Sex differences in the regulation of serotonergic transmission and behavior in 5-HT receptor knockout mice.
Few studies have examined the relationship between genetics, stress, and sex-linked differences in neurotransmitter systems. Examining serotonin (5-HT) receptor knockout mice on stress-induced behavioral depression, female 5-HT1B receptor knockout mice demonstrated significantly reduced immobility than either male 5-HT1B receptor knockout mice or male and female wild-type mice on the tail suspension test (TST) and forced swimming test. The behavioral phenotype was identified as likely due to a disinhibition of 5-HT release, because depletion of 5-HT with parachlorophenylalanine selectively reduced immobility of female 5-HT1B receptor knockout mice in the TST. In contrast, male and female 5-HT1A receptor knockout mice demonstrated reduced immobility compared with control mice, but the depletion of 5-HT with PCPA did not reverse the antidepressant-like phenotype. Microdialysis studies confirmed significantly higher baseline levels of hippocampal 5-HT in female, but not male, 5-HT1B receptor knockout mice. Both male and female 5-HT1B receptor knockout mice demonstrated augmented dialysate responses to fluoxetine. Also, both male and female 5-HT1B receptor knockout mice demonstrated reductions of immobility in the TST after treatment with fluoxetine. Therefore, female 5-HT1B receptor knockout mice demonstrate a sex-linked disinhibition of 5-HT release that sustained higher baseline levels of hippocampal 5-HT and behavioral vulnerability to 5-HT depletion.
Jones
Michelle D
MD
Department of Psychiatry, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104, USA.
Lucki
Irwin
I
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000033:anatomy & histology; D003863:Depression / Q000523:psychology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D010134:Fenclonine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D019417:Hindlimb Suspension / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000235:genetics; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects / Q000235:genetics; D011985:Receptors, Serotonin / Q000235:genetics / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D018490:Serotonin Agents / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D012727:Sex Characteristics; D013315:Stress, Psychological / Q000523:psychology; D009435:Synaptic Transmission / Q000502:physiology*
D010134:Fenclonine; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012701:Serotonin; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors