Background
We recently identified a facilitory control exerted by serotonin4 (5-HT4) receptors on the in vivo firing activity of dorsal raphé nucleus (DRN) serotonergic
(5-HT) neurons. However, these findings were based on acute administrations of 5-HT4 receptor agonists and antagonists, which were active only in a subpopulation of 5-HT
neurons. We had no evidence that this influence was significant when considering the
entire DRN, nor if it was persistent after chronic treatments. In addition, the poor
distribution of 5-HT4 receptors within the DRN raised the question of the neuroanatomical bases underlying
this control.
Methods and results
Here we show that the subacute intraperitoneal (IP) injection of the 5-HT4 receptor agonists prucalopride (2.5 mg/kg) and RS 67333 (1.5 mg/kg) 30 minutes before
the beginning of recordings augment the mean firing rate of DRN neurons by 40% and
66%, respectively. These increases remain stable when the compounds are administered
continuously during 3 and 21 days; the effects of the 3-day treatment are blocked
by the 5-HT4 receptor antagonist GR 125487 (1000 μg/kg, intravenous [i.v.]). In addition, stereotaxic
microinjections of herpes simplex viruses, transformed to overexpress 5-HT4 receptors, increase DRN 5-HT neuronal mean activity when performed in the medial
prefrontal cortex (mPFC) but not in the striatum or in the hippocampus.
Conclusions
This finding suggests the existence of a 5-HT4-dependent activation of DRN that may involve the mPFC, unveiling the 5-HT4 receptor as a putative player in the physiopathology of several disorders related
to central 5-HT dysfunction
Key words
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References
- Feedback regulation of central monoaminergic neurons.in: Youdim M.B.H. Lovenbery W. Sharman D.F. Lagnado J.R. Essays in Neurochemistry and Neuropharmacology. Wiley, New York1978: 1-32
- cAMP-dependent, long-lasting inhibition of a K+ current in mammalian neurons.Proc Natl Acad Sci U S A. 1995; 92: 6635-6639
- Mechanism of action of antidepressants.Psychopharmacol Bull. 2002; 36: 123-132
- CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli.Proc Natl Acad Sci U S A. 2002; 99: 11435-11440
- Effects of the co-administration of mirtazapine and paroxetine on serotonergic neurotransmission in the rat brain.Eur Neuropsychopharmacol. 2000; 10: 177-188
- Repeated treatment with antidepressant drugs induces subsensitivity to the excitatory effect of 5-HT4 receptor activation in the rat hippocampus.Naunyn Schmiedebergs Arch Pharmacol. 1997; 355: 14-19
- Possible neurobiological mechanisms underlying faster onset of antidepressant action.J Clin Psychiatry. 2001; 62: 7-11
- Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders.Neuropsychopharmacology. 1999; 21: 91S-98S
- The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound.Eur J Pharmacol. 2001; 423: 71-83
- Herpes simplex virus-mediated gene transfer as a tool for neuropsychiatric research.Crit Rev Neurobiol. 2000; 14: 47-67
- Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex.J Neurosci. 2001; 21: 9917-9929
- Control of the serotonergic system by the medial prefrontal cortex.Neurotox Res. 2002; 4: 409-419
- Lesion study of the distribution of serotonin 5-HT4 receptors in rat basal ganglia and hippocampus.Eur J Neurosci. 1996; 8: 2591-2598
- The serotonin neurons in nucleus raphe dorsalis of adult rat.J Comp Neurol. 1982; 207: 239-254
- Full agonistic properties of BAY x 3702 on presynaptic and postsynaptic 5-HT1A receptors electrophysiological studies in the rat hippocampus and dorsal raphe.J Pharmacol Exp Ther. 1998; 286: 1239-1247
- Pharmacological characterization of two novel and potent 5-HT4 receptor agonists, RS 67333 and RS 67506, in vitro and in vivo.Br J Pharmacol. 1995; 115: 1387-1392
- Mechanisms of action of antidepressants.Encephale. 2003; 29: 259-265
- Serotonin receptors modulate GABAA receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons.J Neurosci. 2001; 21: 6502-6511
- GR125487.Br J Pharmacol. 1994; 113: 120P
- Effect of the alpha-2 adrenoceptor antagonist mirtazapine on the 5-hydroxytryptamine system in the rat brain.J Pharmacol Exp Ther. 1996; 277: 861-871
- Long-term antidepressant treatments result in a tonic activation of forebrain 5-HT1A receptors.J Neurosci. 1998; 18: 10150-10156
- Role of the medial prefrontal cortex in 5-HT1A receptor-induced inhibition of 5-HT neuronal activity in the rat.Br J Pharmacol. 1999; 126: 1741-1750
- Electrophysiology of hippocampal neurons. II. After-potentials and repetitive firing.J Neurophysiol. 1961; 24: 243-259
- Enhancement of place and object recognition memory in young adult and old rats by RS 67333, a partial agonist of 5-HT4 receptors.Neuropharmacology. 2001; 41: 844-853
- 5-HT4 receptors exert a frequency-related facilitatory control on dorsal raphe nucleus 5-HT neuronal activity.Eur J Neurosci. 2002; 16: 817-822
- Electrophysiological evidence for postsynaptic 5-HT1A receptor control of dorsal raphe 5-HT neurons.Neuropharmacology. 2001; 41: 72-78
- The serotonergic and noradrenergic systems of the hippocampus.Brain Res Brain Res Rev. 1997; 23: 145-195
- Elevated expression of 5-HT1B receptors in nucleus accumbens efferents sensitizes animals to cocaine.J Neurosci. 2002; 22: 10856-10863
- Forebrain afferents to the rat dorsal raphe nucleus demonstrated by retrograde and anterograde tracing methods.Neuroscience. 1998; 82: 443-468
- Central serotonin4 receptors selectively regulate the impulse-dependent exocytosis of dopamine in the rat striatum.Neuropharmacology. 2002; 43: 1099-1109
- Efferent projections of the infralimbic (area 25) region of the medial prefrontal cortex in the rat.Brain Res. 1991; 566: 26-39
- Localization of 5-HT4 receptor mRNA in rat brain by in situ hybridization histochemistry.Brain Res Mol Brain Res. 1996; 43: 356-360
- Regional distribution and ontogeny of 5-HT4 binding sites in rodent brain.Neuropharmacology. 1994; 33: 527-541
- Repeated corticosterone administration increases excitatory effect of 5-HT4 receptor agonist in the rat hippocampus.Pol J Pharmacol. 2000; 52: 107-109
Article info
Publication history
Published online: February 10, 2005
Accepted:
December 10,
2004
Received in revised form:
December 3,
2004
Received:
September 10,
2004
Footnotes
This research was supported by grants from FRSQ and CIHR. GL is a fellowship recipient from Wyeth-Ayerst Canada in partnership with the CIHR and GD is a national researcher from the FRSQ.
Identification
Copyright
© 2005 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
