From obesity to substance abuse: therapeutic opportunities for 5-HT2C receptor agonists

Higgins, Guy A.; Sellers, Edward M.; Fletcher, Paul

doi:10.1016/j.tips.2013.08.001

Cited by 90 publications

(72 citation statements)

References 109 publications

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“…Unlike typical pharmacotherapies for drug abuse, which often target the primary site of action of the abused drug (e.g., methadone and naltrexone, both acting at m-opioid receptors, for treating opioid addiction), it is also possible to reduce abuse-related effects through actions at sites other than the primary site of action of the abused drug. Because of their role in modulating dopamine neurotransmission, 5-HT 2C receptors have received considerable attention as a potential target for treating cocaine abuse (Higgins et al, 2013a;Higgins and Fletcher, 2015;Howell and Cunningham, 2015); however, the relative lack of highly selective compounds has limited a full characterization of the effectiveness of 5-HT 2C receptor agonists to reduce cocaine self-administration. Lorcaserin is 18-and 100-fold selective for 5-HT 2C over 5-HT 2A and 5-HT 2B receptors, respectively (Thomsen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys

Collins

Gerak

Javors

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Cocaine abuse and obesity are serious public health problems, and studies suggest that both dopamine and serotonin systems are involved in regulating the consumption of drugs and food. Lorcaserin has serotonin (5-HT) 2C receptor agonist actions, is approved by the U.S. Food and Drug Administration for treating obesity, and might be effective for treating cocaine abuse. These studies characterized the pharmacokinetic and behavioral profiles of lorcaserin (intragastric administration) and determined the effectiveness of lorcaserin to alter discriminative stimulus and reinforcing effects of cocaine (intravenous administration) in rhesus monkeys. Administered acutely, lorcaserin dosedependently increased the occurrence of yawning while decreasing spontaneous activity and operant responding for food. These effects appeared within 30-60 minutes of administration and began to dissipate by 240 minutes, a time course closely matching plasma concentrations of lorcaserin. In monkeys discriminating cocaine from saline, lorcaserin alone did not occasion cocaine-appropriate responding but shifted the cocaine dose-response curve to the right and down in two of three monkeys. When administered acutely, lorcaserin dosedependently decreased the rate at which monkeys responded for infusions of cocaine. When administered chronically, 3.2 mg/kg lorcaserin reduced the rate of cocaine-maintained responding by 50% for the duration of a 14-day treatment period. Together, these results show that lorcaserin attenuates the discriminative stimulus effects of cocaine after acute administration and the reinforcing effects of cocaine after acute and repeated administration, consistent with the view that it might have utility in treating cocaine abuse.

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Section: Discussionmentioning

confidence: 99%

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys

Collins

Gerak

Javors

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…The 5-HT 2C receptor agonist lorcaserin reduces feeding behavior (Grottick et al, 2000) and has been approved for the treatment of obesity. However, the ability of lorcaserin to reduce motivation may extend to nonfood reinforcers: lorcaserin reduces responding for drugs of abuse such as cocaine and nicotine, and prevents reinstatement of responding for these drugs following periods of abstinence (as reviewed by Higgins et al, 2013). A recent study also demonstrates that the 5-HT 2C receptor antagonist SB 242084 enhances motivation under certain circumstances (Bailey et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Decreased Incentive Motivation Following Knockout or Acute Blockade of the Serotonin Transporter: Role of the 5-HT2C Receptor

Browne

Fletcher

2016

Neuropsychopharmacol

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Acute pharmacological elevation of serotonin (5-hydroxytryptamine; 5-HT) activity decreases operant responding for primary reinforcers, suggesting that 5-HT reduces incentive motivation. The mechanism by which 5-HT alters incentive motivation is unknown, but parallel evidence that 5-HT 2C receptor agonists also reduce responding for primary reinforcers implicates this receptor as a potential candidate. These experiments examined whether chronic and acute disruptions of serotonin transporter (SERT) activity altered incentive motivation, and whether the 5-HT 2C receptor mediated the effects of elevated 5-HT on behavior. To assess incentive motivation, we measured responding for three different reinforcers: a primary reinforcer (saccharin), a conditioned reinforcer (CRf), and an unconditioned sensory reinforcer (USRf). In the chronic condition, responding was compared between SERT knockout (SERT-KO) mice and their wild-type littermates. In the acute condition, responding was examined in wild-type mice following treatment with 10 or 20 mg/kg citalopram, or its vehicle. The ability of the selective 5-HT 2C antagonist SB 242084 to prevent the effects of SERT-KO and citalopram on responding was subsequently examined. Both SERT-KO and citalopram reduced responding for saccharin, a CRf, and a USRf. Treatment with SB 242084 enhanced responding for a CRf and a USRf in SERT-KO mice and blocked the effects of citalopram on CRf and USRf responding. However, SB 242084 was unable to prevent the effects of SERT-KO or citalopram on responding for saccharin. These results support a powerful inhibitory function for 5-HT in the control of incentive motivation, and indicate that the 5-HT 2C receptor mediates these effects of 5-HT in a reinforcer-dependent manner.

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“…The combined actions of 5-HT and CCK in the PVN may limit the size of a meal by shifting the animal's motivational state from approach to avoidance of the food, the latter expressed by either increased accumbal acetylcholine, which controls dopamine release, or decreased accumbal dopamine [240]. An involvement of the 5-HT2C 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 29 in brain mechanisms of reward has been suggested [366]. This should be further explored in the light of the recent obesity epidemic, as the 5-HT2C receptor could possibly provide a link between homeostatic and non-homeostatic (hedonic) eating [165].…”

Section: Serotonin and The Pharmacotherapy Of Obesitymentioning

confidence: 99%

“…Berthoud synthesised ideas on the regulation of feeding and satiety and pointed out that food intake follows both homeostatic and ('hedonic') mechanisms. Both are not independent, and while nonhomeostatic eating is frequently attributed to the neurotransmitter dopamine, 5-HT is largely seen as a neurotransmitter within the homeostatic system, interactions between 5-HT and dopamine are being discussed, and 5-HT2C receptor agonists generally inhibit rewardrelated behaviours [366,367].…”

Section: Serotonin and The Pharmacotherapy Of Obesitymentioning

confidence: 99%

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

266

167

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Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 IntroductionWhat are the behavioural and physiological mechanisms that promote satiety? How is satiety defined? Satiety can be seen as a behavioural state which arises from food consumption and suppresses the initiation of eating for a particular period of time [1]. This description alone suggests a high degree of complexity as peripheral post-ingestive and post-absorptive signals need to be relayed to the brain where they are integrated with other signals to produce (or not) the behavioural state called satiety. The state of satiety is brought about a process called satiation, where sensory, cognitive and early post-ingestive mechanisms bring feeding to a halt and thus stopping a meal. Promoting satiation alone must not necessarily lead to reduced total food intake as the frequency of meals could be increased subsequently. Many peripheral and brain mechanisms have been identified that are involved in the expression satiety and it has been suggested that serotonin accelerates satiation and prolongs satiety [2]. In the following, we will review the role of serotonin in satiety in more detail 1 . The reader will see that, despite immense progress made during the last years, the field is still far from being resolved.As serotonin (5-Hydroxytryptamine; 5-HT) is a phylogenetically old neurotransmitter, various functions had time to evolve in different phyla, but maybe also in different species. 5-HT receptors exist in animal cells for millions of years and they are as old as adrenoreceptors ore some peptide receptors, possibly even older [5,6]. Even in invertebrates such as molluscs (Aplysia californica) and annelids (Hirudo medicinalis), 5-HT might functionally be related to food intake [7]. 5-HT is involved in feeding even in the honeybee where it has separate effects in the gut and in the insect brain [8]. In general, however, 5-HT seems rather to be involved in appetitive behaviours in invertebrates whereas it has more of a satiating effect in vertebrates [9]. In general, 5-HT neurons seem to be more extensively distributed throughout the body in lower animals than in higher animals including mammals where 5-HT neurones...

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From obesity to substance abuse: therapeutic opportunities for 5-HT2C receptor agonists

Cited by 90 publications

References 109 publications

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys

Decreased Incentive Motivation Following Knockout or Acute Blockade of the Serotonin Transporter: Role of the 5-HT2C Receptor

Serotonin controlling feeding and satiety

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