The role of noradrenergic tone in the dorsal raphe nucleus of the mouse in the acute behavioral effects of antidepressant drugs.
Serotonin neurons of the dorsal raphe nucleus (DRN) receive dense noradrenergic innervation and are under tonic activation by noradrenergic input. Thus, afferent noradrenergic input to the DRN could modify the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) by regulating serotonergic transmission. This study investigated whether noradrenergic innervation of the DRN contributes to the acute behavioral effects of different types of antidepressant drugs in the mouse tail suspension test (TST). Noradrenergic terminals in the DRN were destroyed selectively by the local application of 6-hydroxydopamine (6-OHDA). Immunohistochemical analysis confirmed the presence of noradrenergic fibers in the mouse DRN, that 6-OHDA-induced destruction of noradrenergic terminals was confined to the DRN, and serotonergic cell bodies were not affected by 6-OHDA treatment. The antidepressants tested included the SSRIs, fluoxetine and citalopram, and the norepinephrine reuptake inhibitor (NRI) desipramine. The behavioral effects of fluoxetine (20 mg/kg, IP) were blocked by the destruction of noradrenergic terminals. In contrast, pretreatment with 6-OHDA did not alter the ability of citalopram (20 mg/kg, IP) or desipramine (10 mg/kg, IP) to reduce immobility in the TST. Destruction of noradrenergic projections from the locus ceruleus (LC) by DSP-4 treatment did not alter the behavioral effects of any of the antidepressants tested, or the presence of noradrenergic terminals in the DRN, thus indicating that noradrenergic pathways originating from the LC do not mediate the acute behavioral effects of antidepressants in this test. Thus, afferent noradrenergic activity at the level of the DRN can modulate serotonergic transmission in forebrain structures and the behavioral effects of SSRIs, such as fluoxetine, which use noradrenergic input to the DRN to increase forebrain serotonin.
O'Leary
Olivia F
OF
Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Bechtholt
Anita J
AJ
Crowley
James J
JJ
Valentino
Rita J
RJ
Lucki
Irwin
I
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001596:Benzylamines / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D015283:Citalopram / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D005473:Fluoxetine / Q000494:pharmacology; D019417:Hindlimb Suspension / Q000523:psychology; D007150:Immunohistochemistry; D008125:Locus Coeruleus / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000502:physiology*; D016627:Oxidopamine / Q000633:toxicity; D017729:Presynaptic Terminals / Q000502:physiology; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D001596:Benzylamines; D015283:Citalopram; D003891:Desipramine; D004299:Dopamine beta-Hydroxylase; D005473:Fluoxetine; D009638:Norepinephrine; D016627:Oxidopamine; D017367:Selective Serotonin Reuptake Inhibitors; C012102:DSP 4