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

Abstract

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.

Chemogenetic Inhibition of Corticostriatal Circuits Reduces Cued Reinstatement of Methamphetamine Seeking

“…Both sexes are included in these studies because differences occur in metabolism 29 and acquisition of drug self-administration 30,31 , and in basic and synaptic excitatory transmission 11,32 . However, our behavioral endpoint, cued reinstatement, is not sensitive to sex as a biological variable 33,34 unless the response ratio is increased during the reinstatement test 33 .…”

Brain and Cognition for Addiction Medicine: From Prevention to Recovery Neural Substrates for Treatment of Psychostimulant-Induced Cognitive Deficits

“…Extinction of cocaine-induced CPP took longer in male compared with female adolescent rats (110). More recent work has shown that after similar extinction training, context-induced reinstatement of methamphetamine seeking was more pronounced in male compared with female rats (381). Further, the study showed that this difference in methamphetamine seeking between male and female rats was possibly mediated by differential plasticity in the dentate gyrus in the hippocampus.…”

Distinct Regulation of Dopamine D3 Receptor in the Basolateral Amygdala and Dentate Gyrus during the Reinstatement of Cocaine CPP Induced by Drug Priming and Social Stress

“…Dopaminergic mesocorticolimbic system has been related with motivation in drug intake and relapse in drug-seeking behaviour [ 2 , 16 ]. Of all the dopaminergic receptors, the D3 receptor (D3R) seems to be uniquely implicated in reward, motivation, emotion, learning, and, by extension, drug seeking and relapse mechanisms, given its restricted distribution in the limbic system [ 17 , 18 , 19 ]. As a member of the D2-like receptor family, D3R is coupled to the Gα i/o protein, and thus inhibits adenylyl cyclase and diminishes the intracellular levels of cAMP.…”