Substances like morphine and cocaine profoundly disrupt the brain’s reward mechanism, intensifying cravings while simultaneously disturbing natural impulses such as hunger and thirst. Australian researchers have now pinpointed a universal reward pathway that seems to recalibrate these basic priorities. Their discovery has been published in the journal Science.
“Natural rewards like food, and drugs both activate the same area of the brain,” explains Jeffrey F. Friedman, a professor at Rockefeller University. “However, our recent findings show that their effects on neural activity are remarkably different. We now understand that addictive drugs uniquely alter these neural pathways in a way that natural physiological responses to hunger or thirst do not.”
The Nucleus of the Problem
The nucleus accumbens (NAc), located in the forebrain, plays a crucial role in processing desires for food, sex, social interaction, and addictive substances. It works closely with dopamine and serotonin—neurotransmitters that modulate pleasure and mood—to guide decision-making, reinforcing behaviours that provide satisfaction and encouraging repetition.
“The NAc is a critical area where dopamine-sensitive neurons influence goal-directed behaviours,” states Bowen Tan, a graduate student in Friedman’s lab. “Until now, it was unclear how drugs repeatedly compromise these neurons, leading to increased drug-seeking behaviours and a shift away from healthy objectives.”
To explore this further, Friedman and Tan collaborated with Eric J. Nestler from Mount Sinai, a psychiatrist and expert in drug addiction’s molecular neurobiology, and Alipasha Vaziri of Rockefeller, who developed new brain imaging techniques. These methods are among the few capable of capturing extensive regions of the mouse cortex in real-time with high resolution. Their technology also permits neuron imaging at great tissue depths, enabling detailed observation of neural activity in the NAc at the single-cell level.
“Our progress in mapping the brain’s intricate network relies on pioneering imaging technologies that not only visualize neuronal activity in distant brain areas but also in deeper ones,” Vaziri explains.
Reducing the Reward
Their research revealed that both cocaine and morphine activate a specific subset of neurons in the mouse NAc that respond to natural rewards. While both drugs stimulate NAc’s D1 medium spiny neurons, which are involved in positive reinforcement and motivation, morphine also affects D2 neurons, which play a role in reducing response to rewarding stimuli.
“This cell-specific response in the NAc was unexpected,” notes Tan. “Cocaine and morphine each trigger distinct neuron types, highlighting the varied neural dynamics induced by drugs, which significantly influence behavioural and physiological reactions to natural rewards.”
Using advanced molecular and genomic techniques such as FOS-Seq, CRISPR-perturbation, and snRNAseq, the team was able to identify how drug addiction diverts natural drives by commandeering a molecular pathway critical to neural plasticity— the process by which neurons strengthen learning and memory.
Activation of neurons expressing a gene called Rheb stimulates the mTOR pathway, potentially altering neuronal communication, learning, and memory related to food and water. This might explain why both mice and humans addicted to these substances appear to neglect the need to eat and drink—responses that the brain typically reinforces as rewards.
Looking ahead, the team aims to delve deeper into addiction neuroscience, exploring how various brain regions collectively influence addiction and the override of natural reward processing by drugs.
