Date Published: September 13, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Naila Rasheed, Abdullah Alghasham.
For decades, it has been suggested that dysfunction of dopaminergic pathways and their associated modulations in dopamine levels play a major role in the pathogenesis of neurological disorders. Dopaminergic system is involved in the stress response, and the neural mechanisms involved in stress are important for current research, but the recent and past data on the stress response by dopaminergic system have received little attention. Therefore, we have discussed these data on the stress response and propose a role for dopamine in coping with stress. In addition, we have also discussed gastric stress ulcers and their correlation with dopaminergic system. Furthermore, we have also highlighted some of the glucocorticoids and dopamine-mediated neurological disorders. 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 surely identify a better understanding of stressful events and will give better ideas for further efficient antistress treatments.
Dopamine (DA) is an important endogenous catecholamine, which exerts widespread effects on both neuronal (as a neurotransmitter) and nonneuronal tissues (as an autocrine or paracrine agent) . Within the central nervous system (CNS), DA binds to specific membrane receptors presented by neurons, and it plays a key role in the control of locomotion, learning, working memory, cognition, and emotion [2, 3]. The brain DA system is involved in various neurological and psychiatric disturbances including Parkinson’s disease, schizophrenia, amphetamine, and cocaine addiction [1, 3]. Therefore, it is considered to be a major target for drug designing applied in the treatment of neurological diseases. Stress has been shown to alter normal dopaminergic neurotransmission , and exposure to stress profoundly increases the dopaminergic activity [4, 5] and induces relevant adaptive response of DA receptors in specific brain regions . Stress also activates the hypothalamus-pituitary-adrenal (HPA) axis and releases glucocorticoids (GCs). The interplay between GCs and the dopaminergic system is linked with various neurological disorders such as schizophrenia, bipolar depressive disorder and major depressive disorder, addiction, and Parkinson’s disease [7, 8]. A number of reports showed the involvement of GCs on DA-mediated behavioral responsiveness by the modulatory effects of corticosterone [8–10]. Many reports suggest the involvement of DA system in locomotors alterations under different stressful conditions [9–11]. The stress-induced adaptation of brain DA function involves receptors, and it has also been demonstrated that DA receptor densities are affected by altered extracellular DA levels [10, 12, 13]. It is also demonstrated that stress manipulations induced the alteration in motor activity of experimental animals, and dopaminergic pathways are crucial to neural substrates for the control of spontaneous locomotor activity [3, 11]. These studies clearly indicated that DA plays an essential role in locomotion via neural transmission.
In 1950, Hns Selye borrowed the term “stress” from physics and hypothesized that a constellation of stereotypic psychological and physiological events occurring in seriously ill patients represented the consequences of a severe, prolonged application of adaptation responses. He recognized that stress plays a very significant role in the development of all types of diseases . Selye believed that daily lives are influenced by two different kinds of stress: pleasant stress contributing to “wellness” and unpleasant stress contributing to disease and sickness . Mesocortical and mesolimbic (M-L) dopaminergic systems are known to mediate HPA axis-induced GC release and other CNS effects [8, 22, 23]. Various neurological disorders are linked with GCs and the dopaminergic system [7, 8, 23]. Evidence shows that central dopaminergic system exerts positive effects on the HPA axis and the sympathetic nervous system (SNS), and reciprocally, glucocorticoids and catecholamines mediated stress-induced alterations [24, 25]. Modulations of DA in major brain regions are mediated by dopaminergic receptors, which are classified as D1 and D2 types. Classification of these DA receptors is based on the mechanism that links these G-protein-coupled receptors (GPCRs) to the second messenger system . Thus, D1-like receptors stimulate the adenylate cyclase activity via Gs subunit leading to an increased cyclic adenosine monophosphate (cAMP) concentration . On the other hand, D2-like receptors are negatively coupled via the Gi subunit to the adenylate cyclase, which leads to a decline in the cAMP concentration. Both D1 and D2 of receptors are abundantly expressed in major brain areas such as nucleus accumbens, striatum, frontal cortex, amygdala, and hippocampus . Furthermore, both D1 and D2 are also involved in vigilance, hormonal homeostasis, and locomotor activities. It is reported that stressful experiences alter DA metabolism through D1 and D2 receptors and release in the M-L system [28–30]. Furthermore, it is also reported that exposure to a single unavoidable/uncontrollable aversive experience may lead to inhibition of DA release in the nucleus accumbens as well as to impair the response to both rewarding and aversive stimuli [25, 31]. The effects of stressful experiences on DA functioning in the M-L system can be very different or even opposite depending on situation, the genetic background of the organism, and its life history . We and the others have shown that stress differentially increases the dynamics of DA depending on the brain regions involved [9, 30]. Reports also stated that stressful stimuli tend to cause the largest increase in DA levels in the PFC (prefrontal cortex) region, with markedly smaller changes in the limbic and dorsal striatal regions [32, 33]; however, this relationship is altered by lesions of different nuclei. Thus, stress causes release of DA in the amygdala, and lesions of the amygdala tend to block stress-induced increases in PFC DA levels . Lesions of the PFC also affect this response. Studies in which the PFC DA innervations are lesioned show that subsequent stressors cause a much larger increase in DA levels within the nucleus accumbens, particularly with respect to the duration of the response [31, 34]. This suggested that PFC DA released in response to stress actually blunts the responsiveness of the subcortical limbic DA system. In contrast, 6-OHDA lesions of PFC DA levels were found to decrease the basal electrophysiologic activity of ventral tegmental area (VTA) DA neurons . Repeated stress also has important clinical implications in regard to the DA system. A recent study examined how chronic stress in the form of cold exposure affects the discharge of VTA DA neurons. Thus, after exposing rats to cold, there was a 64% decrease in the number of spontaneously active DA neurons, with no significant alteration in their average firing rate. Nonetheless, there was a subpopulation of neurons that exhibited excessive burst activity in the exposed rats . Unlike acute exposure to stressful or noxious stimuli, chronic stress actually attenuates DA neuron baseline activity.
Among the various neurotransmitters, the dopaminergic system, in particular, plays an important regulatory role in stress-induced gastric ulcers [6–10]. Interestingly, in DA deficiency diseases (such as Parkinson’s disease), the degree of ulceration was found to be higher [92, 93]; whereas in patients having DA excess amount (such as Schizophrenia), the degree of ulceration was found to be lower [92, 93], this clearly indicate a link between DA levels and gastric pathology. The modulation in dopaminergic transmission by specific DA drugs is also known to affect on gastric cytomodulatory functions . Other contributing factors of DA system to stress ulcers are increased gastric motility, vagal overactivity, decreased gastric mucosal blood flow, and various other neuroendocrinological factors [95–97]. Elevated corticosteroid level is also known to modulate gastric glands to secrete acid and pepsin, which further deteriorate gastric mucosal integrity [97–100]. Stress-mediated peptic ulcer has been involved in various neuropathological conditions . Brain-gut axis plays an important role in controlling gastric functions for various brain neurochemical factors during stress ulcer disease . As early as 1965, Strang  noted an apparent association between central DA and peripheral gastric disease in those Parkinson’s disease patients, characterized by central DA deficiency, exhibited a higher-than-expected incidence of ulcer disease. Later, Szabo  confirmed a protective role for DA in an experimental model of duodenal ulcer. Now, connection between DA activity and gastroduodenal ulcer disease is well established [18, 103]. A number of pharmacological agents have now been designed and tested that showed protective role against brain dysfunctioning [104, 105], but whether they have antiulcer activity that remains to be investigated other than our paper . Previously, we have shown that a drug A68930 has antistress activity in acute and chronic unpredictable stress models . In the same paper, we have shown that stimulated dopaminergic receptors (D1/D2) modulate the activity gastric H+K+-ATPase and PGE2 levels in acute and chronic unpredictable stress models, and the stress-induced gastric ulceration could be attributed to the stimulation of paraventricular nucleus of hypothalamus, increased intestinal motility, acid secretion, and so forth [39, 106, 107]. This has been summarized in Figure 2.
Despite the power of modern molecular or pharmacological approaches and persisting investigative efforts, the complete interaction between the mesocorticolimbic dopaminergic system and stress activation remains to be identified. Recent advancements have contributed to the recognition of dopaminergic innervation as a useful system for determining reactions to perturbations in environmental conditions, for selective information processing and for controlling emotional behavior, all of which play an essential role in the ability (or failure) to cope with the external world. Now, it is well established that stressful events provoke major behavioral, neurochemical, and gastric ulcerative effects involving mesocorticolimbic DA functioning, but the type of alterations induced by these experiences remains highly controversial, but it may depend on the behavioural situation and genetic makeup of the organism. Exposure to uncontrollable aversive experiences leads to inhibition of DA release in the mesoaccumbens DA system as well as impaired responding to rewarding and aversive stimuli. Repeated and chronic stressful experiences can reduce the capability of stressors to disrupt behavior, induce behavioral sensitization to psychostimulants, and to promote adaptive changes of mesolimbic DA functioning. For the last two decades, studies aimed to develop new pharmacological approaches to search for drugs devoid of behaviorally sensitizing effects and capable of protecting the organism against the devastating effects of adaptation to stress. This paper updates the current knowledge on the physiological regulation of DA neurons by glucocorticoids, and gastric ulcer suggests that the blockade of these conditions surely opens new therapeutic strategies for the treatment of neurological disorders.