The neuropharmacology of brain activation during stages of drug abuse

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Project Summary Dopamine lies at the center of drug reward. All drugs with addiction potential increase dopamine levels in the brain in their initial action, whether directly or indirectly. However, drugs of abuse also engage other neurotransmitters and lead to changes in neuronal signaling affecting distributed functional circuitry. Especially in the long term, the modulation of brain activation in response to repeated drug exposure involves neuroadaptations not only at dopamine receptors but at multiple targets. These non-dopaminergic influences on drug reward processing and addiction have not been extensively investigated but are key to understanding the molecular connectome during stages of drug abuse. For this Avenir Award, we propose to develop pharmacological positron emission tomography (PET) simultaneously with functional magnetic resonance imaging (fMRI) as a platform to study neuroadaptations in multi-receptor systems and their effect on functional signaling and networks in the living brain. Based on previous work developed in our lab for imaging dopamine receptor adaptations, we will develop and validate a multi-modal whole-brain imaging-based approach to disentangle how dopamine interacts with multiple neuroreceptors and neurotransmitter systems. Experiments will be carried out in nonhuman primates to ensure the future translational value of the methodologies and findings. The dynamics of multi-receptor targets will be imaged simultaneously with fMRI at key timepoints during repeated exposure to psychostimulants to develop neuroimaging signatures of receptor adaptations. Pharmacological blocking studies will be paired with stimulant- induced dopamine release to unravel the differential contributions of specific pharmacological targets and related neurotransmitter systems at various time points. Given its pivotal role in neuroplasticity, a focus will be on the involvement of the glutamatergic system and its interplay with dopamine. The insight gained from these classes of experiments will advance novel tools and methodology, and enable us to decipher the neuropharmacology of brain activation during stages of drug exposure. This program has the potential to lead to the revelation of novel drug targets for therapeutic intervention and expand our knowledge about the dynamics of neurochemistry underlying the whole-brain functional circuitry involved in drug addiction.