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.

Associations between drugs of abuse and cues facilitate the acquisition and maintenance of addictive behaviors. Although significant research has been done to elucidate the role that simple discriminative or discrete conditioned stimuli (e.g., a tone or a light) play in addiction, less is known about complex environmental cues. The purpose of the present study was to examine the role of a musical conditioned stimulus by assessing locomotor activity and in vivo microdialysis. Two groups of rats were given non-contingent injections of methamphetamine (1.0 mg/kg) or vehicle and placed in standard conditioning chambers. During these conditioning sessions both groups were exposed to a continuous conditioned stimulus, in the form of a musical selection ("Four" by Miles Davis) played repeatedly for ninety minutes. After seven consecutive conditioning days subjects were given one day of rest, and subsequently tested for locomotor activity or dopamine release in the absence of drug while the musical conditioned stimulus was continually present. The brain regions examined included the basolateral amygdala, nucleus accumbens, and prefrontal cortex. The results show that music is an effective contextual conditioned stimulus, significantly increasing locomotor activity after repeated association with methamphetamine. Furthermore, this musical conditioned stimulus significantly increased extracellular dopamine levels in the basolateral amygdala and nucleus accumbens. These findings support other evidence showing the importance of these brain regions in conditioned learning paradigms, and demonstrate that music is an effective conditioned stimulus warranting further investigation.

Owing to multiple anatomical connections and functional interactions between the habenulo-interpeduncular and the mesolimbic pathways, it has been proposed that these systems could together mediate the reinforcing properties of addictive drugs. 18-Methoxycoronaridine, an agent that reduces morphine self-administration and attenuates dopamine sensitization in the nucleus accumbens in response to repeated morphine, has been shown to produce these effects by acting in the medial habenula and interpeduncular nucleus. Acetylcholine, one of the predominant neurotransmitters in the interpeduncular nucleus, may be a major determinant of these interactions. To determine if and how morphine acts in the interpeduncular nucleus, the effects of acute and repeated administration of morphine on extracellular acetylcholine levels in this brain area were assessed. In addition, the motor behavior of rats receiving repeated morphine administration was monitored during microdialysis sessions. Acutely, morphine produced a biphasic effect on extracellular acetylcholine levels in the interpeduncular nucleus such that low and high doses of morphine (i.e., 5 and 20mg/kg i.p.) significantly increased and decreased acetylcholine levels, respectively. Repeated administration of the same doses of morphine resulted in tolerance to the inhibitory but not to the stimulatory effects; tolerance was accompanied by sensitization to morphine-induced changes in locomotor activity and stereotypic behavior. The latter results suggest that tolerance to morphine's effect on the cholinergic habenulo-interpeduncular pathway is related to its sensitizing effects on the mesostriatal dopaminergic pathways.