The 5-HT7 receptor

[C6H6]

There are now lots serotonin receptor subtypes and little information on their behavioural effects. Here is some new information on the 5-HT7 receptor:

Eur J Pharmacol. 2005 Jul 5; [Epub ahead of print]

Effects of a 5-HT(7) receptor antagonist DR4004 on the exploratory behavior in a novel environment and on brain monoamine dynamics in mice.

Takeda H, Tsuji M, Ikoshi H, Yamada T, Masuya J, Iimori M, Matsumiya T.

Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.

The present study examined whether serotonin (5-hydroxytryptamine; 5-HT)(7) receptors play a role in the modulation of emotionality in mice using the selective 5-HT(7) receptor antagonist 2a-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-2a,3,4,5-tetrahydrobenzo (c,d)indol-2-(1H)-one (DR4004). The emotionality of mice was evaluated in terms of exploratory activity in the hole-board test. The mice treated with DR4004 (2.5-10 mg/kg, i.p.) displayed a dose-dependent decrease in locomotor activity by moving less distance in the hole-board, and statistically significant decreases were observed at 5 and 10 mg/kg. On the other hand, DR4004 (10 mg/kg, i.p.) did not affect spontaneous motor activity. In a neurochemical study, decreases in amygdaloid dopamine and 5-HT turnover were observed in mice in which locomotor activity in the hole-board test was attenuated following the administration of DR4004 (10 mg/kg, i.p.). Also, a simple linear regression analysis revealed that locomotor activity on the hole-board was significantly correlated with dopamine and 5-HT turnover in amygdala. Furthermore, co-injection of the selective dopamine reuptake inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine (GBR12909; 1.25-5 mg/kg, i.p.) or the selective 5-HT reuptake inhibitor fluvoxamine (20 mg/kg, i.p.) significantly reversed the DR4004 (10 mg/kg, i.p.)-induced decrease in locomotor activity in the hole-board test. These findings constitute the behavioral evidence that 5-HT(7) receptors may play a role in the modulation of emotionality. Furthermore, it is also suggested that amygdaloid dopamine and 5-HT neuronal systems may be involved in this modulation.

PMID: 16002064

So antagonism at the 5-HT7 receptor decreases dopamine and serotonin release and 'emotionality'. Maybe a 5-HT7 agonist would then increase DA and 5-HT release and emotionality, which would equal to a MDMA-like effect? Here are the tools to achieve this:

Bioorg Med Chem Lett. 2005 Jul 4; [Epub ahead of print]

Phenylpyrroles, a new chemolibrary virtual screening class of 5-HT(7) receptor ligands.

Paillet-Loilier M, Fabis F, Lepailleur A, Bureau R, Butt-Gueulle S, Dauphin F, Delarue C, Vaudry H, Rault S.

Centre d'Etudes et de Recherche sur le Medicament de Normandie, Universite de Caen, UFR des Sciences Pharmaceutiques, 5, rue Vaubenard 14032 Caen Cedex, France.

Virtual screening studies have identified a series of phenylpyrroles as novel 5-HT(7) receptor ligands. The synthesis and the affinity for the 5-HT(7) receptor of these phenylpyrroles are described. Some of these compounds exhibited high affinity for the 5-HT(7) receptors.

PMID: 16002287

However, messing with the 5-HT7 receptor might have some unwanted effects on the immune system:

Neuropharmacology. 2005 Jul;49(1):40-7.

Serotonin 5-HT(7) receptors coupled to induction of interleukin-6 in human microglial MC-3 cells.

Mahe C, Loetscher E, Dev KK, Bobirnac I, Otten U, Schoeffter P.

Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, WSJ-386.7.44, CH-4002 Basel, Switzerland.

Brain serotonin 5-HT(7) receptors are known to be expressed in neurons and astrocytes. We now report the presence of these receptors in a third type of cell, microglial cells. 5-Hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induced concentration-dependent stimulations of cAMP accumulation in the human microglial MC-3 cell line. The maximal effect of 5-HT was 3.4+/-0.3-fold stimulation (mean+/-S.E.M., n=5) above basal levels. The rank order of agonist potency (pEC(50) values) was 5-CT (7.09)>5-HT (6.13)>/=5-MeOT (5.78)>>8-OH-DPAT (ca. 5). The effect of 5-CT was inhibited in a concentration-dependent manner by the selective 5-HT(7) receptor antagonist SB-269970 (pA(2) value 9.03). Western blot analysis revealed the presence of immunoreactive bands corresponding to the human 5-HT(7) receptor in extracts of MC-3 cells. The presence of two splice variants of the 5-HT(7) receptor (5-HT(7(a/b))) was visualized by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis with specific primers. In real-time PCR studies, the mRNA for interleukin-6 (IL-6) was found to be increased by 2.5-fold in MC-3 cells after 1 h incubation with 5-CT (1 muM) and this effect was fully blocked by the 5-HT(7) receptor antagonist SB-269970 (1 muM). These data show that functional 5-HT(7) receptors are present in human microglial MC-3 cells, suggesting that they are involved in neuroinflammatory processes.

PMID: 15992579

 

[BilZ0r]

5-HT7 selective ligands? I didn't even know you could get those. I can't believe the EJP published "5-HT(7) receptors may play a role in the modulation of emotionality". Damn behavioural pharmacologists.

I'm keen to see the effects of the ole 5-HT6 receptor...

 

[C6H6]

I'm keen to see the effects of the ole 5-HT6 receptor...

Pharmacol Ther. 2005 Jul 6; [Epub ahead of print]

5-HT(6) receptors: a novel target for cognitive enhancement.

Mitchell ES, Neumaier JF.

University of Washington, Box 359911, Harborview Medical Center, 325 9th Avenue, Seattle, WA 98104, USA.

Over the past decade, there has been increasing interest in the role of serotonin 6 (5-HT(6)) receptors in higher cognitive processes such as memory. Polymorphisms of the 5-HT(6) receptor have been implicated in syndromes that affect cognition, such as schizophrenia and dementia. Manipulation of 5-HT(6) receptor activity alters the transmission of several neurotransmitters important in memory: acetylcholine and glutamate, as well as dopamine, a-aminobutyric acid (GABA), epinephrine (E), and norepinephrine (NE). Several 5-HT(6) antagonists have been developed, advancing the understanding of the relationship between 5-HT(6) blockade and memory consolidation in diverse learning paradigms. There is also evidence that 5-HT(6) receptor activity affects anxiety behaviors and may be involved in the pathophysiology of schizophrenia. Several clinically useful atypical antipsychotics and antidepressants have 5-HT(6) affinity, but recently developed selective 5-HT(6) receptor antagonists may present attractive, new therapeutic options for several types of disease states.

PMID: 16005519

 

[101]

Whats the porpose of these receptors? What in our body naturally ant/agonizes these (sub)receptors?

Theres 12 different subreceptors for the 5ht right, but a substance our body produces (serotonin) only reacts with the one receptor? What the hell are the other ones for??

 

[BilZ0r]

So serotonin can act in completely different ways in different parts of the brain. And there are 16 subtypes.

Think of it in the body, with the adrenoreceptors. If you only have one adrenoreceptor, the alpha receptor. When adrenaline got released, all of your blood vessels would tighten up. If an animal mutated, so that some of those alpha receptors, changed, to cause blood vessels to relax, that animal could have an advantage if these new receptors were located on muscles. Now when the animal gets an adrenaline surge, lots of blood goes to it muscles. And that's what we have, alpha receptors located on gut blood vessels, and beta adrenoreceptors located on muscle blood vessels.

I'm trying to think of an analogy, but I can't.

Of course, serotonin isn't neccesarily released all over the brain at once. Serotonin can be released in certain areas more specifically (I don't know the details on this). However other neurotransmitters are released with exact, temporal and spatial precession.

 

[101]

So serotonin can act in completely different ways in different parts of the brain. And there are 16 subtypes.

Think of it in the body, with the adrenoreceptors. If you only have one adrenoreceptor, the alpha receptor. When adrenaline got released, all of your blood vessels would tighten up. If an animal mutated, so that some of those alpha receptors, changed, to cause blood vessels to relax, that animal could have an advantage if these new receptors were located on muscles. Now when the animal gets an adrenaline surge, lots of blood goes to it muscles. And that's what we have, alpha receptors located on gut blood vessels, and beta adrenoreceptors located on muscle blood vessels.

I'm trying to think of an analogy, but I can't.

Of course, serotonin isn't neccesarily released all over the brain at once. Serotonin can be released in certain areas more specifically (I don't know the details on this). However other neurotransmitters are released with exact, temporal and spatial precession.

I got you, Im just trying to break my mind into more complex stuff like this.