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35th AM (2025) - Poster Session
Preclinical Evaluation of TMP-301 for the Treatmen ...
Preclinical Evaluation of TMP-301 for the Treatment of CUD, AUD, and OUD
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This study investigates TMP-301, a selective negative allosteric modulator (NAM) of the metabotropic glutamate receptor 5 (mGluR5), for treating substance use disorders (SUDs) involving cocaine, opioids, and alcohol. SUDs impose significant public health burdens, and current FDA-approved treatments have limitations including modest efficacy, poor tolerability, and lack of effectiveness across different drug classes, with no approved therapies for cocaine use disorder (CUD).<br /><br />mGluR5 is expressed in brain reward-related areas such as the nucleus accumbens and plays a key role in aberrant glutamatergic signaling that drives addiction behaviors. Inhibition of mGluR5 reduces rewarding effects of addictive substances and relapse.<br /><br />Preclinical models were used, including conditioned place preference and self-administration paradigms for cocaine, oxycodone, and alcohol. Rats were trained to self-administer drugs intravenously or orally and underwent extinction and reinstatement protocols. Yohimbine, a pharmacological stressor, was used to induce relapse.<br /><br />TMP-301 effectively reduced drug-seeking and intake behaviors in a dose-dependent manner across all tested SUD models. In cocaine models, TMP-301 decreased cocaine preference, suppressed self-administration, and prevented reinstatement after yohimbine-induced stress. Similarly, TMP-301 attenuated oxycodone self-administration and blocked its reinstatement. For alcohol, TMP-301 lowered voluntary consumption, reduced operant self-administration, and inhibited cue-induced relapse behaviors.<br /><br />Importantly, TMP-301 preserved normal glutamatergic function and showed no adverse effects on respiration or non-specific behaviors, including motor activity and anxiety.<br /><br />Overall, TMP-301 demonstrates robust efficacy as an mGluR5 NAM in multiple preclinical SUD models, supporting mGluR5 antagonism as a promising, broadly applicable mechanism for treating cocaine, opioid, and alcohol use disorders. This research highlights TMP-301's potential as a novel therapeutic agent addressing critical gaps in current addiction pharmacotherapy.
Keywords
TMP-301
mGluR5
negative allosteric modulator
substance use disorders
cocaine use disorder
opioid addiction
alcohol use disorder
preclinical models
drug relapse
addiction pharmacotherapy
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