Abstract
Recent research has suggested that the mesolimbic dopamine network that mainly terminates in the nucleus accumbens may positively control the peripheral immune system. The activation of dopamine receptors in neurons in the nucleus accumbens by the release of endogenous dopamine is thus expected to contribute to efferent immune regulation. As in the stimulation of Gs-coupled dopamine D1-receptors or Gi-coupled D2-receptors by endogenous dopamine, we investigated whether specific stimulation of dopamine D1-receptor-expressing neurons or inhibition of dopamine D2-receptor-expressing neurons in the nucleus accumbens could produce anti-tumor effects and improve the immune system in transgenic mice using pharmacogenetic techniques. Repeated stimulation of D1-receptor-expressing neurons in either the medial shell, lateral shell or core regions of the nucleus accumbens significantly decreased tumor volume under a state of tumor transplantation, whereas repeated suppression of D2-receptor-expressing neurons in these areas had no effect on this event. The number of splenic CD8+ T cells was significantly increased following repeated stimulation of D1-receptor-expressing neurons in the nucleus accumbens of mice with tumor transplantation. Furthermore, this stimulation produced a significant reduction in the population of splenic CD8+ T cells that expressed immune checkpoint-related inhibitory receptors, PD-1, TIM-3 and LAG-3. These findings suggest that repeated stimulation of D1-receptor-expressing neurons (probably D1-receptor-expressing medium spiny neurons) in the nucleus accumbens suppressed tumor progression and improved the immune system by suppressing the exhaustion of splenic CD8+ T cells.
Highlights
Dopamine is one of the most well-known neurotransmitters and its transmission in mesolimbic areas controls several physiological functions, such as the modulation of movement and reward [1]
Whole-cell patch-clamp recording showed that D1-cre/ Human muscarinic receptor 3 DREADD subtype (hM3Dq)- or D2-cre/Human muscarinic receptor 4 DREADD subtype (hM4Di)-positive neurons in the nucleus accumbens clearly responded to treatment with Clozapine N-oxide (CNO) (Fig. 1c, d)
As a result, when tumor volume was gradually increased in a time-dependent manner after the transplantation of Lewis lung carcinoma (LLC) cells, activation of D1-receptor-expressing neurons in the medial shell of the nucleus accumbens by the Gq-designer receptors exclusively activated by designer drugs (DREADD) system significantly decreased tumor volume compared to that in D1-WT/ hM3Dq mice (Fig. 1e-i, Two-way repeated measures ANOVA with post-hoc Bonferroni test, ***p < 0.001 vs D1-WT/hM3Dq)
Summary
Dopamine is one of the most well-known neurotransmitters and its transmission in mesolimbic areas controls several physiological functions, such as the modulation of movement and reward [1]. Cancer is a systemic disease that can weaken the immune system by affecting multiple functions of a variety of immune cells [7, 8]. A better understanding of the central and/or efferent immune modification of such systemic immune systems could provide a novel platform for cancer therapies. A growing body of evidence suggests that approximately 95% of nucleus accumbens neurons are GABAergic medium spiny neurons (MSNs) [9]. There are two types of MSNs in the nucleus accumbens: dopamine D1-receptor-expressing MSNs (D1-MSNs) and dopamine D2-receptor-expressing MSNs (D2-MSNs) [10,11,12]. Little is known about the possible role of D1/D2-MSNs in the nucleus accumbens on the regulation of the immune system
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