# Preclinical Psychopharmacology of Substance Abuse

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2021 · —

## Abstract

Substance use disorders are a serious public health problem with medical, societal, and economic costs exceeding
$800B annually. Rates of tobacco, alcohol, and illicit drug (e.g., stimulants, and opioids) use among veterans are as high
or higher than those observed in civilian populations. Despite long-standing efforts to develop pharmacotherapies to treat
substance use disorders, few pharmacotherapies exist for nicotine, opioid, or alcohol use disorders, and there are
currently no US Food and Drug Administration (FDA)-approved pharmacotherapies for stimulant abuse. This relative lack
of pharmacotherapies for substance use disorders is likely due to a variety of factors; however, the time and costs
associated with identifying viable targets and developing effective treatment strategies has discouraged many
companies/individuals from entering this space.
 One strategy to reduce the time and costs required to get candidate medications into the clinic is to leverage knowledge
about the neurobiological substrates of addiction to rationally repurpose drugs already approved by the FDA for other
indications to treat substance abuse. Given the central role for dopamine (DA) in reward, reinforcement, and addiction,
we have focused our efforts on identifying targets, such as 5-HT2C and DA D3 receptor (R)s, that are capable of modulating
the activity of the mesolimbic DA system. Indeed, strong preclinical evidence from our laboratory and others suggests that
targeting each of these receptors with FDA-approved drugs (lorcaserin [Belviq®], a serotonin [5-HT]2CR agonist; and
buspirone [Buspar®], a DA D3R antagonist/5-HT1A agonist) can reduce the abuse-related effects of a variety of drugs (e.g.,
cocaine, methamphetamine, oxycodone, fentanyl, nicotine, and alcohol). In addition, we have recently shown that the
effectiveness of these drugs to reduce drug taking are synergistically enhanced when the drugs are administered in
combination (i.e., mixtures of lorcaserin and buspirone are more potent/effective than either drug alone). Although
promising, each of these drugs have dose-limiting (off-target) effects that reduce the likelihood that these effects will
translate to the clinic.
 For instance, it is important to note that doses of lorcaserin only slightly larger than those approved/required to
produce its therapeutic effects have been reported to producing feelings of “high”, “bad drug effect”, and “hallucination”
in humans; effects that are attributed to off-target actions at 5-HT2ARs. In addition to the off-target effects limiting the
clinical utility of lorcaserin and buspirone for treating substance use disorder, the relatively “dirty” pharmacology of
lorcaserin and buspirone also complicates efforts to isolate the receptor and circuit-level mechanisms that account for
these drugs (and drug mixtures) to effectively reduce drug taking behavior. Accordingly, proposed studies will combine
intravenous drug self-administration with microinjections aimed at par...

## Key facts

- **NIH application ID:** 10075792
- **Project number:** 5I01BX004550-02
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** Gregory Thomas Collins
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075792

## Citation

> US National Institutes of Health, RePORTER application 10075792, Preclinical Psychopharmacology of Substance Abuse (5I01BX004550-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10075792. Licensed CC0.

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