ABSTRACT
BACKGROUND/AIMS: Both the dopamine receptor D(1) agonist SKF 38393 and the antagonist SCH 23390 are benzazepine derivatives that have been widely used as pharmacological tools and radioligands. Evidence suggests that behavioral effects of both compounds do not always correspond to their established receptor subtype selectivity. Here, we assessed the effects of SKF 38393 and SCH 23390 on the synaptosomal uptake of tritiated serotonin. METHODS: Uptake experiments were performed by using [(3)H]serotonin and synaptosomal fractions prepared from the hypothalamus of rat brain. RESULTS: Both SKF 38393 and SCH 23390 inhibited synaptosomal uptake of [(3)H]serotonin, with IC(50) values of 910 ± 60 nmol/l and 1,400 ± 80 nmol/l, respectively. Clomipramine, a known inhibitor of serotonin uptake, and (+)-amphetamine, a weak inhibitor, had IC(50) values of 14 ± 1 nmol/l and more than 10,000 nmol/l, respectively, under the same experimental conditions. The IC(50) values for SKF 38393 and SCH 23390 fall within the broad range of corresponding values for antidepressants that have been shown to inhibit the uptake of serotonin. This finding indicates that SKF 38393 and SCH 23390 can enhance the activity of the serotonergic system in the brain, a mechanism that may be responsible for some of the effects of these drugs. CONCLUSION: SKF 38393 and SCH 23390 are useful tools to differentiate D(1) from D(2) receptors, but their indirect effects on serotonergic mechanisms have to be considered.
Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Benzazepines/pharmacology , Hypothalamus/drug effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/metabolism , Synaptosomes/drug effects , Animals , Antidepressive Agents/pharmacology , Hypothalamus/metabolism , Male , Osmolar Concentration , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D1/agonists , Receptors, Dopamine D1/antagonists & inhibitors , Synaptosomes/metabolismABSTRACT
High concentrations of glucagon-like peptide-1 (7-36) amide (GLP-1) and its specific receptor (GLP-1R) have been found in the rat hypothalamus. In this study the actions of GLP-1 and its related peptides, exendin-4 (GLP-1R agonist), exendin (9-39) (GLP-1R antagonist) and GLP-1 (9-36) amide (the major GLP-1 metabolite) on levels of serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA) and amino acids (Glu, Asp, Gln, Gly, Tyr, Trp, GABA) in the hypothalamus were investigated. Intracerebroventricular (ICV) injection of GLP-1 (4 nmol) produced a significant reduction in levels of 5-HT (54%) and all measured amino acids (34 to 56%) compared with saline injected controls, whereas exendin (9-39) (4 nmol) was ineffective. ICV injection of exendin-4 produced a significant reduction in the levels of 5-HT, 5-HIAA, Trp, Glu, and Tyr. ICV injection of GLP-1(9-36) amide showed a statistically significant increase in the level of 5-HT, 5-HIAA and all the amino acids tested in this study. Prior administration of exendin (9-39) or GLP-1 (9-36) amide blocked the effects of GLP-1 on the levels of 5-HT and the amino acids. These data are consistent with exendin-4 being a GLP-1R agonist and exendin (9-39) being a specific GLP-1R antagonist. GLP-1 (9-36) amide, a primary metabolite of GLP-1, appears to act as an endogenous antagonist at the GLP-1R.
