Lorcaserin is approved by the Food and Drug
Administration for treating obesity and its
therapeutic effects are thought to result from
agonist activity at serotonin (5-HT)2C
receptors. Lorcaserin has affinity for other
5-HT receptor subtypes, although its activity at
those subtypes is not fully described.
The current study compared the behavioral
effects of lorcaserin (0.0032-32.0 mg/kg) to the
effects of other 5-HT receptor selective
agonists in rats (n=8).
The 5-HT2C receptor selective agonist mCPP
(0.032 - 1.0 mg/kg) and lorcaserin induced
yawning that was attenuated by the 5-HT2C
receptor selective antagonist SB 242084 (1.0
mg/kg). The 5-HT2A receptor selective agonist
DOM (0.1-3.2 mg/kg) induced head twitching that
was attenuated by the 5-HT2A receptor selective
antagonist MDL 100907 (0.01 mg/kg), lorcaserin
(3.2 mg/kg), and mCPP (3.2 mg/kg). In rats
pretreated with 5-HT2C SB 242084 (1.0 mg/kg),
lorcaserin also induced head twitching. At
larger doses, lorcaserin produced forepaw
treading that was attenuated by the 5-HT1A
receptor selective antagonist WAY 100635 (0.178
mg/kg). While the behavioral effects of
lorcaserin in rats are consistent with it having
agonist activity at 5-HT2C receptors, these data
suggest that, at larger doses, it also has
agonist activity at 5-HT2A and possibly 5-HT1A
receptors. Mounting evidence suggests that
5-HT2C receptor agonists might be effective for
treating drug abuse.
A more complete description of the activity
of lorcaserin at 5-HT receptor subtypes will
facilitate a better understanding of the
mechanisms that mediate its therapeutic
effects.
Résumé
La Lorcaserin est approuvée par la
Food and Drug Administration pour le traitement
de l'obésité. Ses effets
thérapeutiques sont sensés
résulter d'une activité agoniste
sur les récepteurs de la
sérotonine (5-HT) 2C. Lorcaserin a une
affinité pour les autres sous-types de
récepteurs 5-HT, mais son activité
sur ces sous-types ne sont pas
complètement décrits.
La présente étude a
comparé les effets comportementaux de la
Lorcaserin (0,0032 à 32,0 mg / kg)
à des effets d'autres agonistes
sélectifs des récepteurs 5-HT chez
les rats (n = 8).
L'agoniste sélectif des
récepteurs 5-HT2C, le mCPP (0,032 - 1,0
mg / kg) et la Lorcaserin induisent des
bâillements qui sont réduits par
l'agoniste sélectif des récepteur
5-HT2C, le SB 242084 (1,0 mg / kg).
L'agoniste sélectif des
récepteurs 5-HT2A, le DOM (0,1 à
3,2 mg / kg) induit des mouvements de dystonie
du cou et de la tête qui ont
été atténués par
l'agoniste sélectif des récepteurs
5-HT2A, le MDL 100907 (0,01 mg / kg), la
Lorcaserin (3,2 mg / kg), et la mCPP ( 3,2 mg /
kg).
Chez les rats prétraités avec
5-HT2C SB 242084 (1,0 mg / kg), la Lorcaserin a
également induit des hochements de
tête. A des doses plus importantes, la
Lorcaserin produit mouvements de grattage par
les pattes qui ont été
atténués par l'agoniste
spécifique des récepteurs 5-HT1A
le WAY __100635 (0,178 mg / kg).
Bien que les effets comportementaux de la
Lorcaserin chez le rat soient comparables
à ceux d'autres agonistes des
récepteurs 5-HT2C, ces données
suggèrent qu'à des doses plus
élevées, la Locaserin
possède également une
activité agoniste au niveau des
récepteurs 5-HT2A et
éventuellement des récepteurs
5-HT1A.
Les preuves s'accumulent suggèrant
que les agonistes des récepteurs 5-HT2C
pourraient être efficaces pour le
traitement de l'abus de drogues. Une description
plus complète de l'activité des
sous-types de la Lorcaserin sur les
différents récepteurs 5-HT
permettra de mieux comprendre les
mécanismes qui assurent la
médiation de ses effets
thérapeutiques.
Introduction
Lorcaserin (Belviq®; Smith et al., 2008)
was recently approved by the United States Food
and Drug Administration for treating obesity
(Coleman et al., 2012). The therapeutic effects
of lorcaserin are thought to be due to agonist
activity at serotonin (5-HT)2C receptors. Drugs
that have agonist activity at 5-HT2C receptors
decrease food intake in rats (Clifton et al.,
2000; Kennett and Curzon, 1991; Vickers et al.,
2001a) and they have long been considered for
treating obesity (for a review see Bickerdike,
2003). Agonists acting at 5-HT2C receptors have
other behavioral effects in rats. For example,
the prototypical 5-HT2C receptor agonist mCPP
induces yawning and penile erections (Protais et
al., 1995; Kennett and Curzon, 1988). In
addition to 5-HT2C receptors, lorcaserin also
has affinity for other 5-HT receptor subtypes,
including 5-HT2A, 5-HT2B, and 5-HT1A (Thomsen et
al., 2008). Although lorcaserin has been shown
to have efficacy at 5-HT2A receptors in vitro
(Thomsen et al., 2008), it is unclear whether
lorcaserin has agonist properties in vivo that
are mediated by 5-HT2A receptors. In humans,
drugs with agonist effects at 5-HT2A receptors
are sometimes abused and can produce
hallucinations (Kennett and Clifton, 2010). In
rodents, drugs with agonist activity at 5-HT2A
receptors (e.g., DOI, DOM and LSD) induce a
characteristic head twitch responding (Corne et
al., 1963; Fantegrossi et al., 2010; Darmani et
al., 1992; for a review see Canal and Morgan,
2012). One study compared the behavioral effects
of lorcaserin to DOI, a prototypic 5-HT2A
receptor selective agonist (Thomsen et al.,
2008); lorcaserin did not produce behavioral
effects like those produced by DOI (e.g., wet
dog shakes and back contractions) suggesting
that lorcaserin does not have agonist activity
at 5-HT2A receptors.
Several decades of preclinical research
suggest that 5-HT2C receptor agonists might be
effective for treating substance use disorders
(for a review see Howell and Cunningham, 2015).
For example, 5-HT2C receptor agonists can
attenuate the positive reinforcing effects of
cocaine, as well as reinstatement of responding
by cocaine and cocaine-associated stimuli
(Anastasio et al., 2011; Burbassi and Cervo,
2008; Callahan and Cunningham, 1995; Cunningham
et al., 2012) nicotine self-administration in
rats (Higgins et al., 2012), and clinical trials
were recently initiated to investigate
lorcaserin for smoking cessation
(Clinicaltrials.gov).
Despite having been approved for treating
obesity, the pharmacological profile of
lorcaserin has yet to be fully described. This
study tested the hypothesis that in rats the
behavioral effects of lorcaserin are due to its
agonist actions at 5-HT2C receptors by examining
directly observable behavior induced by
lorcaserin and comparing those effects to
behavior induced by prototypic agonists that
have selectivity for particular 5-HT receptor
subtypes. In order to determine the receptor
subtypes mediating the behavioral effects of
these drugs, agonists were also examined in
combination with 5-HT receptor subtype selective
antagonists. Lastly, lorcaserin was also
examined in combination with other agonists, in
instances when a particular behavior was not
observed with lorcaserin alone, to test whether
it had antagonist properties at specific 5-HT
receptor subtypes.
Discussion
Lorcaserin has highest affinity for 5-HT2C
receptors, although it also binds to other 5-HT
receptor subtypes and at still higher
concentrations to the 5-HT transporter (Thomsen
et al., 2008). It is well established that many
of the behavioral effects of lorcaserin are
mediated by agonist activity at 5-HT2C
receptors. For example, lorcaserin decreases
food intake in rats and that effect is prevented
by the 5-HT2C receptor selective antagonist SB
242084 (Thomsen et al, 2008). In the present
study, lorcaserin increased yawning as well as
other behavioral effects (e.g., penile erections
and grooming, both of which were observed but
not recorded) that are produced by drugs with
agonist activity at 5-HT2C receptors (Kennett
and Curzon, 1988; Protais et al., 1995). When
administered alone, lorcaserin did not produce
head twitching; however, lorcaserin
significantly increased head twitching in rats
that were pretreated with the 5-HT2C receptor
selective antagonist SB 242084. Drugs with
agonist activity at 5-HT2A receptors increase
head twitching (Canal and Morgan, 2012). At
doses larger than those producing head
twitching, lorcaserin induced forepaw treading,
an effect produced by drugs with agonist
activity at 5-HT1A receptors (Haberzetti et al.,
2013). These results extend an earlier study
(Thomsen et al., 2008) by confirming in vivo
agonist properties of lorcaserin that appear to
be mediated by 5- HT2C receptors and by
demonstrating other agonist properties of
lorcaserin that appear to be mediated by 5-HT2A
and 5-HT1A receptors.
The prototypical 5-HT2C receptor agonist
mCPP as well as lorcaserin produced yawning that
was attenuated by the 5-HT2C receptor selective
antagonist SB 242084, suggesting that yawning
induced by both drugs is mediated by agonist
activity at 5-HT2C receptors. When administered
alone, up to a cumulative dose of 32.0 mg/kg,
lorcaserin did not induce head twitching. These
data are consistent with a previous report
(Thomsen et al., 2008) in which lorcaserin,
administered via oral gavage, did not share
behavioral effects with the prototypic 5- HT2A
receptor selective agonist DOI (e.g., wet dog
shakes, back contractions).
Lorcaserin did not produce head twitching
when administered alone, although it attenuated
head twitching produced by the 5-HT2A receptor
selective agonist DOM. The dose- response curve
for head twitching produced by DOM or by other
5-HT2A receptor selective agonists (e.g., DOI)
is an inverted U-shape, with the ascending limb
of the curve being mediated by 5-HT2A receptors
and the descending limb by 5-HT2C receptors
(Vickers et al., 2001b; Fantegrossi et al.,
2010; see Canal and Morgan, 2012 for a review).
Thus, it was possible that attenuation of
DOM-induced head twitching by lorcaserin could
have resulted from agonism at 5-HT2C receptors,
from antagonism at 5-HT2A receptors, or from
both mechanisms. Similarly, that lorcaserin did
not induce head twitching when administered
alone could have occurred either because it does
not have agonist activity at 5-HT2A receptors or
because its agonist activity at 5-HT2C receptors
inhibits the expression of (masks)
5-HT2A-receptor mediated head twitching. When
administered in combination with the 5-HT2C
receptor selective antagonist SB 242084,
lorcaserin significantly increased head
twitching. This result suggests that lorcaserin
has agonist activity at both 5-HT2C and 5-HT2A
receptors and that its agonist activity at
5-HT2C receptors can inhibit the expression of a
behavior (i.e., head twitching) that is thought
to be mediated by agonist activity at 5-HT2A
receptors. The minimally effective dose of
lorcaserin to induce head twitching in rats was
1.78 mg/kg, whereas the therapeutic dose for
treating obesity is 10 mg twice daily (i.e.,
0.29 mg/kg for a 70 kg human). Lorcaserin is
under evaluation for its potential in treating
substance use disorders (e.g., tobacco smoking,
cocaine use disorder) and it is unclear whether
the therapeutic dose of lorcaserin for treating
obesity will be effective for treating substance
abuse disorders. Any agonist activity of
lorcaserin at other 5-HT receptor subtypes
(e.g., 5-HT2A) might be particularly important
when considering its possible use in treating
individuals with a history of substance use
disorder.
Indirect-acting 5-HT receptor agonists
(e.g., selective 5-HT reuptake inhibitors
[SSRIs]) as well as direct-acting 5-HT
receptor agonists that are selective for 5-HT1A
receptors (e.g., 8- OH-DPAT) produce a
characteristic pattern of behavioral effects in
rats that includes forepaw treating, lower lip
retraction, and flat body posture (for a review
see Haberzetti et al., 2013). In the current
study, 8-OH-DPAT produced forepaw treading,
lower lip retraction, and flat body posture (see
Li and France, 2008 for similar results using
i.p. cumulative dosing). In contrast, lorcaserin
produced forepaw treading but not lower lip
retraction or flat body posture. Other results
from this study (see above) suggest that
lorcaserin has agonist activity at both 5-HT2C
and 5-HT2A receptors and it is possible that
activity at those 5-HT receptor subtypes
inhibits the expression of (masks) lower lip
retraction and flat body posture. Consistent
with this possibility, both 5-HT2C receptor
agonists (mCPP) as well as 5-HT2A receptor
agonists (DOI) attenuate 8- OH-DPAT-induced
lower lip retraction (Berendsen et al., 1989).
In the present study, pretreatment with the
nonselective 5-HT2 receptor antagonist
ritanserin did not significantly impact
lorcaserin-induced forepaw treading; however,
doses that failed to produce any flat body
posture when lorcaserin was administered alone,
caused significant, dose-related increases in
flat body posture in rats that were pretreated
with ritanserin, suggesting that activity of
lorcaserin at 5-HT2 receptors might prevent the
expression of a behavior (i.e., flat body
posture) that is thought to be mediated by
agonist activity at 5-HT1A receptors. Lower lip
retraction was not observed with lorcaserin
alone or in combination with ritanserin.
In summary, these results provide further
evidence that lorcaserin has agonist activity at
5-HT2C receptors, the site of action that is
thought to be important for its therapeutic
actions (i.e., treating obesity). However, in
addition to agonist activity at 5-HT2C
receptors, these results also provide evidence
that lorcaserin has agonist activity (in vivo)
at 5-HT2A and 5-HT1A receptors. Moreover, the
rank order potency of lorcaserin for producing
yawning (5-HT2C receptor mediated), head
twitching (5-HT2A receptor mediated), forepaw
treading and flat body posture (5-HT1A receptor
mediated) is the same as its rank order binding
affinities for these 5- HT receptor subtypes
(Thomsen et al., 2008). It is unclear whether
actions at these 5-HT receptor subtypes might
contribute to the adverse effects that can occur
with lorcaserin. Lorcaserin is a controlled
substance (Drug Enforcement Administration
Schedule IV) and its adverse effects include
hallucinations and euphoria (www.belviq.com;
United States Food and Drug Administration,
2012). Overweight patients receiving lorcaserin
are also encouraged to diet and exercise. Food
restriction decreases sensitivity of rats to
some of the behavioral effects of drugs acting
on 5-HT receptors (Li and France, 2008; Serafine
and France, 2014); it is possible that food
restriction and resulting body weight changes
might also impact the therapeutic and/or adverse
effects of lorcaserin. Finally, lorcaserin is
under evaluation for smoking cessation and for
treating cocaine abuse; results of the current
study underscore the importance of full
characterizing the behavior profile of
lorcaserin in order to identify any effects that
could be problematic for individuals with a
history of substance use disorder (e.g., 5-HT2A
agonist activity). A better understanding of the
mechanisms of action of lorcaserin at 5-HT
receptor subtypes might also facilitate the
development of new, improved drugs for treating
obesity as well as substance use disorders.
