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Chronic stimulation of group II metabotropic glutamate receptors in the medulla oblongata attenuates hypertension development in spontaneously hypertensive rats.

ABSTRACT: Baroreflex dysfunction is partly implicated in hypertension and one responsible region is the dorsal medulla oblongata including the nucleus tractus solitarius (NTS). NTS neurons receive and project glutamatergic inputs to subsequently regulate blood pressure, while G-protein-coupled metabotropic glutamate receptors (mGluRs) play a modulatory role for glutamatergic transmission in baroreflex pathways. Stimulating group II mGluR subtype 2 and 3 (mGluR2/3) in the brainstem can decrease blood pressure and sympathetic nervous activity. Here, we hypothesized that the chronic stimulation of mGluR2/3 in the dorsal medulla oblongata can alleviate hypertensive development via the modulation of autonomic nervous activity in young, spontaneously hypertensive rats (SHRs). Compared with that in the sham control group, chronic LY379268 application (mGluR2/3 agonist; 0.40 μg/day) to the dorsal medulla oblongata for 6 weeks reduced the progression of hypertension in 6-week-old SHRs as indicated by the 40 mmHg reduction in systolic blood pressure and promoted their parasympathetic nervous activity as evidenced by the heart rate variability. No differences in blood catecholamine levels or any echocardiographic indices were found between the two groups. The improvement of reflex bradycardia, a baroreflex function, appeared after chronic LY379268 application. The mRNA expression level of mGluR2, but not mGluR3, in the dorsal medulla oblongata was substantially reduced in SHRs compared to that of the control strain. In conclusion, mGluR2/3 signaling might be responsible for hypertension development in SHRs, and modulating mGluR2/3 expression/stimulation in the dorsal brainstem could be a novel therapeutic strategy for hypertension via increasing the parasympathetic activity.

SUBMITTER: Hsu JC

PROVIDER: S-EPMC8133461 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Within the group I family of metabotropic glutamate receptors (mGluRs), substantial evidence points to a role for mGluR5 mechanisms in cocaine's abuse-related behavioral effects, but less is understood about the contribution of mGluR1, which also belongs to the group I mGluR family. The selective mGluR1 antagonist JNJ16259685 [(3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone] was used to investigate the role of mGluR1 in the behavioral effects of cocaine and methamphetamine. In drug discrimination experiments, squirrel monkeys were trained to discriminate cocaine from saline by using a two-lever, food-reinforced operant procedure. JNJ16259685 (0.56 mg/kg) pretreatments significantly attenuated cocaine's discriminative stimulus effects and the cocaine-like discriminative stimulus effects of methamphetamine. In monkeys trained to self-administer cocaine or methamphetamine under a second-order schedule of intravenous drug injection, JNJ16259685 (0.56 mg/kg) significantly reduced drug-reinforced responding, resulting in a downward displacement of dose-response functions. In reinstatement studies, intravenous priming with cocaine accompanied by restoration of a cocaine-paired stimulus reinstated extinguished cocaine-seeking behavior, which was significantly attenuated by JNJ16259685 (0.56 mg/kg). Finally, in experiments involving food rather than drug self-administration, cocaine and methamphetamine increased the rate of responding, and the rate-increasing effects of both psychostimulants were significantly attenuated by JNJ16259685 (0.3 mg/kg). At the doses tested, JNJ16259685 did not significantly suppress food-reinforced behavior (drug discrimination or fixed-interval schedule of food delivery), but did significantly reduce species-typical locomotor activity in observational studies. To the extent that the psychostimulant-antagonist effects of JNJ16259685 are independent of motor function suppression, further research is warranted to investigate other mGluR1 antagonists for potential therapeutic value in psychostimulant abuse.

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Chronic stimulation of group II metabotropic glutamate receptors in the medulla oblongata attenuates hypertension development in spontaneously hypertensive rats.

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