Sex Differences in Context-Driven Reinstatement of Methamphetamine Seeking is Associated with Distinct Neuroadaptations in the Dentate Gyrus

The present study examined differences in operant responses in adult male and female rats during distinct phases of addiction. Males and females demonstrated escalation in methamphetamine (0.05 mg/kg, i.v.) intake with females showing enhanced latency to escalate, and bingeing. Following protracted abstinence, females show reduced responses during extinction, and have greater latency to extinguish compared with males, indicating reduced craving. Females demonstrated lower context-driven reinstatement compared to males, indicating that females have less motivational significance to the context associated with methamphetamine. Whole-cell patch-clamp recordings on dentate gyrus (DG) granule cell neurons (GCNs) were performed in acute brain slices from controls and methamphetamine experienced male and female rats, and neuronal excitability was evaluated from GCNs. Reinstatement of methamphetamine seeking reduced spiking in males, and increased spiking in females compared to controls, demonstrating distinct neuroadaptations in intrinsic excitability of GCNs in males and females. Reduced excitability of GCNs in males was associated with enhanced levels of neural progenitor cells, expression of plasticity-related proteins including CaMKII, and choline acetyltransferase in the DG. Enhanced excitability in females was associated with an increased GluN2A/2B ratio, indicating changes in postsynaptic GluN subunit composition in the DG. Altered intrinsic excitability of GCNs was associated with reduced mossy fiber terminals in the hilus and pyramidal projections, demonstrating compromised neuroplasticity in the DG in both sexes. The alterations in excitability, plasticity-related proteins, and mossy fiber density were correlated with enhanced activation of microglial cells in the hilus, indicating neuroimmune responses in both sexes. Together, the present results indicate sexually dimorphic adaptive biochemical changes in excitatory neurotransmitter systems in the DG and highlight the importance of including sex as a biological variable in exploring neuroplasticity and neuroimmune changes that predict enhanced relapse to methamphetamine-seeking behaviors.