Dopamine is well recognized as a neurotransmitter in the brain, and regulates critical functions in a variety of peripheral systems. Growing research has also shown that dopamine acts as an important regulator of immune function. Many immune cells express dopamine receptors and other dopamine related proteins, enabling them to actively respond to dopamine and suggesting that dopaminergic immunoregulation is an important part of proper immune function. A detailed understanding of the physiological concentrations of dopamine in specific regions of the human body, particularly in peripheral systems, is critical to the development of hypotheses and experiments examining the effects of physiologically relevant dopamine concentrations on immune cells. Unfortunately, the dopamine concentrations to which these immune cells would be exposed in different anatomical regions are not clear. To address this issue, this comprehensive review details the current information regarding concentrations of dopamine found in both the central nervous system and in many regions of the periphery. In addition, we discuss the immune cells present in each region, and how these could interact with dopamine in each compartment described. Finally, the review briefly addresses how changes in these dopamine concentrations could influence immune cell dysfunction in several disease states including Parkinson’s disease, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, as well as the collection of pathologies, cognitive and motor symptoms associated with HIV infection in the central nervous system, known as NeuroHIV. These data will improve our understanding of the interactions between the dopaminergic and immune systems during both homeostatic function and in disease, clarify the effects of existing dopaminergic drugs and promote the creation of new therapeutic strategies based on manipulating immune function through dopaminergic signaling.

Where Is Dopamine and how do Immune Cells See it?: Dopamine-Mediated Immune Cell Function in Health and Disease.

Background and Purpose — Heatstroke is associated with cerebral ischemia as well as increased levels of interleukin-1β, dopamine, and glutamate in the brain. These factors are known to increase free radical production. This study attempted to ascertain whether an excessive accumulation of cytotoxic free radicals in the brain and oxidative stress can occur during heatstroke.

Methods — Urethane-anesthetized rats underwent instrumentation for the measurement of mean arterial pressure, cerebral blood flow, neuronal damage score, and colonic temperature. Rats were exposed to heat stress (ambient temperature, 42°C) until mean arterial pressure and cerebral blood flow began to decrease from their peak levels, which was arbitrarily defined as the onset of heatstroke. Controlled rats were exposed to 24°C. Concentrations of dihydroxybenzoic acid, lipid peroxidation, rate of O2·− generation, superoxide dismutase, and catalase activity of the brain or other vital organs were assessed during heatstroke.

Results — The values of mean arterial pressure and cerebral blood flow after heatstroke onset were all significantly lower than those in control rats. However, the values of colonic temperature, dihydroxybenzoic acid levels in the striatum, and neuronal damage score were greater. The extent of lipid peroxidation in the brain and the rate of O2·− generation in the brain, liver, and heart were all greater in rats after heatstroke onset. In contrast, the values of total superoxide dismutase in the brain, liver, and heart and the catalase activity in the brain were lower.

Conclusions — Taken together, these results indicate that hydroxyl radicals mediate cerebral ischemic injury associated with heatstroke.

Oxidative Stress in Rats With Heatstroke-Induced Cerebral Ischemia

Heat stroke is a life-threatening illness that affects all segments of society, including the young, aged, sick, and healthy The recent high death toll in France (Dorozynski, 2003) and the death of high-profile athletes has increased public awareness of the adverse effects of heat injury However, the etiology of the long-term consequences of this syndrome remains poorly understood such that preventive/treatment strategies are needed to mitigate its debilitating effects Cytokines are important modulators of the acute phase response (APR) to stress, infection, and inflammation Current data implicating cytokines in heat stroke responses are mainly from correlation studies showing elevated plasma levels in heat stroke patients and experimental animal models Correlation data fall far short of revealing the mechanisms of cytokine actions such that additional research to determine the role of these endogenous substances in the heat stroke syndrome is required Furthermore, cytokine determinations have occurred mainly at end-stage heat stroke, such that the role of these substances in progression and long-term recovery is poorly understood Despite several studies implicating cytokines in heat stroke pathophysiology, few studies have examined the protective effect(s) of cytokine antagonism on the morbidity and mortality of heat stroke This is particularly surprising since heat stroke responses resemble those observed in the endotoxemic syndrome, for which a role for endogenous cytokines has been strongly implicated The implication of cytokines as mediators of endotoxemia and the presence of circulating endotoxin in heat stroke patients suggests that much knowledge can be gained from applying our current understanding of endotoxemic pathophysiology to the study of heat stroke Heat shock proteins (HSPs) are highly conserved proteins that function as molecular chaperones for denatured proteins and reciprocally modulate cytokine production in response to stressful stimuli HSPs have been shown repeatedly to confer protection in heat stroke and injury models Interactions between HSPs and cytokines have received considerable attention in the literature within the last decade such that a complex pathway of interactions between cytokines, HSPs, and endotoxin is thought to be occurring in vivo in the orchestration of the APR to heat injury These data suggest that much of the pathophysiologic changes observed with heat stroke are not a consequence of heat exposure, per se, but are representative of interactions among these three (and presumably additional) components of the innate immune response This chapter will provide an overview of current knowledge regarding cytokine, HSP, and endotoxin interactions in heat stroke pathophysiology Insight is provided into the potential therapeutic benefit of cytokine neutralization for mitigation of heat stroke morbidity and mortality based on our current understanding of their role in this syndrome

Heat stroke and cytokines.

The fundamental functions of heat shock proteins (HSPs) are molecular chaperoning and cellular repair. There is little literature on the association between the numerous functions of HSPs and systemic integrative responses, particularly those controlled by the central nervous system. This chapter focuses on the role played by members of the HSP70 superfamily, universally recognized as cytoprotectants during heat stress, within the physiological context of hyperthermia and with its superimposition on situations of chronic stress. In the nucleus tractus solitarius, HSP70 levels enhance the sensitivity of sympathetic and parasympathetic arms of the autonomic nervous system to attenuate heat stroke-induced cerebral ischemia and hypotension. Chronic stressors that alter the heat shock response may affect the physiological profile during hyperthermic conditions. Upon aging, significantly lower HSP70 production is noted in the ventral paraventricular and lateral magnocellular nuclei. Likewise, results from cultured cells suggest that the age-related decline in HSP70 expression is constitutive and is due to decreased binding of the heat shock factor 1 (HSF-1) to the heat shock element (HSE) and diminished HSP70 transcription. These changes may be associated with decreased thermotolerance upon aging, although HSP70 production in response to other stressors is not affected. Heat acclimation (AC), in contrast, increases tissue reserves of HSP70 and accelerates the heat shock response. AC protects epithelial integrity, vascular reactivity and interactions with cellular signaling networks, enhancing protection and delaying thermal injury. The link between HSP70 and the immune system is discussed with respect to exercise. Exercise enhances the immune response via production of HSP72 in central and peripheral structures. At least in part, the effects of HSP72 in the brain are mediated via eHSP72-circulating HSPs providing a "danger signal" to activate the immune response. In summary, HSPs are primarily cytoprotective components, the physiological situations described in this chapter infer their pivotal role in central control of integrative systems.

Heat shock proteins and the heat shock response during hyperthermia and its modulation by altered physiological conditions

Rats, under urethan anesthesia, were exposed to a high ambient temperature (42°C) to induce heatstroke and to assess the hemodynamic changes associated with heatstroke. Compared with normothermic c...

Involvement of interleukin-1 receptor mechanisms in development of arterial hypotension in rat heatstroke

Brain dopamine has been implicated as a mediator of brain neuronal damage resulting from ischemic injury. Augmented interleukin-1 production and cerebral ischemia occurred during onset of heatstroke. This study has attempted to ascertain whether heatstroke resulting from hyperthermia causes an increase in hypothalamic dopamine release and to assess whether the administration of an interleukin-1 receptor antagonist (IL-1ra) can attenuate heat-stroke formation.

Both local cerebral blood flow and hypothalamic dopamine release during onset of heatstroke were assessed in saline-treated rats and in rats treated with an IL-1ra. Heat-stroke was induced by exposing the animals to a high ambient temperature. Hypothalamic dopamine release was determined by carbon fiber electrodes combined with in vivo differential pulse amperometry.

During onset of heatstroke, rats with heatstroke displayed higher values of colonic temperature, higher values of hypothalamic dopamine release, and lower values of blood flow in different brain regions compared with normothermic control rats. In another separate experiment in which IL-1ra (200 micrograms/kg IV) was injected 30 minutes before onset of heatstroke, both the augmented hypothalamic dopamine release and diminished cerebral blood flow during onset of heatstroke were significantly attenuated. In addition, the survival time (interval between onset of heatstroke and death) of the rats with heatstroke was prolonged by pretreatment with IL-1ra.

These results suggest that an increase in hypothalamic dopamine release and a decrease in local cerebral blood flow occur during onset of heatstroke. Pretreatment with IL-1ra attenuates the heatstroke formation resulting from cerebral ischemia by reducing hypothalamic dopamine release.

https://www.ahajournals.org/doi/pdf/10.1161/01.STR.25.12.2483

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Papers

Hypothalamic dopamine release and local cerebral blood flow during onset of heatstroke in rats.