Central cannabinoid signaling in the rat: a pharmacological-challenge MRI and functional histology study

Garron Dodd, Jennifer Stark, Steve Williams, Simon Luckman. The University of Manchester, Manchester, United Kingdom.

Endocannabinoids have a variety of effects by acting on CB1 receptors located throughout the brain. The presynaptic location of CB1 receptors and differences in the strength of negative coupling means that expression studies alone do not provide the basis for interpreting site of action. Likewise, to date, most functional studies have used high drug doses which can bias results toward non-relevant adverse effects, and which mask more behaviourally-relevant actions. To better define sites of action of cannabinoids we have combined blood-oxygen-level-dependent (BOLD) pharmocolgical-challenge magnetic resonance imaging (phMRI) with whole brain c-Fos functional activity mapping to characterise structures responsive to behaviorally- relevant orexigenic or anorectic doses, respectively, of a CB1 agonist (CP-55940, 0.06mg/kg; i.p.) and an inverse agonist (Rimonabant, 0.1mg/kg, i.p.). We also demonstrate the use of a new fMRI analysis tool, which determines regions where the drugs functionally antagonise each other.

For phMRI, rats were imaged using a T2*-weighted gradient echo in a 7T magnet for 70 mins under α–chloralose anaesthesia, while those for immunohistochemistry were unanaesthetised and freely behaving. These complementary methods demonstrated functional activity in the cortico-striatal-hypothalamic pathway which is key to the motivational drive to eat. Furthermore, regions of this pathway affected by CP-55940 were functionally antagonised by co-administration of Rimonabant.

These results provide strong evidence for target sites of cannabinoid signaling with whole brain coverage, and identify common neuronal substrates underlying cannabinoid central effects, elucidating potential targets for the development of viable, cannabinoid-based therapies.