Serotonin-1A receptor function in the dorsal raphe nucleus following chronic administration of the selective serotonin reuptake inhibitor sertraline.
Serotonin-1A (5-HT(1A) receptors in the dorsal raphe nucleus (DRN) function as somatodendritic autoreceptors, and therefore play a critical role in controlling serotonergic cell firing and serotonergic neurotransmission. We hypothesized that a decrease in the capacity of 5-HT(1A) receptors to activate G proteins was a general mechanism by which 5-HT(1A) receptors in the DRN are desensitized following chronic administration of selective serotonin reuptake inhibitors (SSRIs). Using in vivo microdialysis, we found that the ability of the 5-HT(1A) receptor agonist 8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT) (0.025 mg/kg, s.c.) to decrease extracellular 5-HT levels in striatum was attenuated following chronic treatment of rats with the SSRIs sertraline or fluoxetine. This apparent desensitization of somatodendritic 5-HT(1A) autoreceptor function was not accompanied by a decrease in 5-HT(1A) receptor sites in the coupled, high-affinity agonist state as measured by the binding of [3H]8-OH-DPAT. In marked contrast to what was observed following chronic administration of fluoxetine, 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding in the DRN was not altered following chronic sertraline treatment. Thus, desensitization of 5-HT(1A) somatodendritic autoreceptor function following chronic sertraline administration appears not to be due to a decrease in the capacity 5-HT(1A) receptors to activate G proteins in the DRN. Our findings suggest that the SSRIs may not be a homogeneous class of antidepressant drug with regard to the mechanism by which the function of somatodendritic 5-HT(1A) autoreceptors is regulated.
Rossi
Dania V
DV
Department of Pharmacology, University of Texas Health Science Center-San Antonio, San Antonio, Texas 78229-3900, USA.
Burke
Teresa F
TF
McCasland
Melissa
M
Hensler
Julie G
JG
D000818:Animals; D008297:Male; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*; D020280:Sertraline / Q000008:administration & dosage*
D044282:Receptor, Serotonin, 5-HT1A; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline