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Repurposing regulatory agency-approved molecules, with proven safety in humans, is an attractive option for developing new treatments for disease. We identified and assessed the efficacy of 3 drugs predicted by an in silico screen as having the potential to treat l -DOPA-induced dyskinesia (LID) in Parkinson's disease. We analysed ∼1.3 million Medline abstracts using natural language processing and ranked 3539 existing drugs based on predicted ability to reduce LID. 3 drugs from the top 5% of the 3539 candidates; lorcaserin, acamprosate and ganaxolone, were prioritized for preclinical testing based on i) having a novel mechanism of action, ii) having not been previously validated for the treatment of LID, iii) being blood-brain-barrier penetrant and orally bioavailable and iv) being clinical trial ready. We assessed the efficacy of acamprosate, ganaxolone and lorcaserin in a rodent model of l -DOPA-induced hyperactivity, with lorcaserin affording a 58% reduction in rotational asymmetry (P < 0.05) compared to vehicle. Acamprosate and ganaxolone failed to demonstrate efficacy. Lorcaserin, a 5HT2C agonist, was then further tested in MPTP lesioned dyskinetic macaques where it afforded an 82% reduction in LID (P < 0.05), unfortunately accompanied by a significant increase in parkinsonian disability. In conclusion, although our data do not support the repurposing of lorcaserin, acamprosate or ganaxolone per se for LID, we demonstrate value of an in silico approach to identify candidate molecules which, in combination with an in vivo screen, can facilitate clinical development decisions. The present study adds to a growing literature in support of this paradigm shifting approach in the repurposing pipeline. • Novel treatments are needed for l -DOPA-induced dyskinesia in Parkinson's disease. • Natural language processing of published abstracts to identify drugs to repurpose. • 5HT2C agonism is a potential novel mechanism to reduce l -DOPA-induced dyskinesia. • Study supports use of in silico methods in identification of drugs to repurpose. [ABSTRACT FROM AUTHOR]

Lorcaserin (Lorqess, Belviq ® ) is a selective 5-HT 2C receptor agonist that has received FDA approval for the treatment of obesity. 5-HT 2C receptor agonists are also efficacious in decreasing multiple aspects of cocaine motivation and reward in preclinical models. This would suggest that lorcaserin is a clinically available therapeutic with the potential to treat cocaine addiction. Here we report the effects of lorcaserin (0.1 mg/kg–1.0 mg/kg) on multiple aspects of cocaine-related behaviours in rats. We find that lorcaserin dose-dependently decreases cocaine self-administration on progressive and fixed ratio schedules of reinforcement. Lorcaserin also reduces reinstatement of cocaine-seeking behaviour in response to priming injections of cocaine and/or reintroduction of cocaine-associated cues. Finally, lorcaserin dose-dependently decreases cocaine-induced hyperlocomotion. Our results, when considered in concert with similar emergent findings in non-human primates, strongly support continued research into the potential of lorcaserin as a clinical treatment for cocaine addiction. [ABSTRACT FROM AUTHOR]

The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) modulates fundamental motivational processes, and the neurochemical and behavioural effects of drugs of abuse. Recently, attention has focused on the role of 5-HT acting via 5-HT 2A and 5-HT 2C receptor sub-types in this regard. We examined the impact of manipulating 5-HT 2A and 5-HT 2C receptor mediated function on several aspects of alcohol self-administration and alcohol-seeking behaviour in male and female rats. Specifically, experiments investigated the effect of the 5-HT 2A inverse agonist/antagonist pimavanserin, and the 5-HT 2C receptor agonist lorcaserin on these behaviours. In male and female rats trained to respond for alcohol reinforcement on fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement pimavanserin (0.3, 1 and 3 mg/kg) had no consistent effect on responding. Lorcaserin (0.25, 0.5 and 1 mg/kg) reduced these behaviours in both sexes. Following extinction of responding for alcohol, alcohol-seeking was reinstated by cues previously paired with alcohol. Pimavanserin (1 mg/kg) and lorcaserin (0.5 mg/kg) significantly reduced this reinstatement. In a two-bottle 24 h intermittent access procedure pimavanserin had no significant effects, but lorcaserin reduced alcohol consumption in both sexes at 1, 4 and 24 h after access to alcohol was allowed. Finally, as determined using in vivo microdialysis, alcohol increased, and lorcaserin (0.5 mg/kg) reduced, extracellular levels of DA in the NAc in male rats. In rats treated with lorcaserin prior to alcohol injection the net effect was that DA levels were not changed compared to those measured in control rats. These results suggest that blocking 5-HT 2A receptor activity has a very limited action to reduce alcohol-seeking. Activating 5-HT 2C receptors had a broader behavioural profile to reduce alcohol self-administration, alcohol drinking and alcohol seeking. These effects may partly result from a blunting of the effect of alcohol on mesolimbic DA release. • The 5-HT 2C receptor lorcaserin reduced operant responding for alcohol. • Lorcaserin also reduced reinstatement of alcohol seeking, and alcohol drinking. • The 5-HT 2A receptor inverse agonist reduced reinstatement only. • Lorcaserin reduced extracellular DA in nucleus accumbens. • The 5-HT 2C receptor is a potential target for treating alcohol use disorders. [ABSTRACT FROM AUTHOR]

Abstract: 5-HT2C receptor agonists have considerable therapeutic potential, however there is little in vivo data to compare the potency and selectivity of 5-HT2C receptor agonists. Since 5-HT2C receptor agonists reduce locomotor activity and food intake, changes in these drug-induced behaviours in 5-HT2C receptor knockout mice could provide a means to examine receptor selectivity in-vivo. Initially this study compared older 5-HT2C agonists mCPP and MK212, to newer, apparently more selective compounds: Ro 60-0175, WAY161503, CP809,101 and lorcaserin (APD356) on motor activity in wild-type, and 5-HT2C receptor knockout mice. Two 5-HT2C receptor antagonists SB242084 and SDZ SER 082 were also examined. mCPP did not significantly alter activity in wild-type mice, but enhanced activity in knockout animals. MK212 (3 and 10 mg/kg) and Ro 60-0175 (1 and 3 mg/kg) reduced activity in wild-type but not knockout animals. At 10 mg/kg, Ro 60-0175 reduced activity in knockout animals, suggesting loss of 5-HT2C receptor selectivity. CP809,101 and lorcaserin reduced activity in wild-type but not knockout mice. In subsequent feeding studies, Ro 60-0175 and lorcaserin reduced food intake in wild-type animals only. Selectivity of effect for mCPP was marginal. The antagonist SB242084 increased activity in wild-type animals but not in knockout mice; SB242084 did not alter feeding in either genotype. SDZ SER 082 reduced activity in both genotypes implying poor selectivity for 5-HT2C receptors. The data demonstrate that studying food intake, and particularly motor behaviour, in the 5-HT2C receptor knockout mouse is a useful and relatively simple approach for screening 5-HT2C receptor ligands in vivo. [Copyright &y& Elsevier]

Drug repositioning has gained strategic value as a reaction to high attrition rates of new drugs as they pass through the clinical development process. The 5-HT2C receptor agonist lorcaserin (Belviq®), and the selective NA reuptake inhibitor atomoxetine (Strattera®) represent two drugs FDA approved for obesity and ADHD respectively. Although both drugs are of differing pharmacological class, each share a property of regulating impulsive behaviours in preclinical studies, and thus represent candidates for consideration in clinical conditions labelled as 'impulsive-compulsive disorders'. The present studies investigated both drugs, as well as the highly selective 5-HT2C agonist CP-809101 in two tests of compulsive action: schedule-induced polydipsia (SIP) and increased perseverative [PSV] (and premature [PREM]) responses emitted during an extended ITI 5-choice task. While lorcaserin (0.06–0.6 mg/kg), CP-809101 (0.1–1 mg/kg) and atomoxetine (0.1–1 mg/kg) each reduced both PREM and PSV measures in the 5-choice task, at equivalent doses only lorcaserin and CP-809101 affected excessive water intake in the SIP task, atomoxetine (0.1–2 mg/kg) was essentially ineffective. Further evidence supporting a role of the 5-HT2C receptor as an important regulator of impulsive-compulsive behaviours, the selective antagonist SB-242084 produced the opposing effects to lorcaserin, i.e promoting both impulsive and compulsive behaviours. The profile of atomoxetine may suggest differences in the nature of compulsive action measured either as non-regulatory drinking in the SIP task, and PSV responses made in a 5-choice task. These studies support the consideration of 5-HT2C receptor agonists, typified by lorcaserin, and atomoxetine as potential treatments for clinical conditions categorised as 'impulsive-compulsive disorders'. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'. • Lorcaserin (5-HT2C agonist) and atomoxetine examined on measures of impulsivity and compulsivity. • Lorcaserin reduced both measures, particularly in extreme (high) phenotype subjects. • SB-242084 (5-HT2C antagonist) increased impulsive and compulsive measures. • Atomoxetine reduced impulsivity, but had differential effects against compulsive behaviour. • Implications for 5-HT2C agonists and atomoxetine as treatments for impulsive-compulsive disorders. [ABSTRACT FROM AUTHOR]

Cocaine use disorder (CUD) is a major public health challenge for which there are no pharmacotherapeutics approved by the United States Food and Drug Administration (FDA). The propensity to relapse in CUD involves several vulnerability factors including sensitivity to cues associated with cocaine-taking. Serotonin (5-hydroxytryptamine, 5-HT) neurotransmission, particularly through the 5-HT 2A receptor (5-HT 2A R) and 5-HT 2C receptor (5-HT 2C R), is mechanistically linked to cocaine-seeking in preclinical models. In the present experiments, we employed self-administration assays in male rats to investigate whether acute and/or repeated administration of the FDA-approved selective 5-HT 2A R antagonist/inverse agonist pimavanserin, selective 5-HT 2C R agonist lorcaserin or their combination would alter cocaine intake and/or cocaine-seeking behavior. We found that acute administration of lorcaserin, but not pimavanserin, attenuated cocaine intake while pimavanserin plus lorcaserin did not impact cocaine self-administration. In contrast, 10-days of repeated administration of pimavanserin, lorcaserin, or pimavanserin plus lorcaserin during forced abstinence from cocaine self-administration, blunted cocaine-seeking, similar to the acute administration of each ligand. Taken together, these data reveal the efficacy of repeated treatment with pimavanserin plus lorcaserin to attenuate factors important to relapse-like behaviors in rodent models of CUD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'. • Lorcaserin, but not pimavanserin, suppresses cocaine self-administration in rats. • Repeated pimavanserin or lorcaserin sustains reduced cocaine-seeking behavior. • Low doses of pimavanserin plus lorcaserin reduce cocaine-seeking during abstinence. [ABSTRACT FROM AUTHOR]

Opioid-sparing adjuncts are treatments that aim to reduce the overall dose of opioids needed to achieve analgesia, hence decreasing the burden of side effects through alternative mechanisms of action. Lorcaserin is a serotonin 5-HT 2C receptor (5-HT 2C R) agonist that has recently been reported to reduce abuse-related effects of the opioid analgesic oxycodone. The goal of our studies was to evaluate the effects of adjunctive lorcaserin on opioid-induced analgesic-like behavior using the tail-flick reflex (TFR) test as a mouse model of acute thermal nociception. We show that whereas subcutaneous (s.c.) administration of lorcaserin alone was inactive on the TFR test, adjunctive lorcaserin (s.c.) significantly increased the potency of oxycodone as an antinociceptive drug. This effect was prevented by the 5-HT 2C R antagonist SB242084. A similar lorcaserin (s.c.)-induced adjunctive phenotype was observed upon administration of the opioid analgesics morphine and fentanyl. Remarkably, we also show that, opposite to the effects observed via s.c. administration, intrathecal (i.t.) administration of lorcaserin alone induced antinociceptive TFR behavior, an effect that was not prevented by the opioid receptor antagonist naloxone. This route of administration (i.t.) also led to a significant augmentation of oxycodone-induced antinociception. Lorcaserin (s.c.) did not alter the brain or blood concentrations of oxycodone, which suggests that its adjunctive effects on opioid-induced antinociception do not depend upon changes in opioid metabolism. Together, these data indicate that lorcaserin-mediated activation of the 5-HT 2C R may represent a new pharmacological approach to augment opioid-induced antinociception. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'. • Intrathecal administration of lorcaserin induces antinociception whereas subcutaneous injection lacks antinociceptive effect. • Adjunctive subcutaneous administration of lorcaserin augments opioid-induced antinociception. • These included oxycodone, morphine and fentanyl. • Adjunctive antinociceptive effect of lorcaserin is prevented by a 5-HT 2C receptor antagonist. • Lorcaserin may serve as a new approach to augment opioid-induced analgesia. [ABSTRACT FROM AUTHOR]

Substance abuse is serious public health problem for which there are few effective pharmacotherapies. Traditional strategies for drug development have focused on antagonists to block the abuse-related effects of a drug at its site of action, and agonists to replace/mimic the effects of the abused substance. However, recent efforts have targeted receptors, such as serotonin (5-HT) 2 receptors, that can indirectly modulate dopamine neurotransmission with the goal of developing a pharmacotherapy that might be effective at reducing the abuse-related effects of drugs more generally. Lorcaserin is a 5-HT 2C receptor-preferring agonist that is approved by the US Food and Drug Administration for the treatment of obesity. Mounting evidence from preclinical and clinical studies suggests that lorcaserin might also be effective at reducing the abuse-related effects of drugs with different pharmacological mechanisms (e.g., cocaine, heroin, ethanol, and nicotine). Lorcaserin represents a promising and important first step towards the development a new class of pharmacotherapies that have the potential to dramatically improve the treatment of substance abuse. This article will review the behavioral pharmacology of 5-HT 2C receptor-preferring agonists, with a focus on lorcaserin, and evaluate the preclinical evidence supporting the development of lorcaserin for treating substance abuse. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'., (Copyright © 2017 Elsevier Ltd. All rights reserved.)