Blockade of 5-Hydroxytryptamine 2A Receptor Attenuates Precipitation of Naloxone-Induced Withdrawal Symptoms in Opioid-Exposed Mice

Abstract

Heroin dependency has become a global problem and has caused significant clinical and socioeconomic burdens along with devastating medical consequences. Chronic drug exposure alters the expression and functional activity of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) in the brain. Furthermore, pharmacological blockade of 5-HT2ARs reduces cue-induced cocaine craving behaviors. In this study, we explored the influence of 5-HT2ARs on heroin-withdrawal behaviors in mice. Black C57BL/6J mice were given gradually increasing (10–50 mg/kg over 4.5 days) doses of heroin to induce heroin dependency, after which naloxone was given to precipitate withdrawal symptoms. MDL100907, a selective and potent 5-HT2AR antagonist, attenuated naloxone-precipitated withdrawal symptoms in these mice. In addition, 5-HT2AR protein levels increased significantly in the medial prefrontal cortex (mPFC), while phosphorylation of extracellular signal-regulated kinase (p-ERK) decreased in the mPFC after heroin exposure. In conclusion, these results suggest that 5-HT2ARs might be involved in the development of opioid dependency and that pharmacological blocking of 5-HT2ARs might be a new therapeutic strategy for heroin dependency.

Monoamine Neurotransmitters and Drug Addiction

“…Morphine stimulates 5-HT metabolism in the nucleus accumbens (NAc) and ventral tegmental area (VTA), systemically enhances 5-HT synthesis in the brain, and increases 5-HT transport in the NAc and other brain regions (6). The transmission of 5-HT is inhibited during chronic morphine withdrawal and increasing the level of 5-HT can alleviate withdrawal symptoms, reduce the desire for morphine, reduce the concentration of 5-HT, and lead to aggravated withdrawal reactions (7,8). 5-HT can stimulate the D release of DA: increasing the level of 5-HT in the brain can stimulate the DA system, thereby increasing the levels of DA and 5-HT transporters and increasing DA can eliminate symptoms during morphine withdrawal (9,10).…”

μ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges

“…Furthermore, analyses of anecdotal and self-reported data support the consideration of psychedelics for treatment of OUD ( Savage and McCabe, 1973 ; Garcia-Romeu et al, 2019 ; Argento et al, 2022 ; Jones et al, 2022 ), and several clinical trials with psilocybin are ongoing for OUD (e.g., NCT0416066, NCT0542029, NCT06005662) and pain conditions (e.g., NCT06001749, NCT05224336, NCT05068791). MOR function is fundamentally integrated with 5-HT neurotransmission ( Tao et al, 1998 ; Tao and Auerbach, 2002b ; Tao et al, 2003 ; Ozdemir, 2017 ) with a prominent role for the 5-HT 2A R ( Aira et al, 2012 ; Heijmans et al, 2021 ; Li et al, 2021 ; Sierra et al, 2022 ), from the 5-HT 2 R family (5-HT 2A R, 5-HT 2B R, 5-HT 2C R) ( Barnes et al, 2021 ). As opposed to the MOR, the coupling of the 5-HT 2A R to Gα q/11 heterotrimeric G proteins triggers phosphatidylinositol-4,5-bisphosphate hydrolysis and subsequent release of inositol triphosphate, diacylglycerol, and other effectors ( Barnes et al, 2021 ).…”