Project 8K: Mapping Circadian Modulation of Methamphetamine Response using Functional Imaging

Eilis Boudreau, M.D., Ph.D., Principal Investigator

Many drugs of abuse, including methamphetamine, are known to disrupt sleep-wake cycles in humans, and the dosage and timing of administration has been shown in animals to influence patterns of drug use. Furthermore, there is evidence to suggest that there is a methamphetamine-specific circadian oscillator that strongly influences the body's main circadian clock located in the suprachiasmatic nucleus (SCN).

However, there is little data about the location and physiological networks associated with this oscillator. We propose characterizing the in vivo physiological changes associated with acute methamphetamine ingestion at two different times during the 24-hour circadian cycle.

We hypothesize that methamphetamine ingestion will induce greater increases in cerebral blood flow (CBF) and cerebral blood volume (CBV) in mice during their active period (circadian night) than during their rest period (circadian day). Because CBF and CBV are linked to cerebral metabolism, they are often used as surrogate markers for neuronal function.

We plan to test our hypothesis by: (1) mapping cerebral blood flow in DBA/2J (D2) mice before and after methamphetamine ingestion during active (circadian night) and rest (circadian day) periods, and (2) mapping cerebral blood volume in D2 mice before and after methamphetamine ingestion during active (circadian night) and rest (circadian day) periods using 3-dimensional optical microangiography (OMAG). OMAG is a new technique developed by one of the co-investigators that can be used to quantitatively measure changes in CBV and CBF down to the resolution of the capillary bed (10 microns).

The proposed research is innovative because, to our knowledge, it is the first study designed to investigate changes in key physiological parameters during methamphetamine ingestion and to functionally fine-map neural response to a drug of abuse at different times of day. This, in turn, may contribute to the development of novel circadian-based strategies for treating methamphetamine abuse.