title: Destruction of serotonergic nerve terminals prevents fluoxetine-induced desensitization of hypothalamic 5-HT(1A) receptors.
abstract: BACKGROUND
  Selective serotonin (5-HT, 5-hydroxytryptamine) reuptake inhibitors (SSRIs) such as fluoxetine produce a gradual desensitization of hypothalamic post-synaptic 5-HT(1A) receptor systems. It is assumed that the effects of SSRIs on post-synaptic 5-HT(1A) receptors are mediated by 5-HT reuptake inhibition, leading to an increase of 5-HT in the synapse. However, there is no direct evidence to support this hypothesis.
  
  
  OBJECTIVE
  The present study determined whether 5-HT(1A) receptor desensitization was mediated by fluoxetine's effects on serotonergic nerve terminals.
  
  
  METHODS
  Serotonergic nerve terminals were destroyed by intracerebroventricular (i.c.v.) injection of the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) combined with injection of the norepinephrine/dopamine reuptake inhibitor nomifensine. 5,7-DHT-induced loss of serotonergic terminals was confirmed by a 95% reduction in the density of [(3)H]paroxetine-labeled 5-HT transporters in the hypothalamus and a 97% reduction in the levels of 5-HT and 5-hydroxyindoleacetic acid in the cortex. Two weeks after the 5,7-DHT injections, rats were injected daily with fluoxetine (5 mg/kg or 10 mg/kg, i.p.) or saline for 14 days.
  
  
  RESULTS
  Injections of 10 mg/kg fluoxetine produced a significant decrease in body weight gain. Destruction of serotonergic nerve terminals reduced body weight and potentiated the ability of fluoxetine to further inhibit body weight gain. Increases in plasma levels of adrenal corticotrophic hormone (ACTH, corticotropin), corticosterone, and oxytocin after injection of the 5-HT(1A) agonist 8-hydroxy-2-dipropylaminotetralin [(+/-)8-OH-DPAT] were used as peripheral markers of 5-HT(1A) receptor function in the hypothalamus. In vehicle-pretreated rats, fluoxetine produced a dose-dependent reduction in the (+/-)8-OH-DPAT-induced increase in plasma ACTH and oxytocin levels. Destruction of serotonergic nerve terminals blocked the ability of fluoxetine to produce a desensitization in the ACTH, corticosterone, and oxytocin responses to (+/-)8-OH-DPAT.
  
  
  CONCLUSIONS
  The ability of fluoxetine to induce a desensitization of hypothalamic post-synaptic 5-HT(1A) receptor systems is dependent on the integrity of serotonergic nerve terminals in the hypothalamus, while its effect on body weight is not mediated by serotonergic nerve terminals in the hypothalamus.
authors.affiliation: Department of Pharmacology, Center for Serotonin Disorders Research, Loyola University of Chicago, Stritch School of Medicine, 2160 South First Avenue, Maywood, IL 60153, USA.
authors.forename: D N
authors.initials: DN
authors.lastname: D'Souza
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: F
authors.initials: F
authors.lastname: Garcia
authors.forename: G
authors.initials: G
authors.lastname: Battaglia
authors.forename: L D
authors.initials: LD
authors.lastname: Van De Kar
mesh_terms: D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects*; D007276:Injections, Intraventricular; D008297:Male; D010121:Oxytocin / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D015116:5,7-Dihydroxytryptamine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone; D005473:Fluoxetine; D010121:Oxytocin; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors