Background Serotonin (5-HT) is one of three monoamines that are widely distributed in the brain and play important roles in affect and goal-directed behaviors. Limbic structures that underlie behavior motivated by palatable food and drugs of abuse receive dense projections from brainstem serotonergic nuclei. In rats, light and sound cues associated with access to cocaine strongly stimulate drug-seeking behavior. Agonists for the type 2C serotonergic receptor (5-HT2CR) attenuate this responding. Drug taking (cocaine self-administration) is also attenuated at 5-HT2CR agonist doses similar to those that decrease food-reinforced responding and cause reductions in locomotor activity. Lorcaserin is a novel and selective agonist of the 5-HT2CR recently approved by the FDA for weight loss therapy. It acts selectively at this receptor subtype with minimal activation of 5-HT2AR or 5-HT2BR receptors. Based on initial clinical studies leading to its approval, lorcaserin is well tolerated and probably does not cause cardiac valve disease or other serious side effects. Rationale In preclinical studies, agonists for the 5-HT2CR potently attenuate cocaine-seeking behavior. Lorcaserin is a recently approved selective 5-HT2CR agonist with an acceptable safety profile in humans. No studies have reported its effects on cocaine-induced craving or drug-reinforced responding in humans.
Specific Aims : 1. Determine whether lorcaserin pretreatment attenuates the positive subjective effects of cocaine and drug- reinforced behavior. 2. Evaluate whether active treatment modifies cocaine- or script- induced craving. 3. Characterize the bioavailability of lorcaserin in individual participants and determine whether it modifies plasma levels of cocaine. Methods This is a randomized, cross-over, double-blind, placebo-controlled, research-unit, single-center, multiple-panel evaluation of the potential for oral lorcaserin to modify craving and cocaine self-administration in a laboratory setting. A total of 24 non-treatment-seeking, regular cocaine users will receive pretreatment with single doses of oral placebo, lorcaserin 10 mg (panel 1), or lorcaserin 20 mg (panel 2). Script-guided imagery of autobiographical memories will be developed based on experiences related to cocaine use, anger, and a neutral event. Following treatment with lorcaserin, script-induced emotional states will be assayed. Sampling doses of cocaine (0.0, 0.23, and 0.46 mg/kg) will be administered, and participants will choose between self- administering additional intravenous doses or receiving monetary alternatives. Detailed measures of the negative and positive subjective effects of intravenous infusions will also be made. As noncontingent infusions of cocaine are administered, the pharmacokinetics of cocaine and lorcaserin will be determined.

Public Health Relevance

No medications are currently available for treatment of psychostimulant addiction, a compulsive preoccupation with use of cocaine and related compounds. Lorcaserin is a medication that is currently prescribed for treatment of obesity. Medications that are similar to lorcaserin can decrease the amount of cocaine injections that laboratory animals choose to inject by vein. This project will determine if lorcaserin can also decrease cocaine-motivated behavior for human subjects in a laboratory setting.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA037556-02
Application #
8918564
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Hampson, Aidan
Project Start
2014-09-01
Project End
2019-02-28
Budget Start
2017-09-01
Budget End
2019-02-28
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Midwest Biomedical Research Foundation
Department
Type
DUNS #
798845053
City
Kansas City
State
MO
Country
United States
Zip Code
64128