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Neurogenesis during Abstinence Is Necessary for Context-Driven Methamphetamine-Related Memory
Melissa H Galinato1,2,3, Yoshio Takashima4,2, McKenzie J Fannon2
1Departments of Neuroscience.
Summary
Abstinence from methamphetamine addiction increases neurogenesis, which contributes to drug-seeking behavior. Inhibiting this neurogenesis blocked context-driven methamphetamine seeking by altering synaptic plasticity in the brain.
Area of Science:
- Neuroscience
- Addiction Research
- Cell Biology
Background:
- Abstinence from methamphetamine addiction is associated with increased adult neurogenesis in the dentate gyrus (DG).
- Adult neurogenesis in the DG is hypothesized to contribute to context-driven drug-seeking behaviors.
Purpose of the Study:
- To investigate the role of neurogenesis during abstinence in context-driven methamphetamine-seeking behaviors.
- To determine if inhibiting neurogenesis affects synaptic plasticity and neuronal excitability in the DG.
Main Methods:
- Used a pharmacogenetic rat model (GFAP-TK rats) to specifically ablate neurogenesis in the DG.
- Administered valganciclovir (Valcyte) to inhibit neurogenesis during abstinence in rats trained to self-administer methamphetamine or sucrose.
- Assessed neurogenesis markers (Ki-67, NeuroD, DCX), mossy fiber density (synaptoporin), and plasticity-related proteins (CaMKII).
- Performed whole-cell patch-clamp recordings to measure spontaneous EPSCs and intrinsic excitability of granule cell neurons (GCNs).
Main Results:
- Inhibition of neurogenesis during abstinence prevented context-driven methamphetamine seeking.
- This prevention correlated with reduced CaMKII autophosphorylation, increased mossy fiber density, and reduced GCN excitability.
- Context-driven sucrose seeking remained unaffected.
- Methamphetamine seeking enhanced CaMKII autophosphorylation, reduced mossy fiber density, and induced GCN hyperexcitability.
Conclusions:
- Neurogenesis during abstinence plays a critical role in facilitating methamphetamine context-driven memory and compulsive-like drug reinstatement.
- Inhibiting neurogenesis during abstinence prevents the maladaptive changes in synaptic proteins and basal synaptic function associated with drug-seeking behavior.
- This study highlights a dysfunctional role of adult hippocampal neurogenesis during abstinence in methamphetamine addiction.
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