Modulation of sibutramine‐induced increases in extracellular noradrenaline concentration in rat frontal cortex and hypothalamus by α₂‐adrenoceptors

Abstract

1 The eects of sibutramine (0.25 ± 10 mg kg 71 i.p.) on extracellular noradrenaline concentration in the frontal cortex and hypothalamus of freely-moving rats were investigated using microdialysis. The role of presynaptic a 2 -adrenoceptors in modulating the eects of sibutramine in these brain areas was also determined. 2 Sibutramine induced an increase in extracellular noradrenaline concentration, the magnitude of which paralleled dose, in both brain areas. In the cortex, this increase was gradual and sustained, whereas in the hypothalamus it was more rapid and of shorter duration. 3 In both the cortex and hypothalamus, pretreatment of rats with the a 2 -adrenoceptor antagonist RX821002 (3 mg kg 71 i.p.) potentiated increases in the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg 71 i.p.), by 7 and 10 fold respectively. RX821002 also reduced the latency of sibutramine to reach its maximum eect in the cortex, but not in the hypothalamus. 4 Infusion of RX821002 (1 mM) via the probe increased the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg 71 i.p.) in both brain areas. In the hypothalamus, the eects of RX821002 on the accumulation of noradrenaline induced by sibutramine were 2 fold greater than those in the cortex. 5 These ®ndings support evidence that sibutramine inhibits the reuptake of noradrenaline in vivo, but that the accumulation of extracellular noradrenaline is limited by noradrenergic activation of presynaptic a 2 -adrenoceptors. Furthermore, the data suggest that terminal a 2 -adrenoceptors in the hypothalamus exert a greater inhibitory eect over the control of extracellular noradrenaline accumulation than do those in the cortex.

Effects of Chronic Administration of Sibutramine on Body Weight, Food Intake and Motor Activity in Neonatally Monosodium Glutamate-Treated Obese Female Rats: Relationship of Antiobesity Effect with Monoamines

“…On the other hand, the changes caused by MA uptake inhibitors in the MA level in cerebral tissue were statistically almost insignificant [17,22,24,26,28]. Wortley et al and we have already reported that sibutramine strongly inhibited reuptake of 5-HT, norepinephrine and dopamine in mice in vivo, and caused large increases in extracellular 5-HT and norepinephrine levels and a small increase in the dopamine level, as measured by microdialysis, in the hypothalamus and striatum of rats [28,33,44]. Inhibitory effects of sibutramine on this MA reuptake have also been confirmed by in in vitro studies [5].…”

“…It is of an interest to determine whether the food intake suppression by acute administration of sibutramine to normal rats is attributable to effects of this agent mediated by the VMH and ARC or effects of this agent in other brain areas, e.g., the LH and PVN, etc., and whether sibutramine acts on these hypothalamic nuclei to activate the sympathetic nervous system to increase energy expenditure [16,19,20,44].…”

Chronic Reboxetine Desensitizes Terminal but not Somatodendritic α2-Adrenoceptors Controlling Noradrenaline Release in the Rat Dorsal Hippocampus

“…NA is taken up by the NA transporter found exclusively on the neuronal membrane of noradrenergic cells (Lorang et al, 1994). Activation of terminal a 2 -adrenoceptors by the endogenous transmitter or exogenous receptor agonists reduces NA release (L'Heureux et al, 1986;Starke, 1977;Westfall, 1977), whereas blockade of these receptors has the opposite effect (Dennis et al, 1987;Gobert et al, 1997;Mateo et al, 1998;Wortley et al, 1999). Somatodendritic a 2 -adrenoceptors, by controlling the firing activity of NA neurons of the LC (Cedarbaum and Aghajanian, 1976;Svensson et al, 1975), contribute to the regulation of action potential-dependent release of NA (Florin-Lechner et al, 1996).…”

RX 821002 as a Tool for Physiological Investigation of α2‐Adrenoceptors

“…Similar results for norepinephrine release in frontal cortex were recorded by Hudson et al (54), who further showed augmented release of norepinephrine in ventral hippocampus, and dopamine in the striatum. RX 821002 also enhances norepinephrine release in frontal cortex after administration of the uptake blocker sibutramine (115). Direct application of the antagonist to locus coeruleus induces a large increase in norepinephrine output in the cingulate cortex per se (72), and augments the norepinephrine releasing action of desipramine in the same area (74).…”