D-Serine and D-Cycloserine Reduce Compulsive Alcohol Intake in Rats

Area of Science:

• Neuroscience
• Pharmacology
• Addiction Research

Background:

• N-methyl-D-aspartate receptor (NMDAR) modulators are investigated for memory enhancement and neuropsychiatric disorders like addiction.
• D-serine and D-cycloserine activate NMDARs at the glycine site and have a favorable human safety profile.
• Hyperpolarized-active NMDARs (HA-NMDARs) in the nucleus accumbens core (NAcore) are implicated in compulsive alcohol drinking.

Purpose of the Study:

• To investigate the effects of D-serine and D-cycloserine on aversion-resistant alcohol intake in a rat model.
• To determine the specific brain regions and NMDAR subtypes targeted by these compounds in modulating alcohol consumption.

Main Methods:

• Systemic administration of D-serine and D-cycloserine in rats exhibiting aversion-resistant alcohol drinking.
• In vivo microinjections into the nucleus accumbens core (NAcore) and dorsolateral striatum.
• In vitro electrophysiological recordings (EPSCs) following optogenetic stimulation of medial prefrontal cortex (mPFC)-NAcore terminals.

Main Results:

• Systemic D-serine selectively reduced aversion-resistant alcohol intake but not quinine-free alcohol or saccharin consumption.
• D-serine administration into the NAcore, but not the dorsolateral striatum, reduced aversion-resistant alcohol drinking.
• D-serine and D-cycloserine inhibited HA-NMDARs in the NAcore, reducing compulsive alcohol consumption.

Conclusions:

• HA-NMDAR modulators, including D-serine and D-cycloserine, can effectively reduce aversion-resistant alcohol drinking.
• Targeting HA-NMDARs in the NAcore offers a potential therapeutic strategy for alcohol use disorders (AUDs).
• D-serine and D-cycloserine represent promising, readily available therapeutic candidates for AUD treatment.