Wednesday, October 10, 2007

The Joy of 5-HT4 Receptors

Move over, melanocortin receptors, 5-HT4 receptors are ready to take your place. Agonists of the 5-HT4 receptor, a subtype of the serotonin receptor family, seem to do the following, according to recently published reports:

(1) mediate the appetite-suppressing qualities of ecstasy (MDMA), and supposedly the self-reinforcing qualities of starving for individuals with anorexia nervosa (Jean et al., 2007). This paper was the one in PNAS mentioned the other day by The Neurocritic.
We [Jean et al., 2007] hypothesized that anorexia may involve altered signaling events within the nucleus accumbens (NAc), a brain structure involved in reward. We show here that direct stimulation of 5-HT4R in the NAc reduces the physiological drive to eat and increases CART (cocaine- and amphetamine-regulated transcript) mRNA levels in fed and food-deprived mice. ... Considering that CART may interfere with food- and drug-related rewards, we tested whether the appetite suppressant properties of MDMA involve the 5-HT4R. Using 5-HT4R knockout mice, we demonstrate that 5-HT4R are required for the anorectic effect of MDMA as well as for the MDMA-induced enhancement of CART mRNA expression in the NAc. ...
(2) act as a rapid-onset antidepressant (Lucas et al., 2007); no more waiting 3-6 weeks for treatment response from those pesky SSRIs. In a rodent model of depression, acute administration of 5-HT4 agonists was more effective than citalopram in reducing immobility in the forced swimming test.
Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2–3 week treatments with classical molecules: desensitization of 5-HT1A receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters.
(3) improve memory and affect amyloid metabolism (Lezoualc'h, 2007), making it a possible target for drugs to treat Alzheimer's disease (Maillet et al., 2004).

Fig. 1 (Lezoualc'h, 2007). In vivo and in vitro evidence for a beneficial effect of 5-HT4 receptor agonists in AD. 5-HT4 agonists facilitate ACh [acetylcholine] release in rat frontal and hippocampus and modulate different aspects of memory performance in behavioural experiments. In addition, they increase the extracellular release of sAPPα [non-amyloidogenic soluble form of APP] and decrease Aβ [amyloid β-peptide] secretion in primary neurons. sAPPα has potent memory-enhancing effects and displays neuroprotective and neurotrophic properties.

The one major thing the MC4R subtype of melanocortin receptors has over 5-HT4R is its potential as an aphrodisiac, in the form of PT-141 (company press release and PDF).


Alexandra Jean, Grégory Conductier, Christine Manrique, Constantin Bouras, Philippe Berta, René Hen, Yves Charnay, Joël Bockaert, and Valérie Compan (2007). Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens. PNAS published online October 3, 2007.

Lezoualc'h F. (2007). 5-HT4 receptor and Alzheimer's disease: the amyloid connection. Exp Neurol. 205:325-9.

Lucas G, Rymar VV, Du J, Mnie-Filali O, Bisgaard C, Manta S, Lambas-Senas L, Wiborg O, Haddjeri N, Pineyro G, Sadikot AF, Debonnel G. (2007 ). Serotonin-4 (5HT-4) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 55:712-25.

Maillet M, Robert SJ, Lezoualc'h F. (2004). New insights into serotonin 5-HT4 receptors : a novel therapeutic target for Alzheimer's disease? Curr Alzheimer Res. 1(2):79-85.

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At October 29, 2008 9:37 AM, Anonymous Anonymous said...

Which are the antidepressants who have highly selective 5-HT4 agonist?
Tarciso, (
PS: I´m not american.

At October 29, 2008 10:15 AM, Blogger The Neurocritic said...

The study of Lucas et al. (2007) was conducted in rats with an experimental drug, the 5-HT4 agonist RS 67333.

The drug Zelnorm (tegaserod) had been approved for treatment of irritable bowel syndrome but was withdrawn from the market because it increases the risk of heart attack or stroke. HOWEVER, Zelnorm's therapeutic action is peripheral (i.e., 5-HT4 receptors in the gut), and only negligible amounts cross the blood/brain barrier (see this PowerPoint presentation). Since this drug, and others like it, do not get into the brain, they have no use as antidepressants.

The bottom line: there aren't any selective 5-HT4 agonist drugs on the market for major depression.


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