Attenuated dopaminergic tone in the paraventricular nucleus contributing to sympathoexcitation in rats with Type 2 diabetes

Abstract

The study was conducted to investigate the role for dopamine in the centrally mediated sympathoexcitatory response in rats with Type 2 diabetes (T2D). T2D was induced by a combination of high-fat diet (HFD) and low-dose streptozotocin (STZ). HFD/STZ treatment for 12-14 wk resulted in significant increase in the number of FosB-positive cells in the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM). In anesthetized rats, administration of exogenous dopamine (dopamine hydrochloride, 20 mM) in the PVN, but not in the RVLM, elicited decreases in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in control rats and but not in the T2D rats. Blocking the endogenous dopamine with dopamine D1/D5 receptor antagonist SCH39166 (2 mM) in the PVN and RVLM, resulted in increases in RSNA, MAP, and heart rate (HR) in both control and T2D rats. These responses were significantly attenuated in T2D rats compared with control rats (PVN - ΔRSNA: 21 ± 10 vs. 44 ± 2%; ΔMAP: 7 ± 3 vs. 19 ± 6 mmHg, ΔHR: 17 ± 5 vs. 32 ± 4 bpm, P < 0.05). There were no significant increases in response to dopamine D2/D3 receptor antagonist raclopride application in the PVN and RVLM of both control and T2D rats. Furthermore, there were decreased dopamine D1 receptor and D2 receptor expressions in the PVN of T2D rats. Taken together, these data suggest that reduced endogenous dopaminergic tone within the PVN may contribute to the sympathoexcitation in T2D.

Age‐dependent alterations to paraventricular nucleus insulin‐like growth factor 1 receptor as a possible link between sympathoexcitation and inflammation

“…Similarly, pharmacological blockade of catecholaminergic receptors or degeneration of tyrosine hydroxylase‐positive neuron population in the PVN disrupts metabolism and heart rate (Zheng et al . ).…”

A novel role for dopamine signaling in the pathogenesis of bone loss from the atypical antipsychotic drug risperidone in female mice

“…It is important to note that RIS has more complex receptor pharmacology and elicits a greater negative effect on bone vs SSRIs, indicating that additional pharmacological mechanisms are involved in AA-induced bone loss. Reduced dopaminergic tone in the paraventricular nucleus has been tied to sympathetic activation in rats with type 2 diabetes mellitus (T2DM), thus dopaminergic signaling is a mechanism that is worth exploring in AA-induced bone loss [31]. …”

Effect of bromocriptine-QR therapy on glycemic control in subjects with type 2 diabetes mellitus whose dysglycemia is inadequately controlled on insulin

“…Importantly, in animals made insulin resistant by such high fat feeding, a 1-min administration of dopamine to the SCN made once daily for a 2-week period at the time of day that dopamine activity peaks at the SCN of normal insulin-sensitive animals reverses the insulin resistance/glucose intolerance while animals are maintained on the high fat diet [27]. Such circadiantimed dopamine treatment at the SCN reduces abnormally elevated noradrenergic (NA) input activity to the ventromedial hypothalamus (VMH) and the paraventricular nuclei (PVN) and is coupled to decreases in elevated neuropeptide Y (NPY) and corticotropin releasing hormone (CRH) at the PVN [25][26][27][28]31], two neurophysiological conditions precipitating the insulin resistance syndrome [25,26,28,30,33,[41][42][43] in part by inducing overactivation of sympathetic tone and hypothalamic-pituitary axis (HPA) drive to the viscera and vasculature that potentiate the syndrome [43][44][45][46][47]. That is, a diminution of the circadian peak dopaminergic activity at the SCN is a neuromodulatory signal that initiates output signals from the SCN to other hypothalamic nuclei (e.g.…”

“…Such circadiantimed bromocriptine treatment also reduces abnormally elevated NA and serotonergic (S) input activity to the VMH [28,31] and CRH and NPY activities at the PVN [30], which are all neuromodulatory activities that, as described above, act to potentiate insulin resistance and glucose intolerance [28][29][30][31][41][42][43]. In particular, elevated VMH NA input activity functions to attenuate appropriate glucose and free fatty acid nutrient sensing at meal time [34] that in turn potentiates postprandial insulin resistance and reduced glucose disposal [48][49][50].…”