CENTER COMPONENTS >
Component 5: Neurochemical involvement of methamphetamine seeking in mice

Lay-language summary

This component looks at the neurochemistry involved in "drug-seeking," the behavior that addicts engage in when they craving and taking action to find their next dose of drugs. Specifically, this component investigates the role of acetyl choline (ACh), which is an important neurotransmitter in areas of the brain involved in addiction. Using a technique called microdialysis, investigators can see what happens with ACh and its receptors if a mouse is actively addicted to and seeking methamphetamine. We can also compare the brain chemistry of "normal" mice with the special mice developed in Component 6. These mice were bred to have a particularly high or low attraction to methamphetamine, or to be unusually affected behaviorally by methamphetamine.

Scientific Abstract

The dramatic rise of methamphetamine use in recent years has targeted serious research efforts at identifying the neurobiological substrates of the development of methamphetamine addiction. Despite much progress, we still lack an understanding of the neurochemical systems involved in the motivational aspects of drug-seeking.

A key example is the role of acetylcholine (ACh) receptors. Even though many methamphetamine addicts also self-administer nicotine, a cholinergic agonist, by smoking, we still have only a rudimentary understanding of the role nicotinic receptors may play in maintaining methamphetamine addiction.

To expand this understanding, we need to learn more about how methamphetamine-seeking behaviors affect the release of ACh and, in the opposite direction, how manipulations of the cholinergic system impact methamphetamine-seeking behaviors.

Our first objective is to understand the effects of methamphetamine-seeking behavior on brain chemistry. We will compare ACh levels in relevant brain structures between mice that are actively seek methamphetamine and mice that have had the drug administered passively. We will use microdialysis to measure ACh in the nucleus accumbens, dorsolateral striatum, hippocampus, and prefrontal cortex of mice that are trained to press a lever to self-administer methamphetamine through chronically implanted ICV cannulae.

The results from these mice will be compared to matched controls that will receive equal amounts of methamphetamine (or vehicle) in a yoked fashion. This project will provide neurochemical data on structures relevant to drug-seeking for use in other MARC components.

We will also study the induction of genetic transcription factors (TFs) in cholinergic cells (identified by co-labeling for the ACh catabolic enzyme, choline acetyltransferase) and terminal fields after active and passive MA administration. We will measure TFs in genetically identical B6D2F1 mice and in mice selectively bred in Component 6 (below) for differences in methamphetamine drinking and in methamphetamine-induced locomotor sensitization. In addition to regional changes in molecular signaling events such as TF levels, we will measure the effect of active and passive methamphetamine use on choline uptake and vesicular ACh transporters.

Finally, to look at effects of cholinergic manipulations on drug-seeking behavior, we will study how brain-site-specific microinjections of drugs that affect either nicotinic or muscarinic ACh receptors impact the reinstatement of methamphetamine-seeking behavior in mice presented with a stressful stimulus. This series of studies addresses the issue of “stressor responsivity” which is directly relevant to other work in the clinical and behavioral-genetic components of the center.