Adaptations in 5-HT receptor expression and function: implications for treatment of cognitive impairment in aging.
Malfunction of the serotonin system may contribute to memory deficits during aging. We evaluated the 5-HT(6) antagonist RO4368554 in two models of learning and memory in aged rats. Male rats (18 months) were assigned to two groups of equal cognitive performance. After 2 weeks of 5-HT(6) antagonist RO4368554 (5 mg/kg, i.p.) treatment, rats showed significant improvement in object recognition and social discrimination compared with rats given chronic vehicle. Brains from these animals were examined for changes in plasticity-associated proteins Ki-67 and PCNA. No differences were seen between groups in any of these markers. We also measured mRNA expression of 5-HT(6), along with 5-HT(1A), 5-HT(1B), and tryptophan hydroxylase-2 mRNAs in 4-month-old and 24-month-old F344 rats. Decreases in 5-HT(1B) expression were observed in several forebrain regions in the old rats. These results demonstrate that 5-HT(6) and 5-HT(1B) receptors are potential targets for treatment of age-related memory disorders.
Mitchell
Ellen S
ES
Department of Psychiatry and Behavioral Sciences, University of Washington, Harborview Medical Center, Seattle, Washington 98103, USA.
McDevitt
Ross A
RA
Neumaier
John F
JF
D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020318:Rats, Long-Evans; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D014365:Tryptophan Hydroxylase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D007211:Indoles; D019394:Ki-67 Antigen; D010879:Piperazines; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; C507242:Ro4368554; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D014365:Tryptophan Hydroxylase; C504569:tph2 protein, rat