18-Methoxycoronaridine: a potential new treatment for obesity in rats?

Abstract

Rationale Excessive eating often leads to obesity. Although a variety of neurotransmitters and brain regions are involved in modulating food intake, a role of accumbal dopamine is thought to be critical for several aspects of this behavior. Since 18-methoxycoronaridine (18-MC), a selective antagonist of α3β4 nicotinic receptors, was previously shown to alter dopamine release in the nucleus accumbens in response to chronic injections of cocaine and morphine, this drug could be a promising therapy for abnormal eating behavior. Objectives Assess the effect of 18-MC on the consumption of sucrose (15%) vs. water in a self-administration paradigm and on the intake of freely available palatable fluids (i.e., 5% sucrose, 0.1% saccharin, and 0.6% saline solutions) as well as on water intake. Determine whether repeated administration of 18-MC (20 mg/kg i.p.) affects weight gain, food intake, and fat deposition in rats drinking 30% sucrose solution. Results Acute administration of 18-MC (10–40 mg/kg i.p.) reduced operant responding for sucrose and decreased ad libitum ingestion of sucrose, saccharin, and saline. The highest dose of 18-MC also reduced consumption of water when palatable fluids were not available. In rats having unlimited access to sucrose (30%), chronic treatment with 18-MC (20 mg/kg i.p.) prevented sucrose-induced increases in body weight, decreased fat deposition, and reduced consumption of sucrose while not altering food intake. Conclusions These data suggest that antagonism of α3β4 nicotinic receptors may be involved in the regulation of intake of palatable substances regardless of its caloric value and may participate in maintaining obesity.

18-Methoxycoronaridine, a potential anti-obesity agent, does not produce a conditioned taste aversion in rats

“…Assessed in the same experiment, the consumption of sucrose was also reduced 24 h after association with an injection of 18-MC (20 mg/ kg, i.p.). This effect could be due to either the direct pharmacological action of 18-MC on sucrose intake (Taraschenko et al 2008) or to an aversion to sucrose. Sucrose intake was not altered in vehicle-injected control rats.…”

“…In order to distinguish a direct effect of 18-MC on sucrose intake (Taraschenko et al 2008) from that produced by a conditioned taste aversion, the effects of a single 18-MC treatment were examined at 24 h intervals following injection. During the training session, animals were allowed access to sucrose and water in the test cages for 30 minutes, were returned to their home cages, transported to the colony room and injected with 18-MC (20 mg/ kg, i.p.…”

“…In animal studies, 18-MC has been shown to reduce the intravenous self-administration of morphine, cocaine, methamphetamine and nicotine (Glick et al 1996;Glick et al 2000) and to alleviate several signs of opioid withdrawal in rats (Rho and Glick 1998). In recent studies, 18-MC has also been shown to reduce sucrose intake, both in an operant model and in a free-access drinking paradigm (Taraschenko et al 2008). Furthermore, 18-MC reduced sucrose intake, weight gain and fat deposition without altering food and water intake in rats consuming a high sucrose diet (Taraschenko et al 2008).…”

“…In recent studies, 18-MC has also been shown to reduce sucrose intake, both in an operant model and in a free-access drinking paradigm (Taraschenko et al 2008). Furthermore, 18-MC reduced sucrose intake, weight gain and fat deposition without altering food and water intake in rats consuming a high sucrose diet (Taraschenko et al 2008). The mechanism for 18-MC's attenuation of sucrose drinking and its anti-obesity effect has not been elucidated; however,18-MC antagonizes α3β4 nicotinic receptors with high specificity and potency and this action could be responsible (Glick et al 2002).…”

“…Although the effect of 18-MC on taste perception has never been assessed, such a study is necessary in light of our new discovery regarding obesity. Specifically, it is important to know whether the dose of 18-MC (i.e., 20 mg/kg) previously shown to reduce sucrose intake (Taraschenko et al 2008) did so by eliciting an aversive response to sucrose.…”