NIDA Notes

Serotonin Receptor Agonist Lorcaserin Reduces Relapse to Drug Use in Monkeys

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By Stacey C. Tobin, Ph.D., ELS, NIDA Notes Contributing Writer

This study reported:

  • The serotonin 2C receptor agonist lorcaserin reduced reinstatement of drug-seeking behavior in response to heroin or cocaine in a nonhuman primate model of relapse.
  • Lorcaserin was slightly more potent in reducing reinstatement after an initial heroin dose than after a cocaine dose.

Dopamine is thought to reinforce the desire to use drugs. Reducing dopamine activity in the brain—for example, by activating serotonin receptors—therefore has emerged as a promising approach for treating drug misuse. Previous studies found that the serotonin receptor agonist lorcaserin could reduce self-administration of cocaine and nicotine. Now, a study in rhesus monkeys shows that lorcaserin could also reduce relapse to drug use after cocaine or opioid self-administration. "Lorcaserin may be useful for treating one or more substance use disorders, and the positive results obtained thus far might be even greater if lorcaserin is combined with other drugs that modulate drug reinforcement by different mechanisms," says Dr. Charles France, the study’s senior investigator.

In their study, Dr. Lisa Gerak, Dr. France, and colleagues at the University of Texas Health Science Center at San Antonio trained rhesus monkeys to self-administer either cocaine or the opioid remifentanil by pressing a lever in response to a visual cue (a green light). To model relapse, the respective drug was first withdrawn through an extinction protocol, where lever pressing did not lead to drug administration and no visual cue was shown. For drug reinstatement, the researchers then administered a single dose of cocaine or heroin with or without the visual cue and measured how often the monkeys would press the lever that previously delivered the drug. To determine the effects of lorcaserin, the monkeys received either lorcaserin or a saline solution 15 minutes before the self-administration, extinction, or reinstatement sessions.

Figure. Lorcaserin Reduces Rhesus Monkeys’ Drug Seeking for Heroin and Cocaine After Extinction and Reinstatement Rhesus monkeys were trained to self-administer heroin or remifentanil before undergoing a period of extinction and then receiving a single reinstatement dose of cocaine or heroin to model relapse. The animals could then press a lever to obtain more of the drug. In the absence of lorcaserin (Control), lever-pressing responses were high. Pretreatment with lorcaserin reduced responses in a dose-dependent manner, with a smaller dose of lorcaserin significantly decreasing responding after heroin reinstatement than after cocaine reinstatement. See full text description at end of article.

The experiments found that monkeys that were pretreated with lorcaserin were less likely to seek cocaine or heroin (i.e., made fewer lever presses) after withdrawal and reinstatement than control monkeys. Lorcaserin’s effect on drug reinstatement was dose-dependent for both heroin and cocaine, but overall, lorcaserin was slightly more potent in reducing the response to heroin because a smaller lorcaserin dose was sufficient to suppress lever pressing after heroin than after cocaine (see Figure).

Although the study included only a few monkeys, it provides strong evidence in a nonhuman primate model that suppressing dopamine by activating serotonin receptors with lorcaserin may reduce relapse in people with opioid or cocaine use disorder, or both. The findings are particularly compelling because there are currently no effective treatments for people who use more than one drug. Moreover, lorcaserin has already been approved by the U.S. Food and Drug Administration for supporting weight loss by reducing food cravings, indicating that it affects processes potentially involved in drug relapse. Although clinical trials will need to test lorcaserin for reducing relapse to polydrug use in humans, Dr. Gerak is cautiously optimistic. "Our study extends the possibility of targeting serotonin mechanisms to modify misuse-related effects of opioid use disorder,” she says.

This study was supported by NIDA grants DA005018 and DA034992.

Text Description of Figure

This bar chart illustrates the effects of treatment with lorcaserin on reinstatement of heroin or cocaine use in rhesus monkeys. The horizontal x-axis shows the lorcaserin doses used in reinstatement of heroin use (blue bars) or cocaine use (gold bars). For heroin reinstatement, doses of 0 mg/kg (control), 0.032 mg/kg, 0.1 mg/kg, 0.32 mg/kg, and 1 mg/kg were used. For cocaine reinstatement, doses of 0 mg/kg (control), 0.1 mg/kg, 0.32 mg/kg, and 1 mg/kg were used. The vertical y-axis shows the number of lever presses to obtain the drug on a scale from 0 to 800.

When the animals were tested for heroin reinstatement, control animals made about 720 lever presses, those receiving 0.032 mg/kg lorcaserin made about 620 lever presses, those receiving 0.1 mg/kg made about 580 lever presses, those receiving 0.32 mg/kg made about 400 lever presses, and those receiving 1 mg/kg made about 130 lever presses. Asterisks above the latter two bars indicate that these values were significantly different from the control animals.

When the animals were tested for cocaine reinstatement, control animals made about 550 lever presses, those receiving 0.1 mg/kg lorcaserin made about 500 lever presses, those receiving 0.32 mg/kg made about 350 lever presses, and those receiving 1 mg/kg made about 170 lever presses. The asterisk above the last bar indicates that this value was significantly different from the control animals.

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