Noradrenergic modulation of ephedrine‐induced hypophagia

Abstract

The hypophagic action of the sympathomimetic amine ephedrine (EPH) in the rat may reflect actions on central dopaminergic (DA) and noradrenergic (NE) systems. EPH indirectly facilitates DA and NE activity and acts as a partial agonist at alpha(1)-adrenergic receptors. Two approaches were used to assess the possible contribution of NE and DA pathways to EPH-induced hypophagia. In the first, regression analyses of published archival data were computed to characterize the relation between the hypophagic potency values of (-)-(EPH) and related sympathomimetic drugs, including (+)-amphetamine, aminorex, mazindol, and phentermine (data derived from Blosser JC et al., 1987) and the most potent action of these drugs on facilitating NE activity or DA activity in rat brain (data derived from Rothman RB et al., 2001). In the NE analyses, the ED(50) values for these drugs for the inhibition of eating in rats were significantly related (r = 0.91, P = 0.03) to the potency of each drug in facilitating NE activity (either release or inhibition of [(3)H]NE reuptake), whereas in the DA analyses the correlation between ED(50) values and DA activity for these drugs was also significant (r = 0.98, P = 0.003). The regression analyses are thus supportive of a role for NE or DA in the hypophagic capacity of EPH. Although an earlier study noted that administration of the putative DA antagonist pimozide in rats attenuated EPH hypophagia, pimozide exerts similar potency in antagonizing DA receptors and alpha(1)-adrenergic receptors. To clarify the role of alpha(1)-adrenoceptors in EPH-induced hypophagia, adult male rats were pretreated with the alpha(1)-adrenergic receptor antagonist prazosin (0.0.5 and 2 mg/kg) prior to the administration of (-)-EPH (0, 5, 10, or 20 mg/kg, IP). Prazosin pretreatment at 2.0 mg/kg significantly attenuated the hypophagia, but not the hypodipsia, induced by administration of 10 mg/kg and by 20 mg/kg (-)-EPH. Collectively, these results confirm a critical contribution of of alpha(1)-adrenoceptors to the hypophagic action of (-)-EPH in rats.

Pharmacological Effects of Ephedrine Alkaloids on Human α1- and α2-Adrenergic Receptor Subtypes

“…However, a mechanism of direct action for 1R,2S-ephedrine on ARs has been proposed to explain the observed in vivo effects for the pharmacological treatment of asthma (Griffith and Johnson, 1995;Hoffman, 2001) and for its CNS stimulatory and/or cardiovascular (heart and stroke) adverse effects observed with its abuse and misuse in humans (Haller and Benowitz, 2000). Interestingly, our findings contrast with recent in vivo reports on pressor effects (Liles et al, 2006) and hypophagic activity in rats (Wellman et al, 2003), in which they demonstrated that 1R,2S-ephedrine exhibits its agonist activity via direct effects on the ␣ 1 -AR receptors. In this regard, an in vitro study involving mutational changes (Waugh et al, 2000) in the ␣ 1A -AR demonstrated a 4-fold increase in functional potency for the 1R,2S-ephedrine isomer, whereas potency for epinephrine was decreased by 36-fold.…”

“…In another study by Lee et al (1974) using rat epididymal fat tissue and measurement of lipolysis, the ephedrine isomers were devoid of ␤-AR activity on lipolysis, and they reported that 1R,2S-ephedrine is more potent as an antagonist than 1S,2R-ephedrine. In this regard, Wellman et al (2003) recently reported that 1R,2S-ephedrine-induced hypophagia in rats was attenuated by prazosin, which suggested that this in vivo ephedrine action was mediated via the ␣ 1 -AR. The ␣ 1 -AR subtype that mediated this CNS effect of ephedrine on hypophagia was not established.…”

“…The beneficial and adverse effects of ephedrine and related analogs are known to be mediated via the ␣-and ␤-adrenergic receptors (ARs) and can be elicited by either direct interactions with the receptors as agonists or antagonists or indirectly by either causing a release of endogenous catecholamines and/or by preventing their neuronal reuptake (Trendelenburg, 1963;Trendelenburg et al, 1963;Patil et al, 1967;Vansal and Feller, 1999;Rothman et al, 2003;Wellman et al, 2003). The relative contribution of these direct and indirect interactions to the pharmacological effects of the ephedrine isomers in vivo on ARs has remained controversial.…”

Monoamine Receptors in the Regulation of Feeding Behaviour and Energy Balance

“…There is also some evidence supporting a role of noradrenergic systems in the actions of ephedrine and related sympathomimetics. For example it has been shown that the reduction in food intake induced by these agents correlates well with the ability to either release or inhibit the reuptake of noradrenaline, and that it is reduced by pretreatment with the 1 AR antagonist prazosin [192]. In a similar way, the reduction in feeding induced by phenylpropanolamine is attenuated by the 1 AR antagonist prazosin although it was unaffected by the 1A AR antagonist RS-17053 [193].…”

Effects of ICV administration of the alpha1A-adrenoceptor antagonist 5-methylurapidil on concurrent measures of eating and locomotion after cocaine in the rat

“…Psychostimulants also inhibit eating (Bellinger et al, 2003;Blavet and DeFeudis, 1982;Blosser et al, 1987;Cooper and van der Hoek, 1993;Wellman et al, 2003). Hypophagia has been attributed to dopamine receptor activation in the perifornical hypothalamus (Leibowitz, 1975;Leibowitz and Rossakis, 1979;Wellman, 2005) as well as to activation of α 1 -ARs in brain (Wellman et al, 1993).…”