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.
Highlights
Clinical and preclinical research indicates that female subjects, compared to male subjects, exhibit greater vulnerability toward drug abuse at stages of the addiction process that mark transitions in drug use, including drug initiation, bingeing, and dependence [1,2,3]
We have previously reported that extended access to saline self-administration, followed by extinction and reinstatement does not alter neurogenesis, the number of progenitors in the dentate gyrus (DG), and plasticity related proteins in the DG compared to age matched behavior naïve controls [23]
Previous studies studieshave have examined sex differences in animal models of methamphetamine and have and focused differences during self-administration, extinction, and drugordrugcue-induced addiction haveon focused on differences during self-administration, extinction, and or cuereinstatement of methamphetamine seeking
Summary
Clinical and preclinical research indicates that female subjects, compared to male subjects, exhibit greater vulnerability toward drug abuse at stages of the addiction process that mark transitions in drug use, including drug initiation, bingeing, and dependence [1,2,3]. With respect to relapse to drug seeking, prior research in rats show that while males and females do not differ in responding on the first day of extinction, females are more likely than males to show resistance to extinction when behavior is tested immediately after cessation of self-administration [14,15]. This sex difference in extinction behavior is not evident when rats experience extinction sessions weeks into abstinence [10,14,16], suggesting that the period of abstinence predicts distinct neurobiological alterations in male and female subjects that may relate to the behavioral responses. Given these stimulus dependent sex differences in drug seeking, it is notable that sex differences in relapse to drug seeking driven by drug context have not been investigated
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