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Methamphetamine and Neurogenesis: The Role of Adult Hippocampal Neurogenesis in Drug Seeking Behavior

  • Author(s): Galinato, Melissa
  • Advisor(s): Mandyam, Chitra D
  • Chiba, Andrea
  • et al.
Abstract

The research field of drug addiction is vast with multiple drugs, models, techniques, and brain regions to explore with hope of improving therapeutic treatments. Much of the work has focused on dopamine systems and brain structures important for reward related behavior. More recently the role of the hippocampus in drug addiction has been studied for its importance in learning and memory. One unique feature of the hippocampus is that it produces newborn neurons that become mature granule cell neurons in the dentate gyrus. This process, adult hippocampal neurogenesis, is important for specific memory functions involving discrimination; however, the functional role of neurogenesis has often been disputed.

Adult hippocampal neurogenesis is impacted by several environmental factors including drugs of abuse. The studies presented in this dissertation aim to understand the nature of altered neurogenesis caused by methamphetamine, which is a strongly reinforcing psychostimulant drug of abuse. The overall goal of the dissertation was to investigate changes occurring in the dentate gyrus during abstinence that could contribute to drug seeking behavior. In chapter 2, we investigate changes in hippocampal biochemistry during acute withdrawal, measuring proteins involved in cell growth, cell death, and synaptic plasticity needed for memory. We found significant changes primarily in animals that exhibited escalating drug intake patterns demonstrating compulsive-like drug seeking, which later results in enhanced neurogenesis during abstinence.

The following two studies tested the hypothesis that increased hippocampal neurogenesis induced by abstinence from meth plays a functional role in promoting drug seeking behavior during abstinence from meth. We used two different approaches for manipulating neurogenesis in order to test its effects on drug seeking. In chapter 3, the study used a synthetic compound, isoxazole-9, which reduced the abstinence induced neurogenesis back down to control levels. Normalized neurogenesis was associated with reductions in drug seeking behavior in response to the drug-related context. In chapter 4, our study used a transgenic rat that allowed us to completely ablate neurogenesis during abstinence. Animals with inhibited neurogenesis showed impairments in drug seeking behavior during extinction and context reinstatement. Our findings from the studies in this dissertation supported the hypothesis that abstinence induced neurogenesis plays a direct role in reinstatement of drug seeking behavior.

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