Methamphetamine-Fentanyl Polysubstance Administration Produces Social Deficits and Corticolimbic Stress-Reward...

Area of Science:

• Neuroscience
• Psychopharmacology
• Addiction Research

Background:

• Polysubstance use of psychostimulants and opioids presents significant public health challenges, including increased overdose risk and treatment difficulties.
• The neurobiological underpinnings of social dysfunction associated with opioid-stimulant withdrawal are not well understood.
• Understanding these consequences is crucial for developing effective therapeutic interventions.

Purpose of the Study:

• To investigate the impact of repeated methamphetamine-fentanyl polysubstance treatment on social preference during withdrawal.
• To determine if psilocybin administration can restore social behavior in withdrawn rats.
• To examine the effects of these drug treatments on the expression of stress- and opioid-related genes in key brain regions.

Main Methods:

• Male and female rats received repeated injections of methamphetamine and fentanyl or saline.
• Social preference was assessed at baseline and after 10 days of withdrawal.
• Rats were treated with psilocybin or saline during withdrawal, with subsequent reassessment of sociability.
• Gene expression of CRHR1 and OPRM1 in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) was quantified using RT-qPCR.

Main Results:

• Withdrawal from polysubstance treatment significantly reduced social preference, confirming withdrawal-induced social deficits.
• Psilocybin treatment did not restore social preference at the tested time point.
• Psilocybin modulated CRHR1 expression in the mPFC in a drug-history-dependent manner.
• Polysubstance administration decreased CRHR1 expression in the NAc.
• OPRM1 expression exhibited sex-dependent regulation, with reduced expression in females in the NAc.

Conclusions:

• Repeated methamphetamine-fentanyl exposure leads to persistent social deficits during withdrawal.
• These deficits are associated with region- and sex-specific alterations in corticolimbic gene expression.
• While psilocybin did not reverse social deficits, it demonstrated an ability to regulate cortical CRHR1 expression based on prior drug exposure.