Lorcaserin and CP-809101 reduce motor impulsivity and reinstatement of food seeking behavior in male rats: Implications for understanding the anti-obesity property of 5-HT2C receptor agonists

Higgins, Guy A.; Silenieks, Leo B.; Altherr, Everett B.; MacMillan, Cam; Fletcher, Paul; Pratt, Wayne E.

doi:10.1007/s00213-016-4329-3

Cited by 35 publications

(29 citation statements)

References 86 publications

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“…In the recent study showing that lorcaserin doses of 1 mg/kg and higher decrease oxycodone self-administration (Neelakantan et al 2017), the effects of lorcaserin on food self-administration were not tested. In previous studies of impulsivity, delay discounting was increased by serotonin depletion (Mobini et al 2000) or treatment with the 5-HT 2A/C agonist DOI (Hadamitzky et al 2009), and decreased by the 5-HT 2C/B agonist SER-082 (Talpos et al 2006), but it was not affected by lorcaserin (0.1–0.6 mg/kg) in what appears to be the only previous study where lorcaserin was tested (Higgins et al 2016). It has been proposed that 5-HT 2A and 5-HT 2C receptors have opposing effects, such that impulsivity can be decreased by either a 5-HT 2A antagonist or a 5-HT 2C agonist (Homberg 2012).…”

Section: Discussionmentioning

confidence: 98%

“…It has been proposed that 5-HT 2A and 5-HT 2C receptors have opposing effects, such that impulsivity can be decreased by either a 5-HT 2A antagonist or a 5-HT 2C agonist (Homberg 2012). However, there are clearly different forms of impulsivity (Talpos et al 2006), and lorcaserin might affect premature operant responding more than it affects delay discounting (Higgins et al 2016; Higgins et al 2012). …”

Section: Discussionmentioning

confidence: 99%

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Choice between delayed food and immediate opioids in rats: treatment effects and individual differences

et al. 2017

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Rationale Addiction involves maladaptive choice behavior in which immediate drug effects are valued more than delayed nondrug rewards. Objectives and Methods To model this behavior and extend our earlier work with the prescription opioid oxycodone, we allowed rats to choose between immediate intravenous delivery of the short-acting opioid remifentanil and delayed delivery of highly palatable food pellets. Treatment drugs were tested on a baseline where remifentanil was preferred over food. Results Treatment with a high dose of the opioid antagonist naltrexone decreased but did not reverse the preference for remifentanil. Treatment with the serotonin 5-HT2C agonist lorcaserin decreased remifentanil and food self-administration nonselectively. Across conditions in which the alternative to delayed food was either a moderate dose of oxycodone, a moderate or high dose of remifentanil, a smaller more immediate delivery of food, or timeout with no primary reinforcement, choice was determined by both the length of the delay and the nature of the alternative option. Delayed food was discounted most steeply when the alternative was a high dose of remifentanil, which was preferred over food when food was delayed by 30 s or more. Within-subject comparisons showed no evidence for trait-like impulsivity or sensitivity to delay across these conditions. Conclusions Choice was determined more by the current contingencies of reinforcement than by innate individual differences. This finding suggests that people might develop steep delay-discounting functions because of the contingencies in their environment, and it supports the use of contingency management to enhance the relative value of delayed non-drug reinforcers.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Choice between delayed food and immediate opioids in rats: treatment effects and individual differences

et al. 2017

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“…Nonetheless, neither study provides data to question the hypothesis of the present work and that of Martin et al (19) that 5-HT 2C receptor agonists prevent OCD-like behaviors and do so as a result of interaction with 5-HT 2C receptors. Indeed, lorcaserin (Belviq ® ), a drug approved for control of obesity, reduced impulsive behaviors (premature responses or reducing false alarms) in rats as did another selective 5-HT 2C receptor agonist CP-809101 (25). The data suggested to Higgins and coauthors that the actions of lorcaserin might be to impede relapse to eating as an impulse control brake.…”

Section: Discussionmentioning

confidence: 99%

Behavioral Effects of a Novel Benzofuranyl-Piperazine Serotonin-2C Receptor Agonist Suggest a Potential Therapeutic Application in the Treatment of Obsessive–Compulsive Disorder

et al. 2017

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Selective serotonin reuptake inhibitors (SSRIs) are the only effective pharmacological treatments for obsessive–compulsive disorder (OCD). Nonetheless, their generally limited efficacy, side-effects, and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT2C) receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5-HT2C receptor agonist ((3S)-3-Methyl-1-[4-(trifluoromethyl)-7-benzofuranyl]-piperazine) (CPD 1) with high potency and full efficacy at 5-HT2C receptors and less potency and partial agonism at 5-HT2A and 5-HT2B receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats) and non-consummatory behaviors (marble-burying and nestlet-shredding in mice) that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine, and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia). The effects of fluoxetine, but not of d-amphetamine, were prevented by the selective 5-HT2C receptor antagonist SB242084. The 5-HT2C receptor agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet-shredding in mice at doses that did not affect rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors suggests a potential therapeutic application in OCD.

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“…Thereby, the size of meals is reduced [121]. Some effects of 5-HT are also indirect, acting on dopamine systems via 5-HT 2C R in cortical and subcortical areas [129][130][131] to reduce the reinforcing features of food and/or to impede impulsive behavior targeting food [132,133]. The stimulation of 5-HT 4 R may also inhibit feeding behavior in rodents, likely via its action at the level of the nucleus accumbens [134,135].…”

Section: Feedingmentioning

confidence: 99%

Serotonin in Animal Cognition and Behavior

Bacqué-Cazenave

Bharatiya

Barrière

et al. 2020

IJMS

216

111

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Serotonin (5-hydroxytryptamine, 5-HT) is acknowledged as a major neuromodulator of nervous systems in both invertebrates and vertebrates. It has been proposed for several decades that it impacts animal cognition and behavior. In spite of a completely distinct organization of the 5-HT systems across the animal kingdom, several lines of evidence suggest that the influences of 5-HT on behavior and cognition are evolutionary conserved. In this review, we have selected some behaviors classically evoked when addressing the roles of 5-HT on nervous system functions.In particular, we focus on the motor activity, arousal, sleep and circadian rhythm, feeding, social interactions and aggressiveness, anxiety, mood, learning and memory, or impulsive/compulsive dimension and behavioral flexibility. The roles of 5-HT, illustrated in both invertebrates and vertebrates, show that it is more able to potentiate or mitigate the neuronal responses necessary for the fine-tuning of most behaviors, rather than to trigger or halt a specific behavior. 5-HT is, therefore, the prototypical neuromodulator fundamentally involved in the adaptation of all organisms across the animal kingdom.The organization of the 5-HT systems is completely different between species ranging from a limited number of cells in Aplysia or Drosophila (100 5-HT immunoreactive cells) to several thousand neurons in vertebrates. The variety and the heterogeneity of 5-HT neurons have been highlighted in vertebrates [7] as well as in invertebrates [8]. In general, the 5-HT systems in animals comprise 5-HT neurons, which share a particular shape made of thousands of varicosities, leading to the concept of volume transmission [9], and several 5-HT receptors (5-HTRs). In vertebrates, 5-HT neurons are localized in the midbrain raphe nuclei described as the B1-B9 cell groups [1,10]. The raphe pallidus, obscurus, and pontis form a caudal cluster (B1-B5), whereas the dorsal raphe and median raphe form a rostral cluster in the pons (B6-B9) [11]. The caudal raphe group projects to the spinal cord and the rostral group to the forebrain via an extensive and diffuse innervation. The dorsal raphe nucleus contains the highest number of 5-HT neurons and its anatomical sub-regions display some degrees of specific innervation of the forebrain [12][13][14]. The median and dorsal raphe nuclei receive excitatory and inhibitory inputs from most brain areas [15]. In crustaceans or insects, 5-HT neurons are widely present in each of the ventral cord ganglia, display large local ramifications that act in multiple neuropil areas, and some axonal branches form three pairs of rostrocaudal fibers [16][17][18][19]. Presumably, two of those fibers would project anteriorly and one posteriorly to the entire nervous system [20]. 5-HT neurons are often localized close to sensory integration input area in the brain of arthropods and some 5-HT cells in the abdominal ganglia of crayfish nerve cord are sensitive to the mechanical stimulation of abdominal segmental fringe hairs [21]. In cnidarians, 5-HT cells ...

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Lorcaserin and CP-809101 reduce motor impulsivity and reinstatement of food seeking behavior in male rats: Implications for understanding the anti-obesity property of 5-HT2C receptor agonists

Cited by 35 publications

References 86 publications

Choice between delayed food and immediate opioids in rats: treatment effects and individual differences

Choice between delayed food and immediate opioids in rats: treatment effects and individual differences

Behavioral Effects of a Novel Benzofuranyl-Piperazine Serotonin-2C Receptor Agonist Suggest a Potential Therapeutic Application in the Treatment of Obsessive–Compulsive Disorder

Serotonin in Animal Cognition and Behavior

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