Serotonin 5-HT<sub>2</sub>Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

Howell, Leonard L.; Cunningham, Kathryn A.

doi:10.1124/pr.114.009514

Cited by 220 publications

(197 citation statements)

References 283 publications

(343 reference statements)

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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%

“…The ability of 5-HT systems to modulate dopamine activity is well documented, and mounting evidence suggests that these effects are mediated by the 5-HT 2 subfamily of receptors, with agonists acting at 5-HT 2A receptors stimulating dopamine release and agonists acting at 5-HT 2C receptors inhibiting dopamine release within the nucleus accumbens. Conversely, antagonists of 5-HT 2A or 5-HT 2C receptors are known to decrease or increase dopamine neurotransmission, respectively (for review, see Howell and Cunningham, 2015).…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

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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“…Dopamine receptor agonists maintain self-administration in monkeys (Woolverton et al, 1984;Weed and Woolverton, 1995;Grech et al, 1996;Sinnott et al, 1999), and antagonism of these receptors can attenuate cocaine self-administration (Woolverton and Virus, 1989;Bergman et al, 1990;Nader et al, 1999;Xi et al, 2005). Conversely, increased 5-HT function appears to attenuate the effects of cocaine (Czoty et al, 2002;Rothman et al, 2005;Howell and Cunningham, 2015). Considering the primary involvement of dopamine in the abuse-related behavioral effects of cocaine, it is unsurprising that brain dopamine transporters and receptors have been targeted frequently in the development of pharmacotherapies for cocaine use disorder (e.g., Davies et al, 1993;Carroll et al, 1999;Grabowski et al, 2004;Heidbreder and Newman, 2010).…”

Section: B Pharmacology Of Cocainementioning

confidence: 99%

Evaluation of the “Pipeline” for Development of Medications for Cocaine Use Disorder: A Review of Translational Preclinical, Human Laboratory, and Clinical Trial Research

2016

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“…Several decades of preclinical research suggest that 5-HT 2C receptor agonists might be effective for treating substance use disorders [for a review, see Howell and Cunningham (2015)]. For example, 5-HT 2C receptor agonists can attenuate the positive reinforcing effects of cocaine as well as reinstatement of responding by cocaine and cocaine-associated stimuli (Callahan and Cunningham, 1995;Burbassi and Cervo, 2008;Navarra et al, 2008;Anastasio et al, 2011;Cunningham et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Directly Observable Behavioral Effects of Lorcaserin in Rats

Serafine

Rice

France

2015

J Pharmacol Exp Ther

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(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (lorcaserin) is approved by the United States 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 5 8). The 5-HT 2C receptor selective agonist 1-(3-chlorophenyl)piperazine (mCPP, 0.032-1.0 mg/kg) and lorcaserin induced yawning which was attenuated by the 5-HT 2C receptor selective antagonist 6-chloro-5-methyl-N-(6-[(2-methylpyridin-3-yl)oxy]pydidin-3-yl)indoline-1-carboxamide (1.0 mg/kg). The 5-HT 2A receptor selective agonist 2,5-dimethoxy-4-methylamphetamine (0.1-3.2 mg/kg) induced head twitching, which was attenuated by the 5-HT 2A receptor selective antagonist R-(1)-2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol] (MDL 100907, 0.01 mg/kg), lorcaserin (3.2 mg/kg), and mCPP (3.2 mg/kg). In rats pretreated with MDL 100907 (1.0 mg/kg), lorcaserin also induced head twitching. At larger doses, lorcaserin produced forepaw treading, which was attenuated by the 5-HT 1A receptor selective antagonist N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (0.178 mg/kg). While the behavioral effects of lorcaserin in rats are consistent with it having agonist activity at 5-HT 2C receptors, these data suggest that at larger doses it also has agonist activity at 5-HT 2A and possibly 5-HT 1A receptors. Mounting evidence suggests that 5-HT 2C 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.

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Serotonin 5-HT₂Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

Cited by 220 publications

References 283 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

Evaluation of the “Pipeline” for Development of Medications for Cocaine Use Disorder: A Review of Translational Preclinical, Human Laboratory, and Clinical Trial Research

Directly Observable Behavioral Effects of Lorcaserin in Rats

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Serotonin 5-HT2Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

Cited by 220 publications

References 283 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

Evaluation of the “Pipeline” for Development of Medications for Cocaine Use Disorder: A Review of Translational Preclinical, Human Laboratory, and Clinical Trial Research

Directly Observable Behavioral Effects of Lorcaserin in Rats

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Serotonin 5-HT₂Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder