The neutral CB1 antagonist AM6527 reduces ethanol seeking, binge-like consumption, reinforcing, and withdrawal effects in male and female mice

Raghav, Jimit Girish; Kumar, Hritik; Ji, Lipin; Vemuri, Kiran; Makriyannis, Alexandros; Suh, Junghyup; Leonard, Michael Z; Dang, Vivi; Ty, Chelsea; Marandola, Stephen; Kane, Natalie; Witt, Annika S; Shaqour, Samar; Miczek, Klaus A.

doi:10.1007/s00213-023-06500-w

Cited by 2 publications

(1 citation statement)

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“…Therefore, there is a pressing need to develop new and more effective pharmacological strategies to treat AUD. Preclinical models using mice, rats, and rhesus macaques have identified the neural and molecular substrates of alcohol consumption and probed the efficacy of novel molecules to mitigate the symptoms of AUD [10][11][12][13][14][15][16][17][18][19][20][21]. In vitro studies reported that through voltage-gated Ca 2+ channels, Ca 2+ influx contributes to regulating neuronal excitability and behavioral responses toward alcohol [22].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Sodium–Calcium Exchanger Reverse Mode Activity Reduces Alcohol Consumption in Rats

Silva-Cardoso,

N’Gouemo

2024

IJMS

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Excessive and uncontrolled consumption of alcohol can cause alcohol use disorder (AUD), but its pharmacological mechanisms are not fully understood. Inhibiting the reverse mode activity of the sodium–calcium exchanger (NCX) can reduce the risk of alcohol withdrawal seizures, suggesting that NCX could play a role in controlling alcohol consumption. Here, we investigated how two potent inhibitors of NCX reverse mode activity, SN-6 (NCX1) and KB-R7943 (NCX3), affect voluntary alcohol consumption in adult male and female rats using the intermittent alcohol access two-bottle choice paradigm. Initially, animals were trained to drink 7.5% ethanol and water for four weeks before administering SN-6 and KB-R7934. Afterward, their alcohol intake, preference, and water intake were recorded 2 and 24 h after exposure to water and 7.5% ethanol. SN-6 significantly reduced alcohol consumption by 48% in male and 36% in female rats without affecting their water intake. Additionally, SN-6 significantly reduced alcohol preference in females by 27%. However, KB-R7943 reduced alcohol consumption by 42% in female rats and did not affect alcohol preference or water intake. These findings suggest that alcohol exposure increased NCX reverse activity, and targeting NCX1 could be an effective strategy for reducing alcohol consumption in subjects susceptible to withdrawal seizures.

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