Jaakko Lappalainen

Effects of acute GR38032F (odansetron), a 5-HT3 receptor antagonist, on dopamine and serotonin metabolism in mesolimbic and nigrostriatal dopaminergic neurons

The acute administration of GR38032F, a selective 5-HT3 receptor antagonist, did not change the concentrations of dopamine (DA) or 5-hydroxytryptamine (5-HT) or their deaminated metabolites in nucleus caudatus, nucleus accumbens or substantia nigra. Pretreatment with GR38032F failed to modify the haloperidol-induced activation of DA turnover. It is concluded that the blockade of central 5-HT3 receptors by GR38032F under these experimental conditions does not result in alternations in metabolism of DA or 5-HT in major ascending dopaminergic areas.

Quantification of sch 39166 a novel selective d1 dopamine receptor antagonist in rat brain and blood

A gas chromatographic method for measuring concentrations of a novel D1 antagonist SCH 39166 [(−)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5-H-benzo[d]naphto(2,1–6)azepine] in rat brain and plasma was developed. The method was applied to descriptive pharmacokinetics of two subcutaneous doses of SCH 39166 (0.25 mg/kg and 2.5 mg/kg). For comparison, concentrations of the “prototype” D1 antagonist SCH 23390 (0.25 mg/kg, SC) [R-(+)-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1-H-3-benzazepine] were also measured in plasma and brain. SCH 23390 (0.25 mg/kg, SC) had a very short elimination half-life of about 30 min in plasma, and disappeared in a slightly slower manner from striatum and cortex. SCH 39166 (0.25 and 2.5 mg/kg, SC), however, had a longer elimination half-life of about 1.5–2.5 h in plasma and brain. Interestingly, the 2.5 mg/kg dose of SCH 39166 produced only two-to five-fold increases in maximum concentrations in plasma and brain compared to the 0.25 mg/kg dose. The reason for this is not clear. The ability of these two doses of SCH 39166 to induce catalepsy in the bar test was also evaluated. It was found that SCH 39166 in these two doses, unlike SCH 23390, was not cataleptic. In conclusion, these pharmacokinetic features of SCH 39166 in the rat should be useful when designing experiments with this novel selective D1 antagonist. Furthermore, the longer elimination half-life of SCH 39166 makes it a more useful probe in pharmacodynamic comparisons of D1 receptor antagonists and classical as well as atypical neuroleptics.

Effects of chronic administration of ondansetron (GR38032F), a selective 5-HT3 receptor antagonist, on monoamine metabolism in mesolimbic and nigrostriatal dopaminergic neurons and on striatal D2-receptor binding

The effects of chronic administration of the selective 5-HT3 receptor antagonist ondansetron (GR38032F) on dopamine (DA) and 5-hydrotryptamine (5-HT) metabolism in the major ascending dopaminergic neurons and on striatal D2-receptor binding characteristics were investigated. The metabolism of 5-HT was also studied in a number of other brain areas. Chronic ondansetron (0.2 mg/kg/day and 1.0 mg/kg/day SC for 16 days) did not change DA or 5-HT metabolism in the nigrostriatal or mesolimbic dopaminergic areas, although the larger dose of ondansetron slightly and statistically significantly reduced basal concentrations of DA and 5-HT in the nucleus caudatus. D2-receptor binding characteristics were not affected in the caudateputamen. Ondansetron did not change 5-HT metabolism in the nucleus raphé dorsalis, amygdala, hippocampus or in habenula. It is concluded that chronic administration of ondansetron does not change DA or 5-HT metabolism in the major ascending dopaminergic neurons. This suggest that unlike chronic D2-receptor blockade, chronic blockade of central 5-HT3 receptors does not result in a similar reduction in the activity of nigrostriatal and mesolimbic dopaminergic neurons.

Chronic treatment with SCH 23390, a selective dopamine D-1 receptor antagonist, decreases dopamine metabolism in rat caudate nucleus

Chronic treatment (18 days; 0.1 and 0.5 mg/kg per day) with the selective dopamine (DA) D-1 receptor antagonist, SCH 23390, significantly reduced the concentration of homovanillic acid (HVA) and the ratios of HVA/DA and DOPAC/DA in the nucleus caudatus of the rat but did not change the metabolism of DA in the prefrontal cortex, substantia nigra or the A10 area. Furthermore, the concentrations of noradrenaline were dose dependently decreased in the A10 area during SCH 23390 treatment. It is concluded that chronic DA D-1 receptor blockade causes changes in the metabolism of DA similar to those caused by classical neuroleptics.

Neurochemical effects of chronic co-administration of ritanserin and haloperidol: comparison with clozapine effects

The effects of chronic treatment with clozapine (20 mg/kg per day), ritanserin (0.5 mg/kg per day), haloperidol (0.5 mg/kg per day), or the combination of haloperidol and ritanserin, on dopamine (DA) and serotonin (5-HT) metabolism were studied. Chronic haloperidol treatment decreased DA metabolism in nucleus caudatus. Chronic ritanserin treatment failed to alter striatal or mesolimbic DA metabolism but decreased the concentrations of 5-HT and 5-hydroxyindoleacetic acid in the nucleus raphe dorsalis. The effects of chronic haloperidol were not altered by concomitant ritanserin administration. In comparison, chronic clozapine treatment affected neither DA nor 5-HT metabolism. These results show that the biochemical effects of chronic haloperidol treatment on the major ascending DA neurons cannot be modulated by concomitant 5-HT2 receptor blockade.

Regulation of dopamine D1 receptors by chronic administration of structurally different D1 receptor antagonist: A quantitative autoradiographic study

The effects of chronic treatment (18 days) with the novel D1 antagonists, the benzonaphthazepine SCH 39166 (2 mg/kg per day) and the tetrahydroisoquinoline A-69024 (10 mg/kg per day), on D1 and D2 receptor binding in the rat brain were studied by quantitative receptor autoradiography. The benzazepine derivatives, SCH 23390 (0.5 mg/kg per day) and SKF 38393 (20 mg/kg per day), the prototype D1 antagonist and agonist, respectively, were also included in the experiment. Chronic treatment with SCH 23390 increased D1 receptor binding, studied with [3H]SCH 23390, in the nucleus accumbens and in all subregions of the anterior caudatus-putamen. However, chronic treatment with SKF 38393 did not alter D1 receptor binding in the brain areas studied. Interestingly, chronic treatment with SCH 39166 increased D1 receptor binding in the anterior caudatus-putamen but not in the nucleus accumbens. In contrast, chronic treatment with A-69024 did not alter D1 receptor binding in the brain areas studied. Treatment with SCH 23390, SCH 39166, A-69024 or SKF 38393 failed to alter D1 receptor binding in the posterior caudatus-putamen and the tuberculum olfactorium. Neither the D1 antagonists nor the D1 agonist investigated altered D2 receptor binding, studied with [125I]sulpiride, in the caudatus-putamen and nucleus accumbens. In summary, the benzonaphthazepine D1 antagonist, SCH 39166, as well as the benzazepine D1 antagonist, SCH 23390, can increase D1 receptor binding without influencing D2 receptor binding. However, a tetrahydroisoquinoline, A-69024, failed to increase D1 receptor binding, suggesting a differential regulation of D1 receptors after treatment with this putative D1 antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of chronic SCH 23390 treatment on dopamine autoreceptor function in rat brain

The effects of chronic treatment with SCH 23390 (0.5 mg/kg per day, 18 days), a selective (DA) D-1 receptor antagonist, on dopamine autoreceptor function in rats were investigated. The decrease of DA metabolism in mesolimbic and nigrostriatal systems and inhibition of spontaneous explorative locomotor activity by low doses of the selective D-2 receptor agonist, quinpirole, were used as behavioral and biochemical indices of DA autoreceptor function. The DA metabolism decreasing effect of quinpirole (20 and 50 micrograms/kg) in mesolimbic or nigrostriatal DA systems was similar in SCH 23390- and vehicle-treated rats. Two-way analysis of variance showed that rats treated chronically with SCH 23390 were significantly more active than vehicle-treated rats. However, there were no statistically significant differences in the quinpirole-induced hypomotility response between these groups. These results indicate that chronic D-1 blockade, unlike classical antipsychotic drugs, does not modulate the biochemical and behavioral indices of DA autoreceptor activation, suggesting a lack of interaction between DA autoreceptors and D-1 receptors in the central nervous system.

Effects of acute administration of SCH 23390 on dopamine and serotonin turnover in major dopaminergic areas and mesencephalic raphe nuclei--comparison with ritanserin.

1. The effects of acute administration of SCH 23390 (0.05 and 0.25 mg/kg s.c.), a dopamine D-1 receptor antagonist having also a moderate serotonin-S2 (5-HT-2) receptor blocking activity, and ritanserin (0.5 mg/kg), a specific 5-HT-2 antagonist, on dopamine (DA) and serotonin (5-HT) turnover were investigated in dopaminergic (nucleus caudatus, nucleus accumbens, substantia nigra, A10 area) and serotonergic (nucleus raphe dorsalis and nucleus raphe medialis) rat brain nuclei. 2. Acute SCH 23390 (both doses) increased the metabolism of DA and tended to augment the rate of DA synthesis (accumulation of DOPA after inhibition of aromatic acid decarboxylase) in the nucleus accumbens, but not in the nucleus caudatus. In addition, SCH 23390 had a moderate effect on DA metabolism in substantia nigra. SCH 23390 did not alter the turnover of 5-HT in any of the nuclei studied. 3. Acute administration of ritanserin did not modify 5-HT or DA turnover in any of the nuclei studied. 4. In conclusion, these results suggest that acute SCH 23390 administration preferentially activates the mesolimbic DA system. The lack of effect of ritanserin on DA or 5-HT turnover in nigrostriatal and mesolimbic DAergic areas suggests that under basal conditions the blockade of 5-HT2 receptors do not change monoamine metabolism in these areas. The role of 5-HT-2 blockade in the actions of SCH 23390 on DA turnover appears thus to be of a minor importance.

CHRONIC D1-RECEPTOR BLOCKADE : EFFECTS ON D2-RECEPTOR AGONIST-INDUCED YAWNING IN RATS

Abstract— The effects of chronic treatment with the selective D1 dopamine receptor antagonist SCH 23390 (0.25 mg kg−1 s.c. twice daily for 18 days, 4 days withdrawal on yawning induced by the D2‐receptor agonist quinpirole has been investigated. Low doses of quinpirole (20 and 50 μg kg−1 s.c.) induced dose‐related yawning behaviour in rats. The yawning response to quinpirole was not significantly different in the presence or absence of SCH 23390 pretreatment. However, chronic treatment with SCH 23390 alone significantly suppressed yawning behaviour. The results suggest that chronic D1‐receptor blockade with SCH 23390 does not alter the function of the D2‐receptor population mediating yawning behaviour. However, after withdrawal it may result in behavioural activation as seen by suppression of yawning behaviour in the present study.