title: Increased expression of 5-HT6 receptors in the rat dorsomedial striatum impairs instrumental learning.
abstract: A number of studies have shown that systemic 5-HT(6) receptor antagonists can improve learning and memory, but the mechanism for these observations is not known. As striatum normally expresses 5-HT(6) receptors abundantly and is important in consolidating stimulus-response learning, we used targeted gene delivery to further increase the expression of 5-HT(6) receptors in rat striatum and then examined learning. Increased 5-HT(6) expression had no effect on performance in the Morris water maze, a hippocampal-dependent learning paradigm, and did not alter the latency to approach or consume sucrose tablets. However, rats with increased 5-HT(6) expression failed to acquire a reward-based instrumental learning task, a striatum-dependent learning model, during 3 days of successive sessions as compared to sham surgery or GFP-expressing control rats. This behavioral deficit was observed in rats overexpressing 5-HT(6) receptors in the dorsomedial striatum, but not in rats with increased dorsocentral striatal expression. The 5-HT(6) receptor-associated deficit was reversed by administration of a 5-HT(6) antagonist, SB-258585, before each training session. When animals learned the instrumental learning task before gene transfer, increased 5-HT(6) receptor expression had no effect on long-term recall or performance of the task or on extinction of operant responding. Thus, 5-HT(6) receptor activity in rat striatum disrupts acquisition of new instrumental learning but does not impair memory or performance of reward-motivated behavior once established.
authors.affiliation: Department of Psychiatry, 1-University of Washington, Harborview Medical Center, Seattle, WA 98104, USA.
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Mitchell
authors.forename: Timothy
authors.initials: T
authors.lastname: Sexton
authors.forename: John F
authors.initials: JF
authors.lastname: Neumaier
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal / Q000502:physiology; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000235:genetics; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D007858:Learning / Q000502:physiology*; D007859:Learning Disabilities / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000235:genetics*; D012201:Reward; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000235:genetics*; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics
chemical_list: D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor; D049452:Green Fluorescent Proteins; D012701:Serotonin