ABSTRACT
The compound, LY368975 ((R)-thionisoxetine) is a potent and selective inhibitor of the norepinephrine (NE) reuptake site. We evaluated the in vivo properties of LY368975 in various animal models. In mice, LY368975 prevented heart NE depletion by 6-hydroxydopamine with an ED50 of 1.22 mg/kg. In rats, orally administered LY368975 inhibited 3H-NE uptake into hypothalamic synaptosomes ex vivo with an ED50 of 2.5 mg/kg and 3H-tomoxetine binding to the NE transporter with an ED50 of 2.7 mg/kg. When rats were deprived of food for 18 hr, 10 mg/kg LY368975 was able to suppress food intake 1, 2 and 4 hr after reintroduction of the feed. In nonfasted rats trained to drink sweetened condensed milk, LY368975 produced a dose-dependent reduction in consumption with a 44% decrease at 3 mg/kg. At doses up to 10 mg/kg p.o., LY368975 produced no significant effects on locomotor activity suggesting the compound does not activate or sedate the animals at pharmacologically relevant doses. Therefore, LY368975 is an orally available and centrally active NE reuptake inhibitor that is capable of reducing food consumption in rodents. Compounds of this class may have use in the treatment of obesity and eating disorders.
Subject(s)
Adrenergic Uptake Inhibitors/pharmacology , Eating/drug effects , Fluoxetine/analogs & derivatives , Norepinephrine/physiology , Symporters , Animals , Atomoxetine Hydrochloride , Carrier Proteins/antagonists & inhibitors , Fluoxetine/pharmacology , Male , Mice , Mice, Inbred ICR , Motor Activity/drug effects , Norepinephrine/analysis , Norepinephrine/metabolism , Norepinephrine Plasma Membrane Transport Proteins , Oxidopamine/pharmacology , Paroxetine/metabolism , Propylamines/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
Administration of fluoxetine (10 mg/kg i.p.) caused a significantly greater increase in extracellular 5-HT levels in hypothalamus of rats adapted to a reverse light period (lights off 9:00 am-9:00 pm) than those adapted to the regular cycle (lights off 6:00 pm-6:00 am). Sequential administration of the antagonist 5-HT1A/beta-adrenergic receptors (-)-pindolol at 0.1, 0.3, 1, and 3 mg/kg s.c. significantly enhanced the fluoxetine-induced elevation of 5-HT levels in both groups of rats. (-)-Pindolol at 0.1 mg/kg potentiated the fluoxetine-induced elevation in 5-HT levels significantly higher in rats adapted to the reverse light cycle than in those accustomed to the regular light cycle. The greater effects of fluoxetine and the subsequent administration of (-)-pindolol in the reverse cycle group may relate to the difference in activity of 5-HT neurons in the dorsal raphe of conscious animals adapted to the two light periods.
Subject(s)
Adrenergic beta-Antagonists/pharmacology , Darkness , Fluoxetine/pharmacology , Hypothalamus/drug effects , Pindolol/pharmacology , Receptors, Serotonin/drug effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/metabolism , Animals , Circadian Rhythm , Drug Synergism , Hypothalamus/metabolism , Male , Microdialysis , Rats , Rats, Sprague-Dawley , Receptors, Serotonin, 5-HT1ABSTRACT
The somatodendritic 5-HT1A autoreceptor is known to regulate activity of 5-HT neurons and consequently 5-HT release. Administration of a selective 5-HT uptake inhibitor, fluoxetine (10 mg/kg, i.p.) increased extracellular 5-HT levels in rat hypothalamus up to 260 percent of basal levels. (-)-Pindolol, and antagonist at the somatodendritic 5-HT1A autoreceptor, dose-dependently (1, 3 and 5 mg/kg, s.c.) potentiated the fluoxetine dependent increase up to 458 percent of basal 5-HT levels for approximately 1.5 hours. Continuous infusion of ( +/- )-pindolol at 30 mg/kg/h s.c. enhanced the fluoxetine dependent elevation of extracellular 5-HT concentrations in hypothalamus up to 464 percent of basal levels and lasted for 3 hours. Thus, the combination of 5-HT uptake inhibition with antagonism at the somatodendritic 5-HT1A autoreceptor can enhance 5-HT release to levels beyond those achieved with uptake inhibition alone. The present findings are consistent with the hypothesis that blockade of somatodendritic 5-HT1A autoreceptors removes the inhibitory effect exerted by the elevated 5-HT levels resulting from uptake inhibition.
Subject(s)
Fluoxetine/pharmacology , Hypothalamus/metabolism , Pindolol/pharmacology , Receptors, Serotonin/physiology , Serotonin Antagonists/pharmacology , Serotonin/metabolism , Analysis of Variance , Animals , Dose-Response Relationship, Drug , Hypothalamus/drug effects , Infusions, Parenteral , Kinetics , Male , Microdialysis , Pindolol/administration & dosage , Rats , Rats, Sprague-Dawley , Receptors, Serotonin, 5-HT1ABSTRACT
Classical conditioning of rhythmic jaw movements in rabbits is an accepted model of associative learning that may be useful in assessing age-related changes in learning and motivation. A saccharin solution has been thought to be rewarding to rabbits and is often used as an unconditioned stimulus (US). To determine whether age-related differences in preference for saccharin exist, we assessed (a) saccharin versus water preferences and (b) fluid intake level differences (which might account for differing drive levels) in young (4-6 months) and old (31-69 months) rabbits. Young animals demonstrated a significant preference for water, whereas old animals strongly preferred the saccharin solution. There were no differences between young and old rabbits in overall fluid intake. These results suggest that whereas saccharin may be an appetitive US for old rabbits, it may be aversive to young ones. Thus aging may affect the incentive value of rewarding stimuli, complicating the interpretation of interactions among aging, learning, and motivational processes.
