Abstract
Systemic administration of selective serotonin reuptake inhibitors (SSRIs) elicits larger increases in serotonin (5-HT) in raphe than in forebrain sites. Because serotonergic neuronal activity is suppressed, the mechanism underlying SSRI-induced increases in extracellular 5-HT is unclear. This study determined whether local infusion of SSRIs also elicited regionally selective increases in extracellular 5-HT, and whether changes depended on serotonergic neuronal depolarization. Conventional microdialysis methods were used to measure 5-HT in dorsal raphe (DRN), median raphe, nucleus accumbens (NAcc), and frontal cortex of unanesthetized rats. During infusion of SSRIs into each site, the maximum response was an ∼6- to 7-fold increase in 5-HT in NAcc and frontal cortex, and an ∼20-fold increase in DRN and median raphe. The larger increase in 5-HT in raphe was confirmed using zero-net-flux microdialysis. In NAcc, baseline 5-HT was 0.7 nM, and levels increased to a maximum of 3.1 nM during infusion of the SSRI citalopram. Baseline 5-HT in DRN was greater, 1.3 nM, and increased to 12.4 nM in response to citalopram. Consistent with evidence that autoreceptor activation inhibits serotonergic neuronal discharge, SSRI infusion into DRN produced a moderate decrease in 5-HT in NAcc. However, increases in 5-HT in DRN elicited by SSRI infusion were attenuated by 8-hydroxydipropylaminotetralin and tetrodotoxin. These data indicate that depolarization-dependent 5-HT release was not fully inhibited during SSRI infusion into DRN. In summary, SSRIs produce larger increases in extracellular 5-HT in raphe than in forebrain sites. Increases depend in part on depolarization-induced release, which may be greater in raphe than in forebrain.
Footnotes
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Send reprint requests to: Sidney B. Auerbach, Department of Cell Biology and Neuroscience, Rutgers University Nelson Biological Laboratories, 604 Allison Rd., Piscataway, NJ 08854-8082. E-mail: auerbach{at}biology.rutgers.edu
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↵1 This work was supported by U.S. Public Health Service Grant MH51080. Some of these results were presented in preliminary form to the Society for Neuroscience (Tao et al., 1997).
- Abbreviations:
- 5-HT
- 5-hydroxytryptamine, serotonin
- SSRI
- selective serotonin reuptake inhibitor
- SERT
- 5-HT reuptake transporter
- TTX
- tetrodotoxin
- 8-OH-DPAT
- 8-hydroxydipropylaminotetralin
- DRN
- dorsal raphe nucleus
- MRN
- median raphe nucleus
- NAcc
- nucleus accumbens
- FCx
- frontal cortex
- aCSF
- artificial cerebrospinal fluid
- HPLC-EC
- HPLC with electrochemical detection
- Received January 7, 2000.
- Accepted April 17, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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