup H, Schmidt U. Anxiety-related processes in anorexia nervosa and their relation to eating disorder pathology, depression and anxiety. Advanced Eating Disorders. 2015; 3 :13-19 - 75.
Haynos AF, Crosby RD, Engel SG, Lavender JM, Wonderlich SA, Mitchell JE, et al. Initial test of an emotional avoidance model of restriction in anorexia nervosa using ecological momentary assessment. Journal of Psychiatric Research. 2015; 68 :134-139. DOI: 10.1016/j.jpsychires.2015.06.016 - 76.
Steinglass JE, Sysko R, Mayer L, Berner LA, Schebendach J, Wang Y, et al. Pre-meal anxiety and food intake in anorexia nervosa. Appetite. 2010; 55 :214-218. DOI: 10.1016/j.appet.2010.05.090 - 77.
Cardi V, Leppanen J, Treasure J. The effects of negative and positive mood induction on eating behaviour: A meta-analysis of laboratory studies in the healthy population and eating and weight disorders. Neuroscience and Biobehavioral Reviews. 2015; 57 :299-309. DOI: 10.1016/j.neubiorev.2015.08.011 - 78.
Lavender JM, De Young KP, Wonderlich SA, Crosby RD, Engel SG, Mitchell JE, et al. Daily patterns of anxiety in anorexia nervosa: Associations with eating disorder behaviors in the natural environment. Journal of Abnormal Psychology. 2013; 122 :672-683. DOI: 10.1037/a0031823 - 79.
Gazendam FJ, Kamphuis JH, Kindt M. Deficient safety learning characterizes high trait anxious individuals. Biological Psychology. 2013; 92 :342-352. DOI: 10.1016/j.biopsycho.2012.11.006 - 80.
Licinio J, Wong ML, Gold PW. The hypothalamic-pituitary-adrenal axis in anorexia nervosa. Psychiatry Research. 1996; 62 :75-83. DOI: 10.1016/0165-1781(96)02991-5 - 81.
Walsh BT, Roose SP, Katz JL, Dyrenfurth I, Wright L, Vande Wiele R, et al. Hypothalamic-pituitary-adrenal-cortical activity in anorexia nervosa and bulimia. Psychoneuroendocrinology. 1987; 12 :131-140 - 82.
Fichter MM, Doerr P, Pirke KM, Lund R. Behavior, attitude, nutrition and endocrinology in anorexia nervosa. Acta Psychiatrica Scandinavica. 1982; 66 :429-444. DOI: 10.1111/j.1600-0447.1982.tb04500.x - 83.
Jászberényi M, Bujdosó E, Pataki I, Telegdy G. Effect of orexins on the hypothalamic-pituitary-adrenal system. Journal of Neuroendocrinology. 2000; 12 :1174-1178 - 84.
Griffond B, Risold PY, Jacquemard C, Colard C, Fellmann D. Insulin-induced hypoglycemia increases preprohypocretin (orexin) mRNA in the rat lateral hypothalamic area. Neuroscience Letters. 1999; 262 :77-80. DOI: 10.1016/S0304-3940(98)00976-8 - 85.
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: A family of hypothalamic neuropéptidos and G protein-coupled receptors that regulate feeding behavior. Cell. 1998; 92 :573-585. DOI: 10.1016/S0092-8674(02)09256-5 - 86.
Berthoud HR, Munzberg H. The lateral hypothalamus as integrator of metabolic and environmental needs: From electrical self-stimulation to opto-genetics. Physiology & Behavior. 2011; 104 :29-39. DOI: 10.1016/j.physbeh.2011.04.051 - 87.
Burdakov D, Karnani MM, Gonzalez A. Lateral hypothalamus as a sensor-regulator in respiratory and metabolic control. Physiology & Behavior. 2013; 121 :117-124. DOI: 10.1016/j.physbeh.2013.03.023 - 88.
Cason AM, Smith RJ, Tahsili-Fahadan P, Moorman DE, Sartor GC, Aston-Jones G. Role of orexin/hypocretin in reward-seeking and addiction: Implications for obesity. Physiology & Behavior. 2010; 100 :419-428. DOI: 10.1016/j.physbeh.2010.03.009 - 89.
Sheng Z, Santiago AM, Thomas MP, Routh VH. Metabolic regulation of lateral hypothalamic glucose-inhibited orexin neurons may influence midbrain reward neurocircuitry. Molecular and Cellular Neuroscience. 2014; 62 :30-41. DOI: 10.1016/j.mcn.2014.08.001 - 90.
Yeoh JW, Campbell EJ, James MH, Graham BA, Dayas CV. Orexin antagonists for neuropsychiatric disease: Progress and potential pitfalls. Frontiers in Neuroscience. 2014; 8 :36. DOI: 10.3389/fnins.2014.00036 - 91.
Salamone JD, Cousins MS, Snyder BJ. Behavioral functions of nucleus accumbens dopamine: Empirical and conceptual problems with the anhedonia hypothesis. Neuroscience and Biobehavioural Review. 1997; 21 :341-359. DOI: 10.1016/S0149-7634(96)00017-6 - 92.
Cousins MS, Salamone JD. Nucleus accumbens dopamine depletions in rats affect relative response allocation in a novel cost/benefit procedure. Pharmacology Biochemistry and Behavior. 1994; 49 :85-91. DOI: 10.1016/0091-3057(94)90460-X - 93.
Nowend KL, Arizzi M, Carlson BB, Salamone JD. D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption. Pharmacology Biochemistry and Behavior. 2001; 69 :373-382. DOI: 10.1016/S0091-3057(01)00524-X - 94.
Salamone JD, Arizzi MN, Sandoval MD, Cervone KM, Aberman JE. Dopamine antagonists alter response allocation but do not suppress appetite for food in rats: Contrast between the effects of SKF 83566, raclopride, and fenfluramine on a concurrent choice task. Psychopharmacology. 2002; 160 :371-380. DOI: 10.1007/s00213-001-0994-x - 95.
Salamone JD, Steinpreis RE, McCullough LD, Smith P, Grebel D, Mahan K. Haloperidol and nucleus accumbens dopamine depletion suppress lever pressing for food but increase free food consumption in a novel food choice procedure. Psychopharmacology. 1991; 104 :515-521 - 96.
Ida T, Nakahara K, Murakami T, Hanada R, Nakazato M, Murakami N. Possible involvement of orexin in the stress reaction in rats. Biochemical and Biophysical Research Communications. 2000; 270 :318-323. DOI: 10.1006/bbrc.2000.2412 - 97.
Abercrombie ED, Keefe KA, DiFrischia DS, Zigmond MJ. Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex. Journal of Neurochemistry. 1989; 52 :1655-1658. DOI: 10.1111/j.1471-4159.1989.tb09224.x - 98.
Imperato A, Angelucci L, Casoloni P, Zocchi A, Puglisi-Allegra S. Repeated stressful experiences differently affect limbic dopamine release during and following stress. Brain Research. 1992; 577 :194-199. DOI: 10.1016/0006-8993(92)90274-D - 99.
Pezze MA, Feldon J. Mesolimbic dopaminergic pathways in fear conditioning. Progress in Neurobiology. 2004; 74 :301-320. DOI: 10.1016/j.pneurobio.2004.09.004 - 100.
Sim H, Choi T-Y, Lee HJ, Kang EY, Yoon S, Han P-L, et al. Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours. Nature Communications. 2013; 4 :1579-1589. DOI: 10.1038/ncomms2598 - 101.
Cabib S, Giardino L, Calzá L, Zanni M, Mele A, Puglisi-Allegra S. Stress promotes major changes in dopamine densities within the mesoaccumbens and nigrostriatal systems. Neuroscience. 1998; 84 :193-200. DOI: 10.1016/S0306-4522(97)00468-5