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Destruction of serotonergic nerve terminals prevents fluoxetine-induced desensitization of hypothalamic 5-HT(1A) receptors.
Psychopharmacology (Berl) 2002; 164(4):392-400P

Abstract

RATIONALE

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.

OBJECTIVES

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+Show Affiliations

Department of Pharmacology, Center for Serotonin Disorders Research, Loyola University of Chicago, Stritch School of Medicine, 2160 South First Avenue, Maywood, IL 60153, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12457269

Citation

D'Souza, D N., et al. "Destruction of Serotonergic Nerve Terminals Prevents Fluoxetine-induced Desensitization of Hypothalamic 5-HT(1A) Receptors." Psychopharmacology, vol. 164, no. 4, 2002, pp. 392-400.
D'Souza DN, Zhang Y, Garcia F, et al. Destruction of serotonergic nerve terminals prevents fluoxetine-induced desensitization of hypothalamic 5-HT(1A) receptors. Psychopharmacology (Berl). 2002;164(4):392-400.
D'Souza, D. N., Zhang, Y., Garcia, F., Battaglia, G., & Van De Kar, L. D. (2002). Destruction of serotonergic nerve terminals prevents fluoxetine-induced desensitization of hypothalamic 5-HT(1A) receptors. Psychopharmacology, 164(4), pp. 392-400.
D'Souza DN, et al. Destruction of Serotonergic Nerve Terminals Prevents Fluoxetine-induced Desensitization of Hypothalamic 5-HT(1A) Receptors. Psychopharmacology (Berl). 2002;164(4):392-400. PubMed PMID: 12457269.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Destruction of serotonergic nerve terminals prevents fluoxetine-induced desensitization of hypothalamic 5-HT(1A) receptors. AU - D'Souza,D N, AU - Zhang,Y, AU - Garcia,F, AU - Battaglia,G, AU - Van De Kar,L D, Y1 - 2002/09/14/ PY - 2002/04/19/received PY - 2002/07/24/accepted PY - 2002/11/29/pubmed PY - 2003/4/24/medline PY - 2002/11/29/entrez SP - 392 EP - 400 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 164 IS - 4 N2 - RATIONALE: 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. OBJECTIVES: 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. SN - 0033-3158 UR - https://www.unboundmedicine.com/medline/citation/12457269/Destruction_of_serotonergic_nerve_terminals_prevents_fluoxetine_induced_desensitization_of_hypothalamic_5_HT_1A__receptors_ L2 - https://dx.doi.org/10.1007/s00213-002-1232-x DB - PRIME DP - Unbound Medicine ER -