Despite considerable research as summarized
in several thorough reviews on serotonin type-6
(5-HT6) receptor physiopharmacology within the
past decade the functional role of 5-HT5
receptors remains ambiguous. For example, it is
not yet understood why putative 5-HT5 receptor
agonists and antagonists may share some odd
similarities in their pharmacological
properties, as in the case of their potential
antidepressant Underlying some of these
behavioral discrepancies are, we believe,
ambiguous results on some basic aspects of 5-HT5
receptor pharmacology. The discrepancies in the
literature began even before the identification
of selective 5-HT5 receptor ligands, in work
with antisense oligonucleotides to critical
portions of the 5-HT6 receptor.
2. A 5-HT6 behavioral syndrome
(yawning,
stretching and chewing)?
A particular behavior syndrome resulting
from blockade of 5-HT5 receptors was
characterized by Bourson et al. (1995). Lacking
selective 5-HT6 receptor antagonists, Bourson et
al. (1995) utilized 5-HT antisense
oligonucleotides (AO) complementary to bases
into 18 of the rat 5-HT6 cDNA. After
intracerebroventricular oligonucleotide
administration twice a day at 6 or 12 pg/rat for
four days, AO-treated animals displayed a
dose-dependent specific behavioral syndrome
consisting of yawning, stretching and chewing 16
h after the final treatment, which continued for
the following 7-8 days. This syndrome was
dose-dependently attenuated by the
antimuscarinic compound atropine, but unaffected
by the dopamine antagonist haloperidol.
Food-intake, body temperature, body weight, and
heat sensitivity were unchanged by AO
administration. The regimen of AU treatment was
found to reduce the number of 5-HT5 receptors by
30% in the frontal cortex, without modifying
5-HT1A and 5-HT2A receptor binding sites. AU
administration also did not affect striatal
dopamine and DOPAC levels.
However, subsequently the same group
reported that intracerebreventricular AU for
5-HT6 receptors reduced body weight and food
intake, in apparent contrast to their prior
publication. Moreover, Yoshioka et al. (1998)
administered intracerebroventricularly 14
pg/rat/day AU with an osmotic pump for 7 days
and also found a reduction in 5-HT6 receptors by
30% in membranes coming from whole brain, with
no specific behavioral signs observed after AO
administration. Similarly, Hamon et al. (1999)
and Utano et al. (1999) with AU administration
regimens lasting 4-7 days also did not observe
the specific behavioral syndrome first reported
by Bourson et al. (1995). Several years later,
Wolley et al. (2001) again found no evidence of
the specific behavioral syndrome after AO twice
daily for 6 days, and again in contrast to the
initial Bourson et al. (1995) results, they
reported an effect on food intake and body
weight reduction after AU administration.
Using the selective 5-HT5 antagonist
Ro04-6790, stretching and chewing were observed
but not yawning. Similar observations were made
by other researchers at Hoffman-LaRoche, by
using a different 5-HT5 receptor antagonist (Bos
et al., 2001). Lindner et al. (2003) found that,
in contrast to cholinesterase inhibitor
physostigmine, Ro04-6790 and the other 5-HT6
receptor antagonist SB-271046 induced
stretching, whereas chewing was increased by
Ro04-6790 and physostigmine but not by
SB-271046; neither Ro04-6790 nor SB-271046 nor
physostigmine modified yawning. Marcos et al.
(2008) found that oral SB-271046 induced
yawning, a behavior that was also maintained
after 7 days of repeated administrations.
However, no behavioral syndrome was observed by
Reavill and Rogers (2001) with SB-271046, as
well as by Stean et al. (2002) after oral
SB-357134 (at doses ranging between 0.1 and 30
mg/kg, either after single or 7-day
administration). Compound 4, a claimed 5-HT5
receptor antagonist, also failed to induce
yawning, stretching and chewing (Russell and
Diaz, 2002).
Although the majority of results with AU
showed that rats did not display the behavioral
syndrome, some of the studies with 5-HT6
receptor antagonists indicate the induction of
at least some elements of the behavioral
syndrome with the drugs tested. However, in
general, the overall behavioral syndrome
(stretching, yawning and chewing) is not a
consistent phenomenon observed with either AO or
5-HT6 receptor antagonists in rats. This points
out how the interpretation of the interaction
between ligands and 5-HT5 receptors may possibly
defect of better understanding of 5-HT6 receptor
ligands, both in their pharmacodynamic and
pharmacokinetics/metabolic properties.
6. Conclusions
Although experimental inconsistencies also
exist for other 5-HT receptors, i.e. 5-HT1A and
5-HT2, the marked paucity of information on
5-HT6 receptors, due to the insufficient data on
5-HT5 receptor ligands, particularly hampers our
understanding of 5-HT5 receptor
pharmacology.
However, the picture of 5-HT5 receptors is
more complex than expected, as their interaction
with 5-HT6 ligands might also depend on
neuroanatomical region. In fact, there is even a
report that shows that the up-regulation in
activity-regulated cytoskeleton-associated
protein (Arc) mRNA expression caused by
subcutaneous administration of the purported
agonist LY586713 is blocked by the subcutaneous
administration of the antagonist/inverse agonist
SB-27 1046 in hippocampus and parietal cortex
but not in cingulate and orbital cortex.
Moreover, in the latter brain regions, the
antagonist SB-27 1046 increased Arc mRNA
expression similarly to the agonist LY-586713.
Thus, regional brain differences also may then
account for some of the inconsistencies. Such
regional difference may well account for the
discrepancies in microdialysis studies as well.
Additionally, it remains to document whether the
G proteins linked to 5-HT6 receptors are
differently expressed in the different brain
regions.
In the field of 5-HT6 receptors there are
several inconsistent findings in need of further
study. We think that experimental and procedural
flaws might be, at least in part, at the source
of these inconsistencies and such
inconsistencies could be avoided if some
precautions were taken. These include: 1) the
use of different radioligands which can provide
quite different results in affinity
characterization studies; 2) the use of
different tissues receptor density and
biochemical readouts as these may affect the
definition of a compound as silent antagonist,
agonist or inverse agonist: 3) more information
on possible active metabolites and/or
pharmacokinetic differences across compounds
that may produce vastly different in vivo
neurochemical and behavioral profiles; and 4)
more information on receptor selectivity.
Additionally, only very few studies use a
5-HT6 receptor antagonist to block the effect of
an 5-HT6 receptor agonist. The reverse (5-HT6
receptor agonist against an effect mediated by
5-HT6 receptor antagonist) has never been
assessed. If the 5-HT6 ligands competitively
bind to the same site, the effect of an agonist
should be counteracted by an antagonist, and
vice versa.
