Reward Circuit Adaptations After Chronic Antipsychotic Treatment Confer Addiction Vulnerability

Area of Science:

• Neuroscience
• Psychiatry
• Pharmacology

Background:

• Antipsychotics are crucial for treating psychiatric disorders but can cause motor and metabolic side effects.
• Antipsychotic medications can disrupt the brain's reward pathways, potentially influencing substance use.
• Previous research indicated haloperidol (a first-generation antipsychotic) increases cocaine relapse after discontinuation.

Purpose of the Study:

• To investigate if second-generation antipsychotics also increase addiction vulnerability in rodents and humans.
• To identify the cellular mechanisms linking antipsychotic exposure to substance use disorders (SUD).

Main Methods:

• Rats received chronic risperidone or olanzapine, followed by cocaine self-administration and cue-induced relapse testing.
• Dendritic spine morphology of D1- and D2-MSNs in the nucleus accumbens core (NAcore) was analyzed.
• A systematic review and meta-analysis assessed the clinical link between antipsychotic use and SUD in human patients.

Main Results:

• Chronic risperidone or olanzapine delayed extinction and increased cue-induced cocaine seeking in rats, but not sucrose seeking.
• Relapse was associated with increased spine head diameter in NAcore D2-MSNs, but not D1-MSNs.
• In humans, antipsychotic treatment duration (>4 months) predicted substance use/craving, irrespective of drug class or substance type.

Conclusions:

• Chronic antipsychotic treatment, irrespective of generation, enhances addiction vulnerability and relapse-like behaviors in rats.
• This effect in rats is associated with D2-MSN potentiation in the ventral striatum.
• Human data from meta-analysis support the association between antipsychotic treatment and increased addictive substance use or craving.