Vol. 298, Issue 3, 1092-1100, September 2001

Regional Patterns of Compensation following Genetic Deletion of Either 5-Hydroxytryptamine_1A or 5-Hydroxytryptamine_1B Receptor in the Mouse

Deborah A. Knobelman, René Hen, Julie A. Blendy and Irwin Lucki

Departments of Pharmacology (D.A.K., J.A.B., I.L.) and Psychiatry (I.L.), University of Pennsylvania, Philadelphia, Pennsylvania; and Center for Neurobiology and Behavior, Columbia University, New York, New York (R.H.)

Plasticity in serotonergic transmission in serotonin or 5-hydroxytryptamine (5-HT) receptor mutants was examined by measuring the regulation of extracellular 5-HT levels in the striatum and ventral hippocampus of 5-HT_1A and 5-HT_1B receptor knockout mice using in vivo microdialysis. The efficacy of genetic deletion was verified by showing blunted regulation of extracellular 5-HT with selective 5-HT receptor agonists. 5-HT_1A receptor knockout mice failed to demonstrate reduction of extracellular 5-HT in response to systemic administration of the 5-HT_1A receptor agonist R-8-hydroxydipropylaminotetralin (R-8-OH-DPAT) and 5-HT_1B receptor knockout mice failed to demonstrate reduction of extracellular 5-HT in response to systemic administration of the 5-HT_1B receptor agonist CP 94,253. Plasticity also developed to deletion of the complementary autoreceptor. 5-HT_1A receptor knockout mice demonstrated a significantly greater response to CP 94,253 in the striatum, but not the ventral hippocampus, suggesting the development of enhanced sensitivity of striatal 5-HT_1B receptors. In 5-HT_1B receptor knockout mice, R-8-OH-DPAT evoked a significantly diminished response in the ventral hippocampus, but not the striatum, suggesting the potential desensitization of 5-HT_1A receptors in the median raphe nucleus. The pattern of regional compensations between somatodendritic and terminal autoreceptors was confirmed by pharmacological challenges using the selective serotonin reuptake inhibitor fluoxetine combined with either a 5-HT_1A (WAY 100635) or a 5-HT_1B/1D (GR 127935) receptor antagonist. The regional pattern of compensation may be determined by the preferential role of 5-HT_1A or 5-HT_1B receptors in regulating 5-HT release. Taken together, these results demonstrate the development of regional plasticity between complementary somatodendritic and terminal autoreceptors after the genetic deletion of 5-HT_1A or 5-HT_1B receptors.