Carisoprodol (Soma(R)) is a centrally-acting skeletal muscle relaxant frequently prescribed for the treatment of acute musculoskeletal conditions. In recent years, there has been increasing concern regarding carisoprodol's potential as a drug of abuse. In 1991, carisoprodol was ranked 54th among 234 drugs with abuse potential. Only eight years later, the Drug Abuse Warning Network identified carisoprodol as the 14th most abused drug, ranking higher than oxycodone, methadone, and LSD. In support of this, recent reports have substantiated the dangers involved in carisoprodol abuse, including severe withdrawal leading to seizures and death. However, its mechanism of action remains unclear. Until recently, it was widely accepted that the sedative effects of carisoprodol were predominantly due to its metabolite, meprobamate. However, preliminary in vivo and in vitro studies conducted in our laboratory demonstrate that carisoprodol itself is active, and its actions appear to be mediated via novel modulation of the GABAA receptor (GABAAR), the predominant inhibitory neurotransmitter receptor in mammalian brain. This may underlie the capacity of carisoprodol to enhance the sedative effects of CNS depressants, contributing to its potential for abuse. Indeed, concerns about the rise in abuse of carisoprodol have led the Drug Enforcement Agency to contact the National Institute on Drug Abuse for assistance in determining the abuse liability of carisoprodol. Based on our preliminary findings, we hypothesize that carisoprodol itself causes depressive CNS effects, and that these actions are mediated via a novel interaction with the GABAA receptor. The overall goal of the proposed study is to identify the mechanisms that mediate carisoprodol abuse, at both the behavioral and molecular level. We will utilize both in vivo (drug discrimination and observation of intoxication, tolerance and withdrawal, and pharmacokinetic analysis) and in vitro (assessment of carisoprodol on specific configurations of recombinant GABAA receptors) approaches to address the following specific aims: 1) To characterize the discriminative stimulus effects of carisoprodol; 2) To investigate whether carisoprodol produces effects on its own in vivo or requires being metabolized to meprobamate; 3) To assess the extent of carisoprodol dependence and severity of withdrawal; 4) To identify GABAA receptor subunits critical for allosteric modulatory and direct gating effects of carisoprodol; and 5) To identify GABAA receptor subunit domains that confer carisoprodol sensitivity. Given the present and potential dangers posed by carisoprodol abuse, it is of crucial importance to determine the mechanism of action of this drug. Our proposed studies will substantially increase our understanding of the mechanism of action of carisoprodol as a therapeutic agent and as a drug of abuse. This knowledge may provide insight into treating carisoprodol dependence, and withdrawal.

Public Health Relevance

The muscle relaxant Carisoprodol (Soma(R)) is being abused increasingly at an alarming rate; withdrawal from overuse of this drug can cause seizures and even death. There is an urgent need to develop new drugs that can treat these symptoms, as well as new drugs that are less likely to be abused. The proposed studies will provide the fundamental information needed to address both of these current unmet medical needs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
7R01DA022370-04
Application #
8432514
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Wu, Da-Yu
Project Start
2009-07-01
Project End
2013-05-31
Budget Start
2012-02-07
Budget End
2012-05-31
Support Year
4
Fiscal Year
2011
Total Cost
$348,109
Indirect Cost
Name
West Virginia University
Department
Physiology
Type
Schools of Medicine
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
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Huang, Renqi; Chen, Zhenglan; Dolan, Sean et al. (2017) The dual modulatory effects of efavirenz on GABAA receptors are mediated via two distinct sites. Neuropharmacology 121:167-178
Kumar, Manish; Dillon, Glenn H (2016) Assessment of direct gating and allosteric modulatory effects of meprobamate in recombinant GABA(A) receptors. Eur J Pharmacol 775:149-58
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