Effect of the beta3 adrenoceptor agonist CL 316243 on hypothalamic 5-HT synthesis and suppression of REM sleep in the rat.
Beta3 adrenoceptor agonists show an antidepressant-like profile in preclinical rodent assays and improve mood in clinically-obese patients. These observations suggest a possible antidepressant utility for beta3 adrenoceptor agonists. The present study examined the effects of acute and chronic administration of the beta3 adrenoceptor agonist CL 316243 on two physiological indicators of antidepressant activity in the rat: hypothalamic 5-HT synthesis and suppression of REM sleep. 5-HT synthesis was estimated by the accumulation of 5-hydroxytryptophan (5-HTP) after treatment with the L-aromatic acid decarboxylase inhibitor NSD 1015. Sleep-wake patterns were monitored using electroencephalogram and electromyogram signals collected by radiotelemetry. Rats were administered CL 316243 acutely or once daily for 11 days. Acute administration of CL 316243 significantly increased hypothalamic 5-HT synthesis, as indicated by increased levels of 5-HTP, and reduced the amount of REM sleep. However, chronic administration produced no changes in 5-HTP or REM compared with vehicle treatment. The present observations suggest that acute administration of CL 316243 causes antidepressant-like effects on REM sleep, possibly mediated by increased central 5-HT synthesis. However, these effects are not maintained with repeated dosing.
Conley
R K
RK
In Vivo Neuroscience Department, The Neuroscience Research Centre, Merck Sharp & Dohme, Harlow, Essex, UK. rachel.conley@pfizer.com
Li
J
J
Ivarsson
M
M
Hutson
P H
PH
D006916:5-Hydroxytryptophan / Q000096:biosynthesis; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051381:Rats; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D012701:Serotonin / Q000096:biosynthesis*; D012895:Sleep, REM / Q000187:drug effects*; D013997:Time Factors; D014851:Wakefulness / Q000187:drug effects
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000928:Antidepressive Agents; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D004149:Dioxoles; D004791:Enzyme Inhibitors; D006834:Hydrazines; D022702:Receptors, Adrenergic, beta-3; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D012701:Serotonin; C004297:3-hydroxybenzylhydrazine; D006916:5-Hydroxytryptophan; D001142:Aromatic-L-Amino-Acid Decarboxylases