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Fetal yawning assessed by 3D and 4D sonography
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mise à jour du
22 septembre 2015
J Pharmacol Exp Ther
2015;335(2):
Directly observable behavioral effects
of lorcaserin in rats
Serafine KM, Rice K, France CP.
 

Chat-logomini

 
Abstract
 
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.