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To further our understanding of the neuropharmacology of psychedelics and alcohol use disorder, the Alex French Lab takes an integrative approach that spans the scales of biology:
Molecular
Cellular
Tissue
Behavior
Project areas
What signal transduction pathways mediate psychedelic-assisted decreases in ethanol consumption?
Our initial work focuses on G proteins and β-arrestins, initiators of two key branches of signaling downstream of G protein-coupled receptor (GPCR) activation by psychedelics. We use mouse models of ethanol consumption coupled with specific knockout of particular signal transduction pathways to study how molecular mediators of these pathways facilitate the ability of psychedelics to reduce ethanol consumption. We also use whole-cell patch-clamp electrophysiology to elucidate how ethanol and psychedelics alter signaling in the brain and relate these changes to their effects on behavior.
What signal transduction pathways mediate psychedelic-induced hallucinations?
We use a magnetometer to measure the head twitch response (HTR), an idiosyncratic behavior rodents display after taking hallucinogenic substances. We couple this with electrocorticography (ECoG), which gives a more detailed picture of which brain areas are being impacted by the psychedelics. By comparing the HTR and the disruption of ECoG brain waves across animals with specific proteins knocked out of neurons, we are developing a better understanding of which biochemical pathways mediate psychedelic-induced hallucinations and what brain regions are involved.
How can psychedelics be refined to retain therapeutic potential for alcohol use disorder but lack hallucinations?
Collaborating with synthetic chemists who can produce the chemical scaffolds of psychedelics, we are using our results in the other areas of the lab to inform screens of psychedelic analogues for novel signaling profiles using high-throughput 384-well plate assays. These assays use cells engineered to give off bioluminescent or fluorescent light when a drug activates a specific molecular pathway at a GPCR.
By integrating this work with the first two areas, our lab will contribute to the development of novel psychedelic analogues that reduce ethanol consumption but lack hallucinogenic potential.
How common is β-arrestin signaling bias and how can it be used to improve drug effect profiles?
β-arrestin isoforms β-arrestin 1 and 2 often mediate different behavioral outcomes of GPCR activation. Designing drugs to bias signaling at their target GPCR toward the desirable β-arrestin could therefore improve their effect profiles. It was previously unknown whether such bias was possible at a GPCR. By designing a novel click beetle β-arrestin assay, called "ClickArr," we definitively showed β-arrestin bias at the delta opioid receptor. By extending ClickArr to other GPCRs we will determine the prevalence and extent of this novel signaling bias among GPCRs.
"Biology occurs at all length scales" -TR Sosnick
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