Serotonin (5-HT) transporter (SERT) function after graded destruction of serotonergic neurons.
The degree of occupancy of the serotonin transporter (SERT) by selective serotonin reuptake inhibitors (SSRIs) appears to be critical in determining therapeutic response. To gain insight into the extent of occupancy required to alter serotonergic neurotransmission we used high-speed chronoamperometry to determine the extent of serotonergic destruction required to reduce the clearance of exogenously administered serotonin from extracellular fluid in the CA3 region of the hippocampus. Rats were pretreated with various doses of 5,7-dihydroxytryptamine to produce either a low, intermediate or high loss of SERTs. Clearance of 5-HT was reduced only in rats with > 90% loss of SERT. In these rats, there was also a trend for peak signal amplitudes to be greater. There was no significant difference in these parameters between the sham group and those with low or intermediate loss of SERTs. The SSRI, fluvoxamine, prolonged clearance of 5-HT in sham, low and intermediate groups, whereas there was no effect of fluvoxamine in those rats with > 90% loss of SERT. Functional loss of SERT activity occurs when destruction of serotonergic innervation is greater than 90% but serotonin clearance and efficacy of fluvoxamine is maintained with as few as one fifth of a full complement of SERTs.
Montañez
Sylvia
S
Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA. montanez@uthscsa.edu
Daws
Lynette C
LC
Gould
Georgianna G
GG
Frazer
Alan
A
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D004567:Electrodes, Implanted; D045604:Extracellular Fluid / Q000737:chemistry / Q000378:metabolism; D016666:Fluvoxamine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism / Q000493:pharmacokinetics; D018490:Serotonin Agents / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D015116:5,7-Dihydroxytryptamine; D002352:Carrier Proteins; D016666:Fluvoxamine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012701:Serotonin; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493232:Slc6a4 protein, rat