Inhibition of the nucleus accumbens core with DREADDs after acute and repeated exposure to oxycodone reduces locomotor activity in female but not male Rattus norvegicus

Abstract

Opioid use disorder affects both men and women, but significant sex differences exist in addiction vulnerability and progression. The nucleus accumbens (NAc) plays a critical role in drug reward and motor outputs, yet its sex-specific functions in opioid response remain poorly understood. We investigated the role of the NAc in acute and repeated oxycodone response using chemogenetics in male and female Sprague Dawley rats. Inhibitory DREADDs (hM4D(Gi)) or control vectors were injected into the NAc core. Rats received oxycodone (1 mg/kg, i.p.) or saline for 5 consecutive days with locomotor activity monitoring. Following a 7-day drug-free period, all rats received oxycodone challenge (1 mg/kg, i.p.) with clozapine-N-oxide (CNO, 3 mg/kg) to activate DREADD-mediated inhibition. Results revealed sex differences in both baseline and drug-induced locomotor activity, with females showing consistently higher activity in response to oxycodone than males across all sessions. Chemogenetic inhibition of the NAc significantly reduced locomotor activity in females but not males during challenge conditions, indicating sex-specific NAc involvement in the opioid response at this dose. These findings reveal sex differences in NAc involvement in acute and chronic oxycodone induced locomotor activity. Our results underscore the need for sex-specific considerations in addiction research.