Understanding developmental trajectories and how drugs can influence the trajectory of an individual is critical to appreciate the way psychiatric drugs can affect a person at different ages. Although we often hear and repeat the trope “your brain matures at age 25,” the mature 25-year-old brain can look much different from person to person and recent research further highlights this fact. In a set of experiments conducted by Suri and colleagues (2023), inhibition of the dopamine transporter (DAT) during the early adolescent period in mice led to altered behaviors in adulthood. Specifically, these researchers found that administration of the DAT inhibitor GBR12909 during the early adolescent period in mice showed increases in amphetamine-induced hyperlocomotion in adulthood. Mice exposed to GBR12909 pre-adolescence, or late in adolescence did not show greater-than-normal increases in locomotion in response to amphetamine. More importantly, the animals exposed to DAT inhibition during early adolescence showed increased aggressive behaviors in adulthood, while DAT inhibition before adolescence and in late adolescence did not affect adult aggression. Additionally, animals treated with GBR in early adolescence showed greater impulsivity in GO/NO-GO trials compared to those treated with just the vehicle.

Next, these researchers examined the underlying dopaminergic neurobiology that may have been modified long-term following early adolescent DAT inhibition. Ex vivo slice electrophysiology recordings revealed that baseline firing rates of dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) showed increases in baseline firing rates following early adolescent DAT inhibition, but not late or pre-adolescent DAT inhibition. These findings were replicated in vivo by conducting voltammetric recordings from the VTA and SNc of anesthetized animals. Like the ex vivo recordings, the in vivo recordings showed increased baseline firing rates in the VTA and SNc in animals exposed to DAT inhibition during early adolescence compared to pre-adolescence or late-adolescence treatment. Ultimately, these studies show that drug-taking at various points in development can lead to altered neuronal signaling, which produces abnormal behaviors in adulthood.

Reference:
Suri, D. et al. Mol Psychiatry 2023. Epub ahead of print. Abstract.