Withdrawal from Voluntary Oral Methamphetamine Reveals Female Specific Susceptibilities to Behavioral Deficits and Neurochemical Perpetuators of Neurotoxicity and Drug Seeking Behavior
MA is a potent, highly addictive psychomotor stimulant known to produce neurotoxic effects on the brain leading to neurological impairments1-6 characterized by neurodegeneration of dopaminergic fibers, cell bodies and pathways, as well as brain regions such as the hippocampus, frontal cortex, and midbrain1,5. In MA addiction, women are more vulnerable to the behavioral and cognitive effects of MA compared to men. Adult human literature reveals gender differences in usage patterns and women demonstrate increased vulnerability to the neurotoxic effects and health effects of MA use. Women begin drug use at an earlier age, escalate drug use quicker, have increased MA rates, and increased relapse rates compared to men7-14. Chronic MA use produces long term impairments in cognitive function ranging from memory deficits, executive function deficits, and cognitive flexibility in chronic MA users15-16. Women demonstrate poor performance on decision making tasks following chronic MA use compared to men16. These MA-induced deficits in learning and memory have been associated with long term deteriorations of hippocampias well as persistent deterioration of other brain regions5. Current rodent models of addiction have been unsuccessful in identifying a therapeutic intervention to mitigate the persistent effects of chronic MA in vulnerable populations, unlike the use of buprenorphine administration to mitigate the detrimental effects associated with opioid abuse17. This highlights the need for the development of a translationally sensitive rodent model of MA addiction to better model human MA use and identify therapeutic intervention for susceptible populations including females. Using the voluntary oral methamphetamine administration (VOMA) model that our lab developed in mice, we identify the molecule mechanisms underlying sex differences in the behavioral and neurotoxic effects of chronic MA following a period of abstinence. Our results may aid in the identification of effective therapeutic targets for pharmacological intervention. Some rodent studies have assessed sex differences in the neurotoxic effects of MA abuse using bolus and binge dosing however the neurochemical changes underling female specific susceptibilities to the behavioral and neurochemical effects of chronic MA are poorly understood. We developed a VOMA model that produces a more naturalistic consumption pattern, replicates the behavioral deficits observed following MA abuse, and produces the neurotoxic molecular changes observed in human MA abuse. The studies presented in this dissertation utilized the VOMA model followed by a two-week period of abstinence to assess 1. sex differences in GluA1, GluA2, and GSK3β signaling in mice that consume variable amounts of MA to investigate differential susceptibility to persistent synaptic plasticity deficits and drug seeking behavior following withdrawal from MA 2. sex differences in GluA1, GluA2, and GSK3β signaling in mice that consume equivalent amounts of MA to determine female specific susceptibility to inflammation and cell death following withdrawal from MA, and 3. sex differences in PKMζ and κOR signaling to assess female susceptibility to AMPAr trafficking dysfunction and drug seeking following withdrawal from MA. These experiments were done to understand the 4. neurochemical shifts underlying female-specific vulnerabilities to persistent behavioral and cognitive deficits following MA abuse to aid in the development of a targeted therapeutic intervention. To achieve our goal, we carried out three (3) specific aims: Specific Aim 1: Does the VOMA model have sufficient sensitivity to identify sex specific differences in MA consumption and cognitive deficits associated with markers of synaptic plasticity and drug seeking? [Chapter 2] Female mice consumed more MA during the binge phase of VOMA (d15-28) compared to male mice indicating that the VOMA model is sensitive enough to detect sex differences in consumption as observed in human MA users. More working memory errors on the RAM were correlated with increased MA consumption in female mice only. Following two weeks of abstinence, female mice displayed decreased GluA1 expression in the hippocampus and increased of GluA1 in the nucleus accumbens (NAc). These neurochemical changes may suggest female specific modulation of reward circuitry producing drug craving and drug seeking behavior potentially exacerbating observed cognitive deficits in female mice. Additionally, these results demonstrate sex differences in AMPAr trafficking that may underly hippocampal spatial working memory deficits and uncover the role of glutamatergic signaling in MA induced craving and drug seeking behaviors driven by the NAc. Specific Aim 2: What is the role of AMPAr and GSK3β signaling in perpetuating sex differences in neurotoxicity and inflammation following abstinence from chronic MA? [Chapter 3] 28d of VOMA produced distinct consumption groups observed in both sexes which mimics human MA use and provides a more naturalistic rodent model of MA addiction. When consumption rates were equivalent between sexes, female mice displayed decreased GSK3β and p-GSK3β expression in the NAc as well as decreased GluA1 expression in the hippocampus. Overall, these results indicate that following abstinence from 28d of VOMA, females are more susceptible to downstream persistent inflammatory pathway activation with associated cell death, mitochondrial dysfunction, as well as synaptic destabilization through AMPAr signaling in the hippocampus irrespective of MA consumption. Specific Aim 3: What is the role of hippocampal PKMζ signaling in short-term working memory deficits and κOR signaling in promoting drug seeking behavior following withdrawal from MA? [Chapter 4] Following two weeks of abstinence from 28d of VOMA, female mice displayed downregulation of hippocampal PKMζ expression and more working memory errors on the RAM compared to males. These neurochemical shifts highlight female susceptibility to long-term synaptic destabilization which may explain cognitive dysfunction in female human MA users. Female mice also upregulated hippocampal κOR expression compared to males which may reflect changes in drug seeking behavior, dysphoria associated with increased drug craving, and changes in the rewarding effects of MA perpetuated by crosstalk with dopaminergic signaling. Conclusion: The VOMA model has provided a more naturalistic approach to investigating sex differences in the behavioral and molecular deficits produced by chronic methamphetamine and abstinence during adolescence. Using this model, we have successfully characterized neurochemical modulations involved in sex specific susceptibilities to the behavioral and cognitive effects of MA in mice that are long lasting. Furthermore, identifying shifts in synaptic plasticity markers, perpetuators of inflammation and cell death, as well as molecular signaling involved in drug craving and drug seeking has provided novel insights into the female specific vulnerabilities progressing MA addiction and may lead to the development of targeted therapeutic intervention to mitigate these deficits in susceptible populations.
Behavioral Neurobiology, Cognition and Perception, Cognitive Neuroscience, Cognitive Psychology, Comparative Psychology, Experimental Analysis of Behavior, Molecular and Cellular Neuroscience, methamphetamine addiction, withdrawal, relapse, drug seeking, hippocampus, nucleus accumbens
City University of New York - Graduate Center
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