¹Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, USA

Correspondence: Dr TA Slotkin, Box 3813/Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710 USA. Tel: +1 919 681 8015; Fax: +1 919 684 8197; E-mail: t.slotkin@duke.edu

Received 13 May 2004; Revised 22 July 2004; Accepted 17 August 2004; Published online 15 September 2004.

Abstract

Aging involves neuronal and synaptic loss, and maintenance of function depends on adaptations in cellular responsiveness. We studied olfactory bulbectomy (OBX), a model that recapitulates monoaminergic dysfunction in depression, in 10-week vs 19-month-old rats, and evaluated 5HT (5-hydroxytryptamine, serotonin) mechanisms. OBX elicited little change in 5HT_1A receptors in the cerebral cortex or striatum of either age group. In contrast, 5HT₂ receptors showed disparate effects, with a decrease in the cerebral cortex of young OBX but not aging OBX rats, whereas the latter group showed a selective decrease in striatal 5HT₂ receptors. Greater differences were apparent for 5HT-mediated cell signaling, assessed for the adenylyl cyclase (AC) cascade. In young animals, 5HT had a stimulatory effect on AC that was unaltered by OBX. However, in aging animals, the pattern of 5HT responses showed marked alterations in response to OBX: under basal conditions, stimulatory effects were enhanced but when AC was activated with forskolin, 5HT became markedly inhibitory in the striatum of aged OBX animals. Assessment of the relative AC responses to two direct stimulants that act on different epitopes of the enzyme, forskolin and Mn²⁺, pointed to a shift in the AC isoform and/or its ability to associate with G-proteins as the mechanism underlying the age-related differences for OBX effects. These data indicate that there are biological distinctions in the response of 5HT systems to OBX in young adult vs aging animals, which, if present in geriatric depression, could provide a mechanistic basis for differences in responses to antidepressants that act on 5HT.